by Kunjumon Vadakkan
Welcome!
Objective: To solve the nervous system. More precisely, to understand how first-person inner sensations (that we refer to as taking place in the "mind") of higher brain functions (such as memory & perception) occur both independently & along with third person observed motor activities such as speech and behavior.
Dedication: To all those who suffer from diseases of the brain (& therefore mind), especially who are abandoned by their families.
Latest pre-print: "The basic concept of "attention heads" in Transformers matches with partial features of "islets of inter-LINKed spine heads", a model of nervous system functions". Summary. Article. If a primary school child asks, here is a Story.
What are the present challenges in brain sciences?
Several unsolved problems still exist in neuroscience (Adolphs, 2015) and are observed in different levels (Edelman 2012; Gallistel & Matzel 2013). Since information exists only in relation to or for some system in context (Brette 2018; Deacon 2021), and it is highly dynamic, the engram is expected to match with these properties. It should also match with the expectation that the operational mechanism of the brain (engram) consists of information bearing physical structures (Galllistel, 2021). Hence, dynamic information-bearing structural changes need to be understood. The field realizes the necessary to utilize synaptic and neuronal firing changes associated with learning and memory to develop a theory on how and in what format the brain stores information (O’Sullivan & Ryan, 2024). This is also expected to unify disparate findings from different levels of the system (Frégnac, 2017). Finally, the engram should have features consistent with that of an evolved mechanism.
In simple words, what is semblance hypothesis?
Systems in the body are being studied by observing them from outside (e.g. pumping of the heart, filtering by the kidneys, structure of DNA and synthesis of proteins). Third-person approaches are suitable for their studies. In contrast, functions of the brain such as perception and memory are first-person inner sensations (within the "mind") to which only the owner of the nervous system has access. But we have been studying these functions by examining the nervous system from outside using third person approaches at various levels (biochemical, cellular, systems, electro-physiological, imaging, and behavioral) and we were trying to find correlations between these findings with the aim of understanding the system. Through these approaches, the first-person internal sensations of different higher brain functions remain unexplored. The reality is that the examiner should become an insider in a subject's nervous system (and become part of the system) to sense the first-person internal sensations! This is practically not possible. This means we are facing a brick wall in our current approaches to understanding its operations. This work aims to overcome this by undertaking a theoretical approach.
Since a universal operational mechanism is expected to be present in the nervous systems of different animal species, we should be able to find it without much difficulty if we are on the right path. We had no previous experience of searching for a biological mechanism that gives rise to virtual first-person inner sensations. This should not hinder our efforts in any way. In fact, we must prepare ourselves to look for a unique mechanism that has the ability to evade our attention! Keeping this in mind, a theoretical examination was carried out to arrive at a specific location where such a unique mechanism can be expected to take place. Further examination of this location showed a set of unique features for a feasible operational mechanism for generating units of inner sensations at specific conditions (that are physiologically present). This mechanism is expected to interconnect all the findings made by third person approaches at different levels. Until now, results using this observation are able to explain and interconnect a large number of findings from different levels. Pathological changes in this cellular mechanism can explain several neurological and psychiatric disorders. Predictions made by this hypothesis are testable.
Are there different ways to view this hypothesis? One, Two
Can you explain the hypothesis using a figure? The connectome is expected to make certain specific changes during learning and is expected to be used during memory retrieval. It should take place within the synaptically connected neuronal network. First, we have to arrive at the location where this is possible. Then explore its nature to understand why we have been failing to recognize it. See Figure 1 below. For more details of the problem see Figure 2 (Note: FAQ page explains the contents of this black box).
Figure 1. Black box where certain changes take place during learning. A) In the conditioned learning paradigm, two different types of stimuli that can provide both first-person inner sensations and motor outputs are used. Here, the association between the sound of a bell (Conditioned stimulus, CS) and the site of food (Unconditioned stimulus, US) is commonly used. B) After learning, the arrival of sound from the bell (CS) alone generates the output features in response to both sound and food. What type of neuronal connection can provide this ability? There is a black box between the pathways through which CS and US stimuli propagate. What is the simplest and evolutionarily selected connection that can occur at timescales of learning (milliseconds) that can then enable CS alone to give outputs expected of both CS and US (in milliseconds)? A summary of the solution based on the semblance hypothesis is shown in Fig.18 on the FAQ page).
Figure 2. Details of the black box are shown in figure 1. A) Five neuronal orders (N1 to N5) starting from the sensory receptor level (Sy1: area dense in sensory receptors; Sy2-Sy5: area dense with synapses; N1-N5: area with neuronal cell body). Note that each neuron is expected to fire an action potential on receiving a relatively small subset of input signals from randomly located spines/input terminals (out of thousands of spines) on its dendritic tree. B) Before learning, arrival of sensory stimulus St1 (CS in Fig.1) leads to firing of a set of 3 neurons (GN1, GN2, GN3) (in green) in neuronal order N5. C) Before learning, arrival of stimulus St2 (US in Fig.1) alone results in the firing of a set of 3 neurons (RN1, RN2 and RN3) (in red) in neuronal order N5. D) During associative learning between St1 and St2, in addition to neurons GN1, GN2, GN3, RN1, RN2 and RN3, an additional neuron YN is also fired. This indicates that learning has opened a new channel through which EPSPs from neuronal circuitry activated by stimulus St1 and St2 arrive at neuron YN that was remaining in sub-threshold activated state before learning. This new channel formation would have taken place at the synaptic region S5 where stimuli St1 and St2 converge. E) After learning, arrival of stimulus St1 alone leads to firing of neurons GN1, GN2, GN3 , YN and RN2. This shows that both YN and RN2 receive the nth EPSPs from stimulus St1 after learning. Inputs to RN2 that lead to its firing is associated with certain specific black box changes that leads to motor actions (& inner sensation of memory) reminiscent of St2. The channel that brings additional EPSP to the neuron RN2 can solve the black box problem. There can be only one unique solution for this. F-H: Seeks a solution for the black box problem. Pre = presynaptic terminal = output terminal of input neuron; Post = postsynaptic terminal = input terminal of output neuron = dendritic spine = spine. waveform = action potential. F) Note that mean inter-spine distance is more than mean spine diameter (Konur et al., 2003). Arrival of St1 and St2 to two adjacent spines will not satisfy the conditions in Fig.1 since the output neuron is the same. G) For the motor actions of CS to take place, St1 should reach the spine of one neuron (GN). H) For the motor actions of the US to take place, St2 should reach the spine of a second neuron (RN). The black box problem (for CS to exhibit features of both CS & US after learning) will have a solution only when a channel gets established between neurons GN and RN (to which St1 and St2 arrive respectively) in such a manner that after learning, arrival of St1 to GN alone will be able to cause firing of both GN and RN. At this point, we must make a reasonable assumption that this channel is also associated with a unique property to generate units of first-person inner sensations & hunt for this logically explainable hidden mechanism. For the location of the new channel, see Fig.19 in the FAQ section. For details of the solution, read the FAQ section.
How can we view the problems in the field?
Nervous system functions observed at different levels are being studied by different faculties of science - biochemistry, cell biology, electrophysiology, systems neuroscience, psychology, imaging, behavior, and consciousness studies. The system is similar to a puzzle lying in multiple dimensions. Solving it requires fitting the correct pieces of the puzzle at the right levels to obtain the right operational function. If we examine only one or a few levels of the system, we might arrive at certain solutions that will allow fitting together some pieces of the puzzle only for those few levels. Features of the unexamined levels will most likely remain unexplainable, and we won't reach a solution for the system. The diverse nature of findings at different levels strongly indicates that the solution is going to be a unique one. At the same time, it is also expected to be a simple one. To solve the system and find out the correct mechanism, it is necessary to examine representative functions from all the levels simultaneously.
A second view of the problem can be described as follows. It begins by examining the following situation: the heart pumps the blood, and the kidneys filter the waste materials from the blood; these functions are observed by us from a third-person perspective. We understood their functions quite well, evidenced by our ability to develop their replacements, such as artificial heart and dialysis. What operational mechanism do we need to understand from the brain to replicate/replace it? The brain generates an inner sense of the external world during perception, stores sensory information during associative learning and later produces the internal sensation of retrieved memories of the learned item when the associatively learned cue stimulus or its partial features arrive, induces thought to connect different items from different sets of learnt events – all of which are first-person properties that cannot be accessed by third-person observers. The only information that is available from the owner of the nervous system to a third person is from the surrogate markers consisting of motor activity - specifically, speech and behavior. Therefore, the pieces of the puzzle mentioned in the above paragraph should be capable of explaining both first- and third-person accessible functions.
A third view of the problem becomes evident when examined from the viewpoint of a builder. Here, the job is to replicate the brain in an engineered system. Since intentionality to feed and carry out all the actions for survival and reproduction are present even among the members of lower-level animal species, a robust evolutionarily conserved circuit mechanism for generating internal sensations is expected to be present in all the nervous systems. Since the first-person properties cannot be accessed by third-person observers, they cannot be studied directly using biological systems. Hence, we should keep replication of the mechanism in engineered systems as the gold standard proof. These systems need to be built to provide readouts for the first-person internal sensations. As a builder, we feel the pressure to know its operational mechanism. We are forced to speculate about all the possible ways and figure out the correct one. We will be concerned mostly with explaining the formation of inner sensations in physiological timescales. Before building the system, we need to draw a sketch of the system's operations.
A fourth view becomes possible by observing the “loss of function” states of the system occurring at various levels. This can help us understand the nature of the pieces of the puzzle. Early genetics research has gained valuable information from "inborn errors" of metabolism that provided guidance to understand the allelic organization of genes. Using various combinations of findings from both neurological and psychiatric disorders it is likely to deduce the operational mechanism.
What are the main reasons why it is difficult to solve the nervous system?
1) Frame of reference problem: Every time we had a frame of reference problem in the past, we needed to pause for some time to make further progress. A typical example is the difficulties in sensing the rotation of Earth (note that the speed of rotation of Earth on its axis is 1670 km per hour). Our sensory systems cannot sense the rotation of Earth towards the East since we are in the same reference frame as that of the Earth. The fact that third-person observers cannot sense first-person inner sensations in a subject can be viewed as another frame of reference problem. In physics, constraints from several findings are used to reach a non-accessible solution. For example, see how Galileo conjectured (see below) that Sun is at the center of the universe (then).
2) Difficulty studying the “virtual” nature of first-person inner sensations: We have dealt with several virtual items in the past. For example, numbers do not exist. We made them. In fact, they are virtual in nature. We can say that they represent real counts of items. What about negative numbers? They can exist only in our imagination. Yet, we use them routinely in mathematics. On a graph, we don’t feel their virtual nature at all. Going one step further, we have invented complex numbers (using an imaginary number). This solved our difficulties in finding square roots of negative integers, which helped to further advance mathematics. Similarly, once we understand where and how units of inner sensations are sparked within the system, we will be able to perceive a virtual space where we can position them and navigate that space to understand their different conformations.
3) Access problem: How to understand something that cannot be accessed by our sensory systems? We are routinely studying several things that our sensory systems cannot access directly. E.g. we cannot see DNA inside the cells or in a gel. But we stain it with ethidium bromide, which will allow us to see the stain through our eyes. This means that our access problem can be overcome by adding one or more steps of actions that will allow our sensory systems to get access towards them indirectly. Understanding inner sensations will need indirect or indirectly indirect methods that we will eventually become familiar with.
How did Galileo show us to put together observations to make an inference even when our sensory systems cannot agree with such an inference?
When there are many observations in a system, putting them together can provide a totally new inference that our sensory systems may not be able to directly sense. An example is that of the inference made by Galileo Galilei using observations that he made. While observing Jupiter in 1610, Galileo found four moons that are orbiting Jupiter. He immediately made the conclusion that if these moons are revolving around Jupiter, then it is unlikely for the Earth to be at the center of the Universe. This video explains further. While watching Venus, he found phases similar to that of Moon - New Moon and Full Moon. Galileo observed both the New and Full faces of Jupiter. When it is New, it is very big. When it is Full, it is very small. He concluded that this could happen only if Venus revolves around the Sun and therefore, he made the inference that the Sun must be at the center of the system. A suitable fit with this observation is that Earth and other planets are also revolving around the Sun. What we now know is that Venus is New when it comes close to the Earth, blocking the light from the Sun. When Venus is on the other side of the Sun during its revolution around the Sun, it is farthest from the Earth. Here, Venus is seen as small, and its face is Full. This video explains it.
The above observations made Galileo conclude that Earth is not at the center of the solar system. Galileo saw the simplicity if all planets revolved around the Sun. He was making logical arguments that allowed him to fit all the findings together. Galileo knew that it was difficult for him to convince others that the Earth is revolving around the Sun. We have such a rich tradition in science of gathering information from different observations and then putting them together to make an inference, even though we cannot appreciate it directly with our sensory systems.
Footnotes:
It was Copernicus, who, based on observations, first proposed that the Sun is stationary and that the Earth and other planets revolve around it. So, the credit must go to him as the first person who reported that Earth is revolving around the Sun. Even though Galileo thought that planets were moving in circles, Kepler found out about the elliptic path of motion of planets.
How can we solve the nervous system?
There are three crucial questions that we must ask. 1) How can we understand the operation of the nervous system even without replicating the mechanism in engineered systems? 2) What solution for the first-person inner sensations can hold all other findings from different levels in an inter-connected manner? 3) How to reach such a solution that can provide testable predictions? The challenge in this approach is to include all the observations to find the solution. Hence, it is necessary to examine findings from different levels of the system simultaneously. Since there is only one unique solution, if we can arrive at a solution that can inter-connect all the findings from different levels, then it is likely to be correct. We must use this solution to make testable predictions and verify them.
As we face situations that have more steps away from reality, we have to rely on our logical reasoning capabilities (see an excerpt from Krakauer et al., 2017 that appeared in the journal Neuron). The unique structure-function mechanism must provide inter-connected explanations. The virtual, first-person non-accessible nature of inner sensations warrant certain approaches that are similar to the core principles behind approaches used in physics (see Table 1). Since our current research efforts in each field are moving towards more specialized and super-specialized areas, finding and verifying the unique solution (to put the pieces of the puzzle together) requires an effort in the opposite direction. Anticipating this is the most important step.
| Physics | Neuroscience | |
|---|---|---|
| 1 | First, a large number of observations are made that appear to be disparate in nature. This means that these findings cannot be explained in terms of each other. | There are many disparate findings in neuroscience (see Table 2) that need inter-connectable explanations. E.g. How does the operation of the system relate to sleep and the electrophysiological finding of LTP? |
| 2 | The above indicates the presence of a deep underlying principle that should interconnect these disparate observations. | There should be a deep underlying principle that interconnects all the observations listed in Table 2. |
| 3 | The features of some of the elements associated with the above principle (e.g. particles and fields) cannot be directly sensed by our sensory systems. | There is a principle, the products of which (inner sensations) cannot be sensed by our (third persons') sensory systems. Yet, the principle of the mechanism should be able to explain and interconnect all the observed findings. |
| 4 | Constraints provided by disparate observations should be able to guide us towards the solution. This is done either by initial deduction followed by mathematical approximations (e.g. special and general Relativity, Higgs Bosons). | A structure-function mechanism must be sought by logical deduction & trial and error methods. The constraints offered by a large number of findings can be used to derive the solution. Success depends on moving along a path as guided by all the constraints. Only when we reach the correct solution, will we be able to explain all the findings in an inter-connectable manner. |
| 5 | The solution is then confirmed by verifying the testable predictions. | Testable predictions made by the derived mechanism can be verified. |
Table 1. Comparison between the steps taken by physics and neuroscience when it becomes necessary to unify disparate findings. This is important especially when dealing with properties that are non-accessible to our sensory systems such as particles, fields, and first-person internal sensations etc.
The deep underlying principle of many studies in physics has similarities to the method used in linear algebra for solving a system of large set of linear equations that has a unique solution. If one tries to solve such a system, one can find that the relationships between the variables in each equation provide hints that can guide us towards the solution. If there are numerous variables, there should be at least an equal number of equations to find the unique solution. Since there are many findings at different levels of the nervous system, we can (and we must) use even minor interconnected features between them to find the solution. It is a gigantic exercise, since there are no easy methods in biology like those that are used in linear algebra. But understanding the logic behind the linear algebraic methods will help in solving the system.
In linear algebra, the Gauss-Jordan elimination method is used to find the solution for a system of linear equations. If we look carefully, we can see that easy methods in linear algebra were designed by someone who understood the deep underlying principle and worked on making it simple for others by developing easy methods. We can examine how the relationships between variables in each equation define the unique solution for a system of linear equations and how the Gauss-Jordan elimination method was invented. It is to be noted that we can also solve linear algebra problems using trial and error methods. But it will take some extra time - more time when more variables are involved. In other words, in mathematics, easy methods are developed for convenience. Whichever method is used, the deep underlying principle is the same - A system exhibiting numerous disparate findings (equations) most likely has a unique solution that binds (interconnects) all the findings (equations) within that system. By finding a solution that can interconnect a subset of findings and by repeating this approach using different subsets of findings, one can hope to reach a common underlying solution, which is the correct solution.
One can start attempting to solve the (nervous) system by using subsets of disparate findings. The optimism of this approach is that there is only one unique solution for the nervous system, and it is easy to rule out many wrong solutions quickly. Using the above principle, subsets of constraints provided by findings from various levels (Table 2) were used to derive a mechanism that can explain, and interconnect findings made by different faculties of brain research. The non-sensible component will remain non-sensible to our sensory systems even after its discovery (Fig.3). However, it is expected to show testable learning-generated change that gets reactivated at the time of memory retrieval to induce basic units of internal sensation who's integral provides qualia of memory.
Figure 3. Method to find a solution for the system from third person observed findings. A) Features of the system are sensed either directly (represented by capital letter K) by our sensory systems or indirectly (represented by capital letters D, E, G, H) through findings such as staining of proteins, observing behavior, etc. (represented by small letters (u, w, v, x) connecting the features through straight lines (for example, observation of u enables sensing D). B) Using both commonly used direct & indirect methods, three clusters of interconnected (represented by dotted lines) findings are found at separate levels (observations from different fields of brain science). In most cases, it was not possible to interconnect these clusters. For example, it was not possible to find interconnected explanations between 1) learning changes and inner sensation of memory both occurring in millisecond timescales, and 2) sleep & LTP. Using constraints from findings within each cluster, it is possible to examine whether they can be interconnected through a common operational mechanism. In the case of the nervous system, a very large number of findings and constraints offered by them can be examined. C) Using constraints available from some of the features of each cluster of unrelated findings (e.g. A, B and C), it is necessary to try to derive a deep underlying principle (a structure-function solution m) that allows interconnection between them and therefore all the findings within each cluster. This solution is expected to provide a mechanism for generation of internal sensations in millisecond timescales. D) The solution m enables explaining how various findings within each cluster are interrelated with each other and with the findings from other clusters shown in B). While remaining non-sensible to our senses by any known methods used in current biological investigations, the ability of the solution m to hold different findings from all the clusters together makes it a further verifiable solution (Figure from Vadakkan, 2019).
There are a very large number of observations from different levels of the nervous system's functions (Table 2). An example of store receipts (this is also the deep principle behind some of the approaches carried out in physical sciences to understand nature) provides us with confirmatory evidence that we can reach a final correct solution, if it becomes possible to obtain a large number of findings so that we include all variables of the system.
Progress: Constraints were drawn from a large number of experimental findings that used behavior as a third person measurable outcome. Using these, a solution was derived. When the neighborhood of the solution point was searched, a mechanism that can generate first-person property was found. For details, see FAQ page.
It is possible to draw constraints from numerous findings in multiple levels of the nervous system. Only when we reach the correct solution that we will be able to explain all these findings. Even if we are unable to directly sense the formation of first-person inner sensations, interconnected explanations suggest their location & mechanism of formation. Several of the following explanations provide retrodictive evidence. (Here is a demonstration how constraints can be used to find a solution: pdf) | |||
| Findings from multiple levels | Constraints offered by the findings (on the left) that direct the inquiry towards a correct solution. | Explanations. Note that all the explanations must be interconnectable to claim that we have a solution (see Fig.3 above). (Please read this column after reading the hypothesis from the FAQ page). | |
| 1 | Both associatively learned stimuli & the prompt (cue) stimulus propagate through synaptically-connected neuronal circuits. | Mechanism should operate synchronously with the synaptically-connected circuitry. | Inter-neuronal inter-postsynaptic functional LINKs (IPLs) form and operate only when synaptic transmission takes place (Vadakkan, 2007; 2013) between connected neurons. |
| 2 | Memories are virtual first-person inner sensations. | It is necessary to provide a location & mechanism for its generation. | In the background state, there is continuous depolarization of the spine head (postsynaptic terminal) region by quantally released neurotransmitter molecules & intermittent arrival of large potentials triggered by the arrival of action potentials at the presynaptic terminal. In this context, lateral entry of depolarization to an inter-LINKed spine through an IPL is expected to trick the inter-LINKed spine (& also the system) to hallucinate that it is receiving inputs from the lower neuronal orders through its presynaptic terminal. Consequently, since tracing back these lower neuronal orders reach the sensory system, the content of the hallucination is first-person inner sensation of memory. |
| 3 | Learning-induced changes occur in physiological timescales (of milliseconds). Foot note1 | A learning-induced mechanism that occurs (& completed) in physiological timescales. | IPL formation is expected to occur in milliseconds between abutted spines at the locations of convergence of pathways along which associated stimuli propagate. |
| 4 | Memory retrieval takes place in millisecond timescales. | Since memory of a learned association can be retrieved immediately following learning, it is necessary to demonstrate a mechanism for memory retrieval that can take place in milliseconds. | Propagation of potentials across the IPLs to the inter-LINKed spines to generate first-person inner sensations is expected to take place in physiological timescales of milliseconds (Vadakkan, 2007; 2013). |
| 5 | After associative learning between two items, arrival of any one of the items generates memory of the second item. | The learning mechanism should have features to explain how either one of the associatively learned items can act as a cue stimulus to generate memory of the other item. Hence, the mechanism must have the ability to show bidirectionality in it. | IPL can be reactivated from either one of its sides to induce semblance on the inter-LINKed spine on the other side (Vadakkan, 2010; 2013). Propagation of potentials across the IPLs & inter-LINKed spines in an islet of inter-LINKed spines can generate semblance even on a distantly located inter-LINKed spine in an islet of inter-LINKed spines. It is to be noted that memory is the net semblance generated by a specific cue stimulus on several inter-LINKed spines. |
| 6 | Even partial features of one of the associatively learned item is capable of retrieving memory of the second item. | The mechanism should have features to explain how stimuli from partial features of one stimulus can retrieve memory of the associatively learned second item. | Partial stimuli propagate to generate a large number of units of inner sensations on numerous inter-LINKed spines. Since extrapolation from the inter-LINKed spines to sensory receptors inevitably leads of huge overlapping of semblances (Figs.9,10 in FAQ section), the net inner sensation is expected to have nearly almost all the features of the item whose memory is expected to get retrieved (Vadakkan, 2010; 2013; 2019). |
| 7 | Memories that can be retrieved long period after learning are also capable of being retrieved immediately following learning (working memory). | Learning generated changes can be used for memory retrieval immediately (working memory). These changes must have a provision for remaining in a stable form for long period, responsible for long-term memory (LTM). | IPL formation takes place at the time of learning. When IPL reverses back, then the short duration of function of an inter-LINKed spine can only contribute towards working memory. Long-term stabilization of IPLs enables them to be used for retrieving memory (by a cue stimulus) for a long period (LTM) (Vadakkan, 2010; 2013). |
| 8 | Gradual changes in qualia of inner sensation of memory in response to gradual changes in cue stimulus. | It is expected to have a mechanism to integrate unitary elements to generate inner sensation of memory. | Integration of units of inner sensations is expected to be carried out by the oscillating potentials within the connected elements of the system as its reflection in the extracellular matrix space is shown by the oscillations of extracellular potentials. As the cue stimulus changes, the new sets of specific units of inner sensations are generated (Vadakkan, 2010). |
| 9 | Absence of cellular changes during memory retrieval. | A passive reactivation of the changes that occur during learning should be used to induce units of internal sensations at the time of memory retrieval. | Since inter-LINKed spines continue to persist from the time of learning, neither propagation of depolarization across the IPLs nor reactivation of inter-LINKed spines to generate units of inner sensations do not require any new cellular changes (Vadakkan, 2010). |
| 10 | The ability to store large sets of learning-induced changes is responsible for the ability to retrieve a large number of memories. | Since brain has a finite set of neuronal processes & cells, to store very large number of memories, it is necessary to explain the presence of a combinatorial mechanism where a specific cue stimulus is able to induce large number of unitary mechanisms that gets integrated to generate a specific memory. | Spines within the islets of inter-LINKed spines can be depolarized by any specific stimulus reaching them. Since sensory stimuli from items/events consist of combinations of sensory stimuli, different combinations of inter-LINKed spines are expected to be used by different cue stimuli to generate corresponding memories. This also makes us to infer that very large memories are stored capable of getting retrieved (Vadakkan, 2010). |
| 11 | Instant access to very large memory stores. | It is necessary to explain how a very large number of memories can be retrieved instantly. There should be demonstration of an instantaneous combinatorial mechanism of unitary operations that takes place instantly. | A specific cue stimulus is capable of re-activating a specific set of IPLs & generating units of inner sensations in milliseconds. Instantaneous integration of these units allows instant access to these large number of memories (Vadakkan, 2010). |
| 12 | Transfer of learning (Dahlin et al., 2008). | It is necessary to show how the criterion & transfer tasks engage specific overlapping processing components and brain regions (Dahlin et al., 2008). It is reasonable to expect generation of surplus number of unitary elements from different locations. | Memory is the integral of units of inner sensations. The unitary elements can originate from different locations. Oscillating extracellular potentials, which is a continuum in multiple brain areas, integrates the unitary elements (Vadakkan, 2013). Hence, units generated from different regions of the brain can substitute each other. |
| 13 | During memory retrieval, there is firing of a subset of neurons that were not firing before learning in response to the same cue stimulus. | It is necessary to provide an explanation, one of which is that - learning has opened certain new channels & the cue stimulus leads to propagation of depolarization through these channels to provide additional potentials to a subset of neurons that are otherwise being held at sub-threshold activation state (without firing). | Formation of IPLs during learning will lead to propagation of depolarization across them to the inter-LINKed spines. This will provide additional potentials to the inter-LINKed spines' neurons and may fire those neurons if they enable them to cross the threshold (Vadakkan, 2013). |
| 14 | The brain operates in a narrow range of frequencies of extracellularly recorded oscillating potentials. | Operational mechanism is expected to provide vector components of the oscillating extracellular potentials. There should be corresponding intracellular changes of ionic concentrations within the neuronal processes of involved neurons. | Synaptic transmission & near perpendicular propagation of depolarization across the IPL can provide vector components (Vadakkan, 2010) to the oscillations. Oscillating extracellular potentials are expected to have the property to bind specific units of inner sensations generated by specific cue stimulus. |
| 15 | Motivation promotes learning. Motivation is associated with release of dopamine & activation of dopamine receptors occurs in different brain locations (lino et al., 2020). | Motivation must be associated with specific factors & their specific actions are expected to promote the learning-induced change and possibly to retain this change for a longer period than those occur in their absence. | Dopamine is known to cause spine expansion (Yagishita et al., 2014). Expanding spines can augment IPL formation and retain the formed IPLs for a long period, which may trigger some stabilization steps. |
| 16 | Most excitatory glutamatergic synapses are located on dendritic spines that enlarge during learning. Glutamate causes spine enlargement in both hippocampal slices (95%) (Matsuzaki et al., 2004) & the neocortex in vivo (22%) (Noguchi et al.,2019). | Spine enlargement is expected to offer certain functional uses, especially in locations where the extracellular matrix (ECM) is very thin. | Enlarging spines in locations where neuronal processes are densely packed can promote IPL formation if two abutted spines where associatively learned stimuli arrive & converge. |
| 17 | Internal sensations of working, short, and long-term memories have similar qualia to generate similar memory. | The same learning-induced change is retained for different duration. Long-term memory loses its clarity both due to loss of some unitary mechanisms & dilution of specificity by combining with newly formed units of inner sensations generated at the islets of inter-LINKed spines. | Memory retrieval after different intervals following learning takes place by reactivation of inter-LINKed spines by depolarization propagating across the IPLs generating units of inner sensations (Vadakkan, 2010; 2013). Hence, they all generate same memory, but with varying clarity. |
| 18 | Most learning events lead to a working memory that lasts only for a short period of time & do not continue to become long-term memories. | Learning-induced change must have a quickly reversible mechanism. | IPL formation is a high energy requiring process as can be inferred from experiments using artificial membranes (Rand & Parsegian, 1984; Martens & McMahon, 2008; Harrison, 2015). Hence, the majority of IPLs are expected to reverse back quickly, re-introducing hydration layer between the membranes. |
| 19 | Some of the memories that can be retrieved as working memories can be retrieved after a long period of time after learning (long-term memories). | It should be possible to explain that the learning-induced change is able to undergo certain changes that will enable it to get maintained for a long period. | Stabilization of IPLs for long periods can induce the same units of inner sensation during this entire period. If the number of inter-LINKed spines that can be reactivated by a cue stimulus decreases with time, then the qualia of memory will deteriorate with time (Vadakkan, 2010; 2013). |
| 20 | Simultaneous existences of the previous two conditions (above two rows) within the system. | Learning-induced mechanism should have an initial, quickly reversible change. But under certain circumstances some of them can get stabilized for long periods of time. | When memory of a beneficial or deleterious item/event becomes advantageous or deleterious for survival, then IPLs responsible for those memories get stabilized for a long period (Vadakkan, 2010; 2013). IPLs formed in response to novel associations of no importance for survival reverse quickly. |
| 21 | Previous finding that memories have time-dependent “tritrace” mechanisms (McGaugh, 1966) | It is necessary to provide a mechanistic explanation for the findings that led to this previous inference. | IPLs are rapidly reversible in nature. Hence majority of them will reverse back after learning. Some will persist for a short period & some for a long-period by stabilization of IPLs. These explains short & long-term memories. |
| 22 | The ability to store new memories without needing to overwrite the old ones. | Sharing of unitary mechanisms for their common features & provision for formation of new units with new associations are expected to be present in the system. Also, there must exist a mechanism to integrate all the unitary elements in response to specific cue stimulus. This will prevent any overwriting of old memories. | Inter-LINKed spines within islets of inter-LINKed spines can be shared by any stimuli reaching them. Hence, there is no need to overwrite old memories. New associations lead to additional spines inter-LINKing to the existing inter-LINKed spines (Vadakkan, 2010; 2013). |
| 23 | Consolidation of memory (apparent transfer of storage locations of memory from the hippocampus to the cortex) over a span of 5 to 8 years. | Addition of specific learning-induced changes in the cortex over the span of years by a similar unitary operational mechanism in the hippocampus. Ability to generate memory by a global integrating mechanism capable of using unitary elements from different locations in the brain. Must go through a stage of having surplus unitary mechanisms. | Convergence of pathways of different sensations in the hippocampus leads to formation of large islets of inter-LINKed spines. Sparse convergence of these pathways in the cortex also generates IPLs. When associative learning events containing shared elements occur, together with new neuron insertion in the granule layer of hippocampus, it will lead to formation of surplus number of new sparse IPLs in the cortex over time (Vadakkan, 2011). Several years of these events will generate a net semblance for memory of the item from the cortex alone in response to cue stimulus. |
| 24 | Mechanism uses pre-existing schemas (Tse et al., 2007) that are expected to be used interchangeably. | Changes induced by one learning event are shared by another learning event. For this to occur, there must be shared unitary mechanisms that can be used for retrieval of different memories. | Inter-LINKed spines can be used by any cue stimulus that can reach them to generate similar units of inner sensations, allowing the unitary structural operations to get shared. In other words, pre-existing inter-LINKed spines are used by similar sensory elements present in a new learning event (Vadakkan, 2010a; 2013). |
| 25 | A constantly adapting dynamic circuit mechanism. | Provisions should be present to accommodate a large number of new learning events. There should be provision for reversal of the learning mechanism explaining forgetting. | Each spine is surrounded by several other spines that belong to different neurons enabling formation of islets of inter-LINKed spines (Vadakkan, 2010; 2013). Most of the newly formed IPLs are reversible. They also have provision to get stabilized. Thus, inter-inter-spine LINKs are highly dynamic. |
| 26 | Framework of a mechanism that can generate a hypothesis by the system. | When one of the elementary mechanisms of an associative learning event between two items (1&2) undergoes association with a third elementary mechanism during a second associative learning event (e. g. 2&3), it will lead to an interconnected chain of associations between 1,2&3. When more than two spines belonging to different neurons are inter-LINKed in this manner, then the system will be able to generate a hypothesis of relationship (e.g. here between 1&3). | When one spine of each of two islets of inter-LINKed spines are inter-LINKed, each spine of the first islet establishes a relationship with each spine of the second islet. This is the basis of generation of hypotheses about the relationship between each stimulus arriving to one islet with each stimulus arriving to the second islet. These unexpected inter-relation between stimuli that reach two separate islets that gets inter-LINKed often in a special associative learning is the basis for hypothesis generation (Vadakkan, 2010; 2013). |
| 27 | A system needs a state of sleep for nearly one third of its operational time. | It is necessary to explain why the system won't be able to exist without sleep. i.e. Need an explanation for the substantive nature of sleep in the operation of the system. | A state of sleep is needed to keep postsynaptic depolarization by presynaptic terminal as the dominant state of the system. Only when this dominant state is maintained, then only a cue stimulus can induce memory. Cue stimulus crossing the IPL cause lateral activation of the postsynaptic terminal (inter-LINKed spine) to induce units of inner sensation of the associatively learned second stimulus (arriving from the environment through the presynaptic terminal) in its absence (Vadakkan, 2016). Hence only a system that undergoes sleep can generate this property (Minsky, 1980). |
| 28 | While living in space, the requirement for sleep reduces by more than one hour (Dijk et al., 2001; Gonfalone, 2016). | Provide a mechanistic explanation why reduced sensory stimuli in space reduces the need for sleep. | Since sensory stimuli are less in space, the number of reactivations of inter-LINKed spines is reduced significantly. This reduces the time needed to set the system to its baseline dominant state of "depolarization of postsynaptic terminal by its presynaptic terminal" (Vadakkan, 2016). |
| 29 | During memory retrieval, the inner sensation of memory can occur with or without motor actions such as speech and behavioral motor actions. | The mechanism that generates inner sensation of memory should have a connection with the mechanism that generates motor action. There should be a provision for disabling this connection at will. | The IPL mechanism can generate both units of first-person inner sensations & provide potentials to motor neurons for generating motor action reminiscent of the arrival of the item whose memory is retrieved. The motor outputs can have inputs to voluntarily block motor actions while inner sensation is being generated (Vadakkan, 2010; 2013). |
| 30 | It is difficult to inhibit a memory which is being retrieved. | A structural mechanistic explanation is needed. | IPL is an inter-membrane connection. Once IPL is present & functions, it is not possible to inhibit its function voluntarily. Additional inter-spine LINK with an inhibitory spine can be introduced through future associative learning events (Vadakkan, 2007; 2010). |
| 31 | The mean inter-spine distance on the dendrite of a pyramidal neuron is more than the mean spine diameter (Konur et al., 2003). | It is necessary to provide a mechanistic explanation for such an organization. It is reasonable to expect some functional importance for such a scheme of inter-spine spacing. | This organization opens the possibility for neuronal processes that belong to other neurons to occupy the inter-spine space. Since spines of different neurons occupy this space & ECM is often negligible (see Fig.13 in FAQ), some of the spines that belong to different neurons can remain abutted to each other. This will lead to inter-neuronal inter-spine interactions. These interactions are the basis of IPL formation proposed by the semblance hypothesis (Vadakkan, 2010; 2013). |
| 32 | Learning and retrieval of memory are associated with the firing of different sets of neurons. | Learning is expected to make certain new channels. Passage of potentials across these channels (both during learning & memory retrieval) is expected to allow certain neurons held at sub-threshold level to cross the threshold to fire a new set of neurons. | This can be a cause or effect & depends on the spatial relationship of the neurons with regard to the location where specific learning changes occur. During learning, stimuli from sensory stimuli cause action potentials (firing of neurons) to reach locations of learning changes. The outputs from these neurons allow potentials to propagate through new IPLs formed at the time of learning. This allows neurons that are being held at sub-threshold activation states to fire action potentials (Vadakkan, 2010; 2013). During retrieval, presence of only one of the associated stimuli will reduce the number of neurons firing. But re-activation of the channel generated during learning will cause neuronal firing in the post-channel area. |
| 33 | Place cells (CA1 neurons that fire in response to a specific spatial location of an animal) fire in response to specific spatial stimuli. | A mechanism that generates the inner sensation of memory for a location is expected to have a mechanistic connection with the firing of a set of CA1 neurons. | Place cells are CA1 pyramidal cells. When islets of inter-LINKed spines of overlapping dendrites of different CA1 neurons receive spatial inputs, they provide potentials to their postsynaptic CA1 neurons. If these CA1 neurons are being held at subthreshold activation states, then they fire in response to a specific place. This explains place cell firing (Vadakkan, 2013; 2016). |
| 34 | Hippocampal neurons in chickadees show patterns of activity of CA1 neurons that are specific to the locations of hidden food (resulting from retrieval of specific memories) but are independent of place fields (set of CA1 neurons that fire when the bird reaches a place) for the same locations (Chettih et al., 2024). | It is necessary to explain how different neurons fire during a visit to a location where the food is hidden (presumably to check the safety of food) & casual visit to the same location. Since the location has same stimulus to offer, how does the set of neurons fire differ? | Based on the semblance hypothesis, the operation of inner sensations (semblance) take place at the islets of inter-LINKed spines. Based on the potentials that reach towards neurons that are being held at sub-threshold activation states, different sets of neurons fire. Even though the same place provide similar sensory inputs to a set of islets, there are additional islets that get activated for generating inner sensation of food search/verification/threat/safety. Hence, the set of postsynaptic neurons that fire during these two events are likely to be different. |
| 35 | An inhibitor of AMPA receptor (AMPAR) endocytosis, partially rescued long-term memory deficits in mice with high levels of amyloid-β (Yan et al., 2024). | Provide a mechanistic explanation for this finding. | Endocytosis of AMPARs utilizes membranes segments from the lateral spine membranes to form endosomes. This will lead to a reduction in the size of the spine heads & leads to the reversal of the IPLs formed during learning. Thus inhibition of AMPAR endocytosis maintains the spines in their maximum possible sizes that will facilitate IPL formation. |
| 36 | Histone acetyl transferase (HAT) injected mice exhibited stronger fear memory. Neurons in which HAT was overexpressed are neurons in the engram (Santoni et al., 2024). | Removal of histones over the DNA increased fear memory. Need to explain how exposing DNA by removing histones over it increases fear memory. It is necessary to show how HAT facilitates expression of genes, whose protein products are essential for memory storage. Alternatively, if other constraints support, memory can be stored in DNA. | To retain the IPLs formed during fear learning (for maintaining memory of a survival requiring action), neuronal cells will restrict using membrane segments from those spines for endocytosis as an evolutionary adaptation. Instead, more phospholipid molecules are expected to be synthesized to make lipid membrane segments to retain the formed IPLs. This leads to synthesis of fatty acids (mainly palmitic acid) by a multi-enzyme complex consists of 7 different enzymes followed by desaturase and elongase enzyme actions, synthesis of phospholipids, their transport & incorporation into the plasma membranes. Here, HAT is expected to remove histones from the corresponding DNA sequences of these enzymes to facilitate their expression. |
| 37 | Firing of an ensemble of neurons during a higher brain function. | Inner sensation generated during a higher brain function is associated with firing of an ensemble of neurons. | Reactivation of IPLs during a higher brain function (generate units of inner sensations) will allow potentials to propagate from inter-LINKed spines to their postsynaptic neurons. If addition of these potentials allow these neurons to cross the threshold, they will fire (Vadakkan, 2010; 2016). |
| 38 | Firing of separate sets of neurons during learning and memory retrieval. | Associative learning between two stimuli is expected to cause firing of a set of neurons. Only one of the associatively learned items is present to retrieve the memory of the second item. Hence, only a subset of neurons that fire at the time of learning is expected to fire at the time of memory retrieval. | During learning, two associating stimuli will propagate depolarization along their paths & lead to firing of a set of neurons. At the time of memory retrieval, only one/ partial feature of one of the associatively learned stimuli is present. In addition, potentials propagating across the learning generated IPLs will lead to firing of a new set of neurons that are being held at sub-threshold activation states along their paths (Vadakkan, 2010; 2016). |
| 39 | Fast changes in both the magnitude & correlational structure of cortical network activity (Benisty et al., 2024). | Rapidly time-varying functional connectivity is responsible for such changes. | Changes in environmental stimuli, self-triggered thought processes, various inner sensations of fear, anticipation, hunger & comfort levels fluctuate moment to moment indicating the formation & reactivation of a new set of IPLs. These will continue to change the network activity (Vadakkan, 2019). |
| 40 | A cortical pyramidal neuron in one neuronal order is receiving input from several neurons of the lower orders (Ecker et al., 2010). | It is most likely that at the resting state pyramidal neurons are being held at a sub-threshold state. If a cue-induced memory retrieval mechanism causes firing of a specific set of neurons that were not firing before learning (in response to the cue stimulus alone), then it is necessary to show that the learning is capable of generating a channel that will get re-activated during memory retrieval to provide potentials to postsynaptic neurons that may allow them to cross the threshold for firing. | Recent modeling studies have shown that a pyramidal neuron can fire an action potential by spatial summation (summation at the same time) of nearly 140 EPSPs at the axonal hillock that arrives from randomly located dendritic spines (Palmer et al., 2014; Eyal et al., 2018). However, based on calculations of energy per bit of information, 2000 synaptic inputs are needed for neuronal firing (Levy & Calvert, 2021). IPL mechanism explains how learning generated change is capable of generating cue-induced inner sensations as well as motor responses reminiscent of the arrival of the item whose memory is being retrieved. In addition, it also leads to the firing of a new set of neurons. |
| 41 | Any set of 140 input signals arriving from random locations on the dendritic tree can fire a neuron (Palmer et al., 2014; Eyal et al., 2018). Hence, there is extreme degeneracy of input signals in firing a neuron. A system operating by such a scheme was selected from a large number of variations since this offered functional advantages to the system. | Since such a scheme is expected to be used specifically, then a possible situation must be there. If a neuron is being held at sub-threshold level by receiving nearly 130 inputs, then it needs 10 more input signals for its firing. If only a specific cue stimulus in a specific context can provide a specific set of input signals for 10 additional input signals, then only the output neuron will fire. It should be possible to verify this stringent condition for firing of certain output neurons. | Islets of inter-LINKed spines can provide an opportunity to pool all the potentials at one location from where it can be delivered in a summated manner. The high potential that can reach the axonal hillock can efficiently cause firing of motor neurons for motor effect. Inter-LINKing with spines that receive different neurotransmitters in the islets can regulate these islets (Vadakkan, 2016). Limited number of muscles in the body has to execute very large number of motor outputs in response to very large number of sensory inputs. Hence, degeneracy of inputs in firing a neuron along with combinatorial motor unit activation can be viewed as a means to increase efficiency (e.g. muscles of face & tongue to generate speech). |
| 42 | Any set of 140 input signals arriving from random locations on the dendritic tree can fire a neuron (Palmer et al., 2014; Eyal et al., 2018). Since there is no input specificity for the firing of a neuron, information can be lost. | It is necessary to provide an explanation how information loss is prevented. Also, explain how this operation has certain advantages. | Degeneracy of inputs in firing a neuron is likely to cause information loss, if neuronal firing has a role in information storage. Since reactivation of IPL generates units of inner sensations, specificity of information is retained at the level of the spines. Since information is retrieved only in response to the nature of the cue stimulus, integration of units of inner sensations enables generation of information back as a first-person property. |
| 43 | Any set of 140 input signals arriving from random locations on the dendritic tree can fire a neuron (Palmer et al., 2014; Eyal et al., 2018). Information arriving to a neuron during supra-threshold activation does not lead to any changes in neuronal firing. | Need an explanation how information loss is prevented even when firing of postsynaptic neuron is not taking place. | Based on the semblance hypothesis, IPLs can be formed during learning and can be reactivated during memory retrieval even without firing of postsynaptic neurons. The semblances generated by this produce inner sensations (cognitive functions) without any corresponding motor actions. |
| 44 | Many neurons are being held at sub-threshold activation state. | By holding a neuron at a certain potential below the threshold, it is possible to regulate the neuronal output, conditional upon arrival of a certain number of inputs. This can be very important to generate certain motor outputs such as speech & behavioral actions. | Several neurons are being held at sub-threshold activation states (Seong et al., 2014). Islets of inter-LINKed spines facilitate summation of potentials if many of its inter-LINKed spines receive simultaneous inputs, which can facilitate crossing the threshold to fire the output neurons. However, arrival only few inputs to an islet may attenuate the output due to propagation of potentials across all the inter-LINKed spines within an islet. |
| 45 | An operational mechanism is expected to take place in an energy efficient location. | Input signals (postsynaptic potentials) have maximum strength at the location of their origin, which is the spine head. As the potentials propagate further, they get attenuated as they propagate towards the neuronal cell body. Furthermore, signals from different spines mix within the dendrite. Hence, the most likely location for a learning mechanism that can maintain specificity until the time of its retrieval is expected to occur in the spine head region. | IPLs are formed between the head regions of abutted spines that belong to different neurons (Vadakkan, 2010; 2016). Hence, information arriving at the input regions are preserved most when learning changes occur at the spine head region. (Note that any set of nearly 140 input signals cause the same neuronal firing (Palmer et al., 2014; Eyal et al., 2018). Hence, neuronal firing is non-specific with respect to specific input signals. This however leads to loss of specificity of information. Hence, it is reasonable to anticipate a mechanism to recover/compensate for the lost information during memory retrieval). |
| 46 | A dendritic spike occurs by the summation of nearly 10 to 50 postsynaptic potentials (on the spines) at the dendritic region (Antic et al., 2010). | It is necessary to explain which spines contribute to the potentials and explain their significance. | Semblance hypothesis explained that the potentials that contribute to a dendritic spike belong primarily to the spines of different neurons that can form an islet of inter-LINKed spines (Vadakkan, 2016). |
| 47 | Certain dendritic spikes are not followed by somatic action potentials (Golding & Spruston, 1998). | Conventionally it is thought that dendritic spikes are efficient detectors of specific input patterns ensuring a neuronal output (action potential) (Gasparini et al., 2004). So, a source for leakage of potentials from the dendritic area other than its propagation towards the soma needs to be explained. | The islet of inter-LINKed spines (IILSs) provides routes for a dendritic spike to propagate. A dendritic spike can propagate to all the inter-LINKed spines within an IILSs (that offer fewer resistant routes) towards the dendritic trees of those IILSs' neurons. Hence, dendritic spikes cannot be followed by somatic action potentials of all the neurons whose spines are inter-LINKed. |
| 48 | When current is injected into the dendrites of human layer 2/3 neurons they generated repetitive trains of fast dendritic calcium spikes, which can be independent of somatic action potentials (Gidon et al., 2020). | It is necessary to explain the routes through which the high potential of a dendritic spike propagate without reaching the cell body to generate a somatic action potential (neuronal firing). | An islet of inter-LINKed spines can explain generation of dendritic spikes. The net potential of dendritic spike can drain through a few of the inter-LINKed spines to their neuronal cell bodies that are not being recorded. Furthermore, some of the inter-LINKed spines may be receiving inhibitory inputs (Vadakkan, 2016). |
| 49 | Inner sensation of certain higher brain functions occurs without any motor actions. | The mechanism that generates inner sensations must be able to demonstrate that either no behavioral motor actions are generated along with a particular inner sensation or that the motor action can be voluntarily suppressed. | It is shown that the apical dendrites in human layer 5 neurons are electrically isolated from that of the somatic compartment (Beaulieu-Laroche et al., 2018). This indicates possible occurrence of independent operations of islets of inter-LINKed spines at those remote dendritic regions. |
| 50 | When two differential electrodes are placed at two extracellular locations, potential difference between them can be recorded as oscillating wave forms. Brain operates only when the frequency of these oscillations remains within a narrow range. | It is necessary to demonstrate that the vector components contributing to these oscillations are likely involved in generating both inner sensations & associated behavioral motor actions (Note: oscillating extracellular potentials are expected to have reciprocal ionic changes within the cytoplasms of processes of cells (mostly neurons)). | While synaptic transmission provides one vector component, something else constitutes the other vector component/s that is/are expected to take place nearly perpendicular to the direction of synaptic transmission. Propagation of depolarization along the IPL matches with the latter (Vadakkan, 2010; 2013). |
| 51 | Apical tuft regions of neurons of all the cortical neuronal orders are anchored to the inner pial surface resulting in overlapping of the dendritic arbors of neurons from different orders. This resulted from a sequence of movement of neuronal precursors during development. | Dendritic spines of neurons that belong to both the same (mainly) and different neuronal orders overlap with each other to serve certain functions. | Overlapping of dendrites that belong to different neurons from different cortical layers facilitate formation of inter-neuronal inter-spine LINKs (Vadakkan, 2016, 2019). Anchoring of apical tuft regions of all the cortical neuronal orders facilitates inter-order neuronal inter-spine LINKs. Since inputs from remote locations usually reach 2nd & 3rd cortical neuronal orders and since upper motor neurons are located in the 5th layer, this organization facilitates both integration of units of inner sensations & facilitate behavioral motor actions such as speech & motor actions. |
| 52 | Following learning, initially there is conscious retrieval of memory in response to a cue stimulus. Eventually this becomes sub-conscious after repeated retrievals. | The process by which repeated retrievals of a memory in response to a cue stimulus led to its sub-conscious nature must be in alignment with a framework of a mechanism of consciousness. | Explained by the semblance hypothesis (Vadakkan, 2010; 2019). A routinely arriving cue stimulus becomes neither essential nor deleterious for survival. Hence the units of inner sensations evoked by its IPL re-activations merge with the net semblance of consciousness, about which the system is unaware of. Hence, memories evoked by repeated innocuous/non-beneficial cues will remain subconscious. |
| 53 | Activity-dependent sof tructural remodeling was proposed to be a cellular basis of learning and memory (Yuste & Bonhoeffer, 2001). | Certain specific mechanical changes are expected to explain the cellular basis of learning and memory. | Simultaneous activation of two synapses whose spines (postsynaptic terminals) are abutted to each other can lead to IPL formation spontaneously. Even though high energy is needed to displace the hydration layer between abutted spines, certain molecular events are expected to overcome this energy barrier while maintaining specificity (Vadakkan, 2019). |
| 54 | Several seizures spread laterally to the adjacent cortices. Focal seizures manifest Jacksonian march (both sensory and motor). | The cellular mechanism responsible for seizures should be capable of explaining the lateral spread. | Seizures are explained as rapid chain generation of IPLs in the cortex (Vadakkan, 2016). This explains how sensory and motor features propagate from one sensory area to the next in the order in which they are represented in the homunculus (sensory & motor). |
| 55 | Several seizures are associated with different hallucinations. | It should be possible to explain how seizure activity reaches different sensory cortices and triggers inner sensations of sensory stimuli in their absence. | Lateral spread of seizures through rapid formation of IPL mechanism explains inner sensation of perception of various sensations (Vadakkan, 2016). |
| 56 | Pathological changes of amyotrophic lateral sclerosis (ALS) spreads laterally. | It is necessary to provide an explanation how certain alterations from the normal operational mechanism aid in the lateral spread of neurodegenerative changes in ALS. | IPL formation is a spectrum of inter-membrane changes. IPL structural stability remains only till the stage of inter-spine membrane hemifusion. Any alterations of membrane structure, or viral fusion proteins can lead to membrane fusion leading to laterally spreading pathological changes of spine loss and eventual neuronal loss as observed in ALS (Vadakkan, 2016). |
| 57 | Transfer of injected dye from one CA1 neuron to the neighboring CA1 neurons is observed in animal models of seizures (Colling et al., 1996). | CA1 neurons are located lateral to each other in the CA1 region of hippocampus. Hence, it is necessary to explain a physical path between laterally located CA1 neurons through which dye can spread. | Increased excitability and lateral spread of potentials across the IPLs can lead to the pathological conversion of IPLs (maximum allowed interactive state is inter-membrane hemifusion) to membrane fusion between spines that belong to to different neurons (Vadakkan, 2016). This explain dye spread between neurons. |
| 58 | Loss of dendritic spines after kindling, during seizures and following LTP induction. | It must be possible to explain a mechanism that causes loss of spines after kindling, during seizures and LTP induction in an interconnected manner. It is also necessary to find certain benefits that the neurons obtain by loss of spines. | Inter-neuronal inter-spine fusion can lead to mixing of cytoplasmic contents between neurons. Since expression profiles of even adjacent neurons of the same type are different (Kamme et al., 2003; Cembrowski et al., 2016), homeostatic mechanisms are expected to favor loss of spines involved in fusion. This is to protect their neurons from further damage (Vadakkan, 2016). |
| 59 | CA2 area of hippocampus is resistant to seizures. | It is necessary to explain a mechanism for seizures using constraints from the findings offered by the disorder & then provide a specific property of CA2 area that enables to resist seizures in that region. | Based on the semblance hypothesis, anything that prevents formation of IPLs blocks induction of LTP (see inter-connected explanation why CA2 region is also resistant to LTP induction). Perineural net proteins around the spine head region (Dansie & Ethell, 2011) can resist IPL formation between spines of different neurons, which provides an explanation (Vadakkan, 2016; Vadakkan, 2019). |
| 60 | Seizures and memory loss are caused by herpes simplex viral (HSV) encephalitis. | Mechanistic explanation for both these features is expected to provide information about the relationship between these findings in HSV encephalitis. | HSV fusion proteins cause rapid formation of large number of non-specific IPLs & rapid inflammatory changes causing seizures. It also leads to conversion of IPL hemifusion state to the fusion state. This will lead to mixing of cytoplasms of different neurons. Since expression profiles of even adjacent neurons of the same type are different (Kamme et al., 2003; Cembrowski et al., 2016), homeostatic mechanisms are expected to favor loss of spines involved in fusion. If not successful, it can lead to neuronal death leading to cognitive defects (Vadakkan, 2016). |
| 61 | Anesthetic agents alleviate seizures. | Mechanism of action of anesthetic agents should be able to explain how seizure generation and propagation are stopped by anesthetic agents. | Anesthetic molecules increase the number of IPLs that will inter-LINK several islets of already inter-LINKed spines. This increases the magnitude of the horizontal component of oscillating potentials severely reducing the frequency of oscillating extracellular potentials. This prevents both inner sensations and motor actions (Vadakkan, 2016). |
| 62 | Memory impairment in patients with seizure disorders (Mazarati, 2008). | It is necessary to explain how the mechanism of learning, memory retrieval and behavioral motor actions are impaired by the mechanism of seizures. | Seizure pathology involves rapid formation of several non-specific IPLs, and IPL fusion between spines leading to spine loss and even loss of neurons. Formation of non-specific IPLs, spine & neuronal loss contribute to reduction in the number of specific IPLs needed from cognitive functions (Vadakkan, 2016). |
| 63 | Intracellular electro-physiological correlate of epileptiform activity is paroxysmal depolarizing shift (PDS), which is a giant excitatory postsynaptic potential (EPSP) (Johnson & Brown, 1981). | A mechanistic explanation is needed for generation of a giant EPSP at the dendritic spine area during a seizure. It has a propensity to propagate laterally to other cortical regions. Need a mechanistic explanation. | Results strongly indicate that a large EPSP is formed through a postsynaptic mechanism (Johnson & Brown, 1981). Since PDS has a maximum voltage of 50 mV & since distal dendrites normally produce EPSP with an amplitude over 10 mV (Spruston, 2008), spatial summation of several of these EPSPs is a feasible mechanism to explain the PDS. IPL formation between spines of different neurons can provide an explanation for PDS in seizures (Vadakkan, 2016). |
| 64 | Though simultaneous reduction in Ca2+ & elevation in K+ in the ECM space during seizure can prevent action potential propagation along the axon (Seignuer & Timofeev, 2011), seizures continue in status epilepticus. | It should be possible to provide an alternate route through which spread of seizure activity takes place. Since PDS is a giant EPSP, it is necessary to explain how such giant EPSPs continue to get generated and spread. | Formation of large number of non-specific IPLs between abutted spines of different neurons provides an alternate route that can favor summation of EPSPs & also provide a route through which PDS-like activity can propagate throughout the cortex (Vadakkan, 2016). |
| 65 | Cell swelling is observed during "spreading depression" phase of seizures (Kempski et al., 2000; Olsson et al., 2006; Colbourn et al., 2021). | It is necessary to explain cell swelling as a cause or effect of seizure associated changes (either prior to seizures or as a result of it). | Enlargement of dendritic spines is expected to compress and even displace the hydration layer of ECM between the spines. This can favor formation of non-specific IPLs, especially when additional factors that favor seizure generation are present. |
| 66 | Ketogenic diet is used to prevent seizures (Martin-McGill et al., 2020; Kossoff et al., 2021). Ketogenic diet increases serum concentration of long chain polyunsaturated fatty acids (LC-PUFA) (Anderson et al., 2001; Fraser et al., 2002). | It is necessary to provide an inter-connected explanation how LC-PUFA can alter the key cellular structures and prevent seizures. | Membrane lipid composition remain optimal when the dietary n-3 PUFA is more than 10% of total PUFA (Abbott et al., 2012). One possible explanation is that LC-PUFAs in the ketogenic diet or their modified forms gets incorporated as side chains on the lipid membrane triglyceride backbone, blocking formation of non-specific IPLs between spine membranes and prevent seizures (Vadakkan, 2016). |
| 67 | Seizure disorders are associated with neurodegenerative changes (Farrell et al., 2017). | It is necessary to provide an explanation how seizures lead to neurodegeneration. | Seizure disorder can be explained as rapid chain formation of IPLs in the cortex. Even though IPL changes are limited only up to the hemifusion stage, changes in cell membrane composition & frequency of repetition of seizures can lead to IPL fusion. When cytoplasms of different neurons mix, it can lead to spine loss & neuronal loss (Vadakkan, 2016). |
| 68 | Loss of consciousness during complex seizures. | It is necessary to provide a framework that generates first-person inner sensation of consciousness & explain how seizure activity leads to loss of consciousness. | Reactivation of a large number of IPLs in response to both internal & external cue stimuli generate background semblance responsible for the inner state of conscious state. Rapid chain generation of a large number of IPLs leads to induction of a large number of non-specific semblances that cause loss of conformation of semblance for consciousness (Vadakkan, 2016). |
| 69 | Multiple vertical sub-pial resections are found to alleviate seizures (Morrell et al, 1989). | Some structural connections are severed when vertical resections are carried out. Neurons are organized in six layers from the cortical surface to the interior aspect near the ventricles. So, it is necessary to explain what lateral connections are sectioned in this procedure. | Both recurrent collaterals and IPLs form horizontal connections. Cutting though the IPLs is expected to prevent IPL-mediated rapid chain lateral propagation of seizure activity (Vadakkan, 2016). |
| 70 | In status epilepticus (continuous seizures) anesthetics are used to obtain a state of "burst suppression" in the EEG. This is a state of lack of electrical activity for several seconds in between periods of high-voltage bursts of activity (Meierkord et al., 2010). | It is necessary to find a feasible explanation of how introduction of a state of "burst suppression" is achieved with anesthetics & this may aid in controlling seizures and preventing cortical damage due to status epilepticus. | Anesthetic agents are expected to induce rapid generation of large number of non-specific IPLs (reversible). Formation of very large number of IPLs is expected to form a very large horizontal component that will lead the oscillating extracellular potentials to flatten out to a straight line. This can explain a reversible state of “burst suppression”. This will reduce firing of downstream neurons and muscle contractions of seizures (Vadakkan, 2016). |
| 71 | Ictal (during seizure) & postictal characteristics in elctroconvulsive therapy (ECT) & patients with generalized tonic-clonic seizures are essentially similar (Pottkämper et al., 2021). | Need an explanation how high energy used in old ECT procedures caused generalized convulsions. | High energy used in ECT will generate large number of non-specific IPLs. It was previously shown that seizures are generated by rapid chain formation of IPLs along the cortical synaptic regions (Vadakkan, 2016). |
| 72 | Electroconvulsive therapy (ECT) alleviates endogenous depression (Subramanian et al., 2022). This has been a standard of care for the last 70 years. | A mechanistic explanation for its effectiveness is needed. | Depression is a state of inner sensation of a depressed mood. It is reasonable to infer that net qualia of semblances from one or more brain regions are responsible for this. Very large energy provided to the cortical regions can lead to the generation of a large number of non-specific IPLs between abutted spines. This changes net semblance that leads to the inner sensation of depression. |
| 73 | There is short term memory loss following ECT using methods used before early 1980s (Duncan, 1949; Squire, 1977; Frith et al., 1983). Since the start of low energy ECT after 1990s, memory impairment reduced (Meeter et al., 2011). | A mechanistic explanation for this effect is needed. | Very large energy provided to the cortical regions can lead to the generation of a large number of non-specific IPLs between abutted spines.Hence, when a specific cue stimulus arrives, it will reactivate very large number of non-specifi IPLs in addition to specific IPLs. This will lead to dilution of specific semblance needed to get generated for a specific memory. |
| 74 | Neurodegenerative disorders show loss of spines and neuronal death. | An explanation is needed for contiguous spread of pathology leading to spine loss and neuronal death. Causative factors should be acting at specific locations to explain all its features. | Changes in lipid membrane composition, viral fusion proteins, and other factors can lead to pathological progression of IPLs to a fusion state. This causes mixing of cytoplasms of two different cells that leads to removal of one or both spines. If at least one of the fused spines cannot be removed, it can progress to neuronal death (Vadakkan, 2016). |
| 75 | Dementia in neurodegenerative disorders. | Need an explanation for the role of spines in both generation of inner sensation of memory along with concurrent behavioral motor activity. | Loss of spines and neurons will lead to reduction in the number of specific IPLs that are necessary to generate specific units of inner sensations for a specific memory (Vadakkan, 2016). |
| 76 | Perception as a first-person inner sensation. | A variant or a modification of the mechanism of induction of inner sensation for memory should be able to explain first-person inner sensation of perception. | Explained by the special property of the IPL that it can be stimulated from its both sides by stimuli from two adjacent locations of an item to generate units of inner sensation of perception (Vadakkan, 2015). |
| 77 | Apparent location of the percept different from its actual location. | Matching explanations using the mechanism of induction of units of inner sensation are needed. | The inner sensation of percept is generated by the integral of all the units of perception (perceptons). Hence, the actual location of an object need not necessarily match the percept. This becomes clear when there is a medium that can shift the path of light towards the eye (Vadakkan, 2015). |
| 78 | Homogeneity in the percept of a stimulus arriving above the flicker fusion frequency. | A mechanism for fusion of separate inner sensations to generate uninterrupted continuous perception of a source of light arriving above the flicker fusion frequency. | Since units of perceptions (perceptons) from IPLs located at different regions in response to a single flicker are generated in a temporal pattern, perceptons from consecutive flickers overlap & generate a continuous percept (Vadakkan, 2015). |
| 79 | Perception of object borders. | A mechanistic explanation for the formation of first-person percept for object borders is needed. | The percept of a stimulus has to be generated from a stimulus at the borders of an object that reaches the brain. When perceptons formed from these stimuli integrate, they generate inner sensation of percept to generate boarder. Similarly, stimuli from outside the borders also do the same to generate a contrasting border of the background (Vadakkan, 2015). |
| 80 | First-person inner sensation of pressure phosphenes. | Mechanism of generation of first-person inner sensations is expected to provide an explanation for phosphenes triggered by pressure over the eyeball. | Stimulation of sensory paths anywhere along it before the locations of their convergence c (such as retina) an lead to reactivation of IPLs for generation of perceptons (Vadakkan, 2015). |
| 81 | Continued perception of moving objects without any interruptions. | It is necessary to explain how the percept is maintained the same while the object is moving. | The perception of a moving object depends on its speed & its distance from the eyes. Smooth pursuit of the eyeballs allows the stimuli to fall on either side of the same set of IPLs. Arrival of stimuli beyond this limit can be perceived as continuous when the perceptons are overlapped. When the object moves faster than certain limits, then it will trigger saccadic eyeball movements that will allow for continuity of the percept. |
| 82 | There are different types of perceptions such as vision and olfaction. | It is necessary to show evidence for the presence of a comparable neuronal circuity for two different sensations (if possible, in two different nervous systems). | Circuitry for perception was conjectured initially for vision in mammalian brains. It was possible to show the presence of a comparable circuitry for olfactory perception in the nervous system of the fly Drosophila (Vadakkan, 2015). |
| 83 | Orientation tuning of a population of neurons in V1 before and after training on a visuo-motor task showed different sets of neurons responding (Failor et al., 2021). | Neurons that fire during associative learning change in the primary visual cortex varies with time. | Based on the semblance hypothesis, the primary mechanism of perception is not through the firing of a specific set of visual cortical neurons. Instead, perceptons are generated when two sides of an inter-LINKed spine is activated (Vadakkan, 2015). |
| 84 | Flash-lag effect (FLE) - When a flash is briefly presented in a specific location adjacent to the path of a uniformly moving object, the former is perceived to lag the latter. | Matching explanation using the mechanism of induction of units of inner sensation is needed. Needs to explain how perception is affected by relative time of arrival of a stimulus. | Explained based on the semblance hypothesis (Vadakkan, 2022). There is a delay of nearly 70ms from retina to perception (Lamme & Roelfesma, 2000). Of this, nearly 12ms can be attributed to synaptic delays in 5 synapses & conduction delay through neurons. The rest is attributed by IPL formation, reactivation, semblance formation & latter's integration. Continuous perception can use the already formed IPLs for perception, compensating for the delay. |
| 85 | A moving object that abruptly appears & starts to move is initially invisible for some distance, a phenomenon known as the Frohlich effect (Frohlich, 1929). There is a delay of at least 100 ms following retinal photo-receptor cell stimulation & conscious perception (De Valois & De Valois, 1991; Nijhawan 2008). | Five synapses are present from the rods & cones to visual cortical neurons. So, synaptic delay (1-2ms) accounts for 5-10 ms delay. 10 cm myelinated optic nerve - 1ms delay. Total delay: 6-11 ms. Need an explanation for rest of the delay (nearly 90 ms, which is 90% of the delay). | Additional delays due to IPL formation, IPL reactivation, formation of perceptons & latter’s integration can account for the rest of the delay. Note: Synaptic & conduction delays constitute only a minor fraction (10%) of the total delay. |
| 86 | A moving object is perceived slightly beyond the end of its trajectory (Hubbard, 2005) and decays within a few hundred milliseconds after the object disappears (Hubbard, 2018). | It is necessary to make sure that the operational mechanism can provide an explanation for this finding. | At the last moment of arrival of a stimulus from a moving object, in addition to synaptic & conduction delays, percept formation suffers delay due to reactivation of continuously maintained IPLs, and formation & integration of perceptons. The latter three steps that contribute to the majority of the delay (90%) will be responsible for perception beyond the end of the trajectory of a moving object. |
| 87 | Observers do not perceive an object beyond a point at which the object changes direction (Eagleman & Sejnowski, 2000). | It should be possible to explain why the object will not be perceived beyond a point at which the object changes direction (if refractive indices of media through which visual stimuli arrives do not change). | When there is no stimulus beyond a point, there is no further IPL formation & percept generation. So, perception stops instantaneously (after normal perception delay) for reversal of already-formed IPLs by moving object. So, there is no perception beyond the location of the object; there can only be delay in perception. |
| 88 | No FLE is perceived when both moving object & flash disappear simultaneously (Eagleman & Sejnowski, 2000). | Need an explanation based on what happens to the last stimuli from both (see row 77). | IPLs formed by a continuously moving object will take more time when compared to reversal of freshly formed IPLs by a flash. Whereas, flash needs time for IPL formation & only less time for reversal of these comparatively newly formed IPLs. When these two conditions are examined, it can be seen that formation of last percepton by the moving object takes place almost at the same time as that of the formation of last percepton by the flash. |
| 89 | FLE is not perceived if the moving object stops moving at the time when a flash is presented as a stationary object (Kanai et al., 2004; Hubbard 2014). | When a moving object is stopped, perception will continue for some more time. A flash (that is going to remain stationary) will have a delay in getting perceived. Need an explanation why there is no FLE. | When a moving object is stopped, perception will continue for some more time due to synaptic, conduction and percepton integration delays. A flash (that is going to remain stationary) will have perception delay due to synaptic, conduction, IPL formation & percepton integration delays. When these two delays match, there will not be any FLE. |
| 90 | In the “high-ϕ illusion”, when a rotating texture is suddenly replaced by a random texture, an82 observer perceives the texture to jerk backwards (Wexler et al., 2013). | It is necessary to show that the sudden appearance of a random texture requires additional time for its perception. | IPLs that are formed by rotation texture are expected to be maintained continuously during its rotation. However, newly arriving random texture need time for the formation of new IPLs, their reactivations & percept formation. Hence, an observer perceives the texture to jerk backward. |
| 91 | FLE increases when the distance between the moving object & flash increases (Hubbard, 2014). | It should be possible to provide a mechanistic explanation for the effect of distance on the time interval between perception of the moving object the flash. | Stimuli from a moving object lead to activation of neurons of 5 neuronal orders involved in visual perception. It will maintain more neurons at sub-threshold activation states such that they can be fired by signals arriving from the flash. Hence, a nearby flash will be able to reach up to more abutted spines in the visual cortex & form sufficient number of IPLs faster & generate more perceptons to get integrated to generate a percept faster compared to a flash located far from the moving object. |
| 92 | Perception of a stimulus can be blocked or modified if it is followed in rapid succession by a second stimulus, which is called backward masking (Bachmann, 1994). | It is necessary to explain certain mechanism that occurs in between two successive stimuli. | Nerve conduction through neuronal paths takes place at slightly different speeds & hence integration of perceptons for the first stimulus can be overlapped by integration of perceptons by the second stimulus. Also, many of the same IPLs that generate perceptons of the first stimulus are likely involved in percept formation for the second stimulus. |
| 93 | When successive stimuli arrive at frequencies above the critical flicker frequency then stimuli will be perceived as a continuous one (Jensen, 2006). | It is necessary to explain how fusion between the percepts occur. | Perceptons for the first stimulus will be overlapped by perceptons by the second stimulus. Also, many of the same IPLs that generate perceptons of the first stimulus are likely involved in percept formation for the second stimulus. |
| 94 | When a stationary object is presented for 2.5 s, then removed for very short interval such as 30 ms & presented again in immediate motion, the object may get continuously perceived (Whitney & Cavanagh, 2000). | A mechanistic explanation is needed how fusion between the percepts occur. | Some of the perceptons for the first stimulus are likely overlapped by perceptons by the second stimulus, thus generating a percept of a continuous stimuli. |
| 95 | When a flash stimulus is more eccentric by reaching retinal periphery, compared to a stimulus reaching fovea, it causes poor performance on a visual task (Staugaard et al., 2016). FLE is more when eccentricity is more (Hubbard, 2014). | It is necessary to explain why the image of a flash falling on the periphery of retina, leads to an increased FLE. | Fovea is a location on the retina where photoreceptors are present in high density (Kolb et al., 2020). Since photoreceptor density is comparatively lower at the periphery, the IPLs are expected to be sparingly distributed in the corresponding areas in the visual cortex. Hence, it will take more time for integrating perceptons to generate a percept of an eccentric flash. |
| 96 | FLE is more when flash is less predictable (Hubbard, 2014). | Need to explain the reason for small FLE when flashes occur at fixed intervals that are predictable. | More predictable flashes will generate certain reverberating circuit that provides potentials to many neurons to keep them in a sub-threshold state. When the next flash arrives, it can depolarize more abutted spines & form more IPLs for the generation of a fast percept. |
| 97 | Predictable moving dots at the leading edge are correlated with suppressed blood oxygenation level dependent (BOLD) responses (Schellekens et al., 2016). | Need to explain a favorable mechanistic change during anticipation & how it is associated with low BOLD signals. | An explanation for Golgi staining reaction led to an inference that oxygen is involved in reversing the IPLs (Vadakkan, 2021). This indicates that suppressed BOLD signals are an indication that decreased oxygen release facilitates continued maintenance of IPLs while observing a moving object. |
| 98 | Percept occurs even when an object moves into the peripheral regions of the blind spot (Maus & Nijhawan, 2008). | A blind spot is observed when only one eye is open & the individual fixates to a single point in the visual field. In the above conditions, blind spot is a location in the visual field at which a visual stimulus cannot be perceived. | Percept formation occurs at a spatial location of integrated perceptons (Vadakkan, 2015a). There are no locations found in the visual cortex equivalent to a blind spot at which visual stimuli do not reach. Blind spot is a conformationally empty space in the net perceptons. During monocular vision when eye fixates to a point, then stimuli arriving at the margins of the blind spot are not capable of forming a percept in this region. In contrast, a visual stimulus arriving at the margin of a blind spot generate perceptons & are expected to reach IPLs in the visual cortex, the integral of which can reach towards the periphery of the blind spot. This is due to the branching of dendritic arbor & their overwhelming overlap that prevents having a cortical equivalent of a blind spot. |
| 99 | It is necessary to provide a mechanistic explanation for changes in brain inflammation & how it can lead to perception of stimuli in their absence. | Inflammation leads to swelling of cells & their processes. This predisposes abutted dendritic spines to form non-specific IPLs & trigger inner sensations in the absence of any sensory stimuli (hallucinations). Specific hallucinations can occur when inflammation occurs in specific brain regions. | |
| 100 | Inner sensation of consciousness. | The presence of a continuous operational mechanism for the generation of inner sensations that depends on/contributes to maintaining the frequency of oscillating extracellular potentials in a narrow range is expected. The combined inner sensation is expected to generate inner sense of being conscious. | There is a continuous baseline oscillating extracellular potentials as recorded by EEG. Both internal & external stimuli continuously reactive numerous IPLs & the resulting units of inner sensations get integrated to generate inner sensation of consciousness (Vadakkan, 2010). A framework for consciousness was explained as the net semblance from non-deleterious & non-beneficial stimuli from environment & body (Vadakkan, 2010; Vadakkan, 2015 ). |
| 101 | Loss of consciousness by anesthetic agents. | It is necessary to first provide a framework of a mechanism that generates first-person properties of consciousness. Then, explain how anesthetic agents block the above mechanism. | A framework for consciousness was explained (see above row) (Vadakkan, 2010; Vadakkan, 2015). Spontaneous curvature induced by anesthetics arriving from the ECM space initially to the outer lipid membrane leads to asymmetry between the outer & inner leaflets of the lipid bilayer (Lipowsky, 2014). In addition, lipophilic anesthetics get partitioned inside the hydrophobic lipid phase in the regions of membrane reorganization on the spines (lateral aspect). The net result is dehydration of the inter-membrane ECM space leading to physical contact between the abutted spine membranes. This leads to the formation of a large number of non-specific IPLs altering inner sensation of consciousness. |
| 102 | Potency of an inhaled anesthetic agent is proportion to its partition coefficient (concentration ratio) between olive oil & water (hydrophobic solubility). This has a correlation coefficient of 0.997 (Firestone et al., 1986), one of the most powerful correlations in biological systems (Halsey, 1992). | It is necessary to show that the mechanism of anesthetic action is dependent proportional to the lipid solubility. | Based on the semblance hypothesis, lipid solubility affects the membrane properties and proportionately leads to formation of non-specific IPLs. Non-specific semblances generated on the inter-LINKed spines of non-specific IPLs lead to proportional loss of consciousness (Vadakkan, 2015). |
| 103 | Anesthetics are known to have different actions - GABA-A receptor agonists, alpha adrenergic receptor agonists, NMDA receptor antagonists, dopamine receptor antagonists and opioid receptor agonists (Kopp et al., 2009). | It is necessary to show either that all these receptor actions lead to a common path responsible for consciousness or that there is a common mechanism of action for these agents other than on those receptors. | A framework for consciousness was explained (see above row) (Vadakkan, 2010; Vadakkan, 2015). Anesthetic actions of general anesthetics are proportional to their lipid solubility - with a very high correlation coefficient of 0.997. Spontaneous curvature induced by anesthetics arriving from the ECM space initially to the outer lipid membrane leads to asymmetry between the outer & inner leaflets of the lipid bilayer (Lipowsky, 2014). This can lead to formation of large number of non-specific IPLs by the anesthetic agents (Vadakkan, 2015). |
| 104 | General anesthesia induced by anesthetics is reversed by the application of pressure outside the animal placed within a closed container. i. e. by application of pressure over an aquatic or terrestrial animal by increasing the pressure of water or air respectively (Lever et al., 1971; Halsey et al., 1986). | It should become possible to show a mechanism that can lead to reversal of actions of anesthetic agents in response to external pressure. | External pressure propagates through middle ear, perilymph, CSF & paravascular space to reach the neuronal processes (Iliff et al., 2012). Based on the Le Chatelier’s principle, when the pressure on a system at equilibrium is disturbed, the equilibrium position will shift in the direction necessary to reduce the pressure. This will lead to removal of anesthetic molecules from the lipid membranes to the ECM volume that will escape through the paravenular space into the venous system (Iliff et al., 2012). This in turn will reverse the non-specific IPLs generated by the anesthetics (Vadakkan, 2015). |
| 105 | Only reduced amounts of anesthetic agents are required for anesthesia in the presence of levodopa (Segal et al., 1990). | It is necessary to explain a specific mechanism of action of dopamine that will augment anesthetic action. | It is known that dopamine can lead to enlargement of spines (Yagishita et al., 2014). This can augment IPL formation and reduce the required concentration of anesthetic agents for generating a certain level of anesthesia compared to that in the absence of dopamine. |
| 106 | Low doses of anesthetics leave very short-term memory intact, so that patients can carry on a conversation & appear to be lucid (Wang & Orser, 2011). A gradual increase in the anesthetic dose produces a gradual worsening of short-term memory & a gradual shortening of the time interval after which memories can be retrieved (Andrade et al.,1994). | It is necessary to explain why low doses of anesthetic agents do not alter the operational mechanism of memory; whereas increasing doses start affecting memory. | Since IPLs are highly reversible, newly formed non-specific IPLs by the anesthetic agents reverse back. Hence, low dose of anesthetic agents may not affect short-term memories. But at higher doses, formation of more non-specific IPLs will generate more non-specific semblances along with generation of specific semblances in response to a specific cue stimulus. Hence, formation of relatively more non-specific semblances in response to high concentrations of anesthetic agents will prevent retrieval of specific memories (Vadakkan, 2015). |
| 107 | General anesthetics generally do not impair existing long-term memory (Bramham & Srebro, 1989). | It is necessary to explain how the mechanism that retains long-term memory remains unaffected by general anesthetics. | IPLs responsible for maintaining long-term memory are well stabilized by maintaining stable inter-membrane interactions at the IPL locations as explained by the semblance hypothesis (see Fig.12D in the FAQ section) (Vadakkan, 2015). Hence, these stable regions will not be affected by anesthetics. |
| 108 | There are several reports of cognitive decline after surgery that uses general anesthetic agents. | It is necessary to provide a plausible explanation of how the normal mechanism responsible for memory is likely getting affected by a common factor in all these surgical cases. | Since IPLs are responsible for generating memories & anesthesia leads to the formation of large number of non-specific IPLs, it is possible that any extension of the IPL structure to form IPL fusion (see Fig.12F in FAQ section) can lead to spine and neuronal loss as a consequence (Vadakkan, 2015; Vadakkan, 2016). |
| 109 | As the anesthetic dose is increased, patients enter a state of excitation characterized by euphoria or dysphoria, defensive or purposeless movements, & incoherent speech. This state is termed "paradoxical" since the anesthetic, intended to induce unconsciousness, cause excitation (Brown et al., 2010). | It is necessary to provide an explanation for the generation of new inner sensations & motor actions during the early stages. | Motor neurons in layer 5 of the motor cortex is being held at a sub-threshold level of activation that will enable them to fire when additional potentials arrive. In the initial stages of anesthesia, when the anesthetics induce more IPLs, it will lead to both generations of certain inner sensations & firing of several sub-threshold activated neurons in the motor cortex. |
| 110 | Loss of consciousness during a generalized seizure and its reversal after seizure. | Mechanism of seizure generation should be able to explain how inner sensation of consciousness is lost. | Rapid chain formation of large number of non-specific IPLs due to changes in ECM properties (e.g. very low serum Na+) or increased excitability of neurons generates seizures (Vadakkan, 2016). This will change the conformation of net semblance generated in the background state altering consciousness. |
| 111 | Changes in consciousness proportional to variations in the frequency of oscillating extracellular potentials beyond a narrow range. | Need an explanation how a narrow range of frequency of oscillating extracellular potentials is associated with normal consciousness. | Explained based on the semblance hypothesis (Vadakkan, 2010; 2015). Unconscious states are associated with large variations in the frequencies of extracellular potentials recorded from the skull surface in EEG (Rusalova, 2006). Conformational changes in the net semblance for consciousness is affected. |
| 112 | Effect of dopamine in augmenting anesthetic action. | Explain a mechanism how dopamine augments anesthetic action. This explanation must match with the explanation for the action of dopamine in augmenting learning (see row 15). | Anesthetic agents generate large number of non-specific IPLs leading to the formation of non-specific semblances, altering conformation of net semblance for conscious state to generate an unconscious state. Spine enlargement by dopamine augments IPL formation. Hence, dopamine augments anesthetic action (Vadakkan, 2016). |
| 113 | Phantom sensation and phantom pain. | Explain a mechanism for the inner sensation of pain from a lost limb at the time of phantom sensation or phantom pain. | As long as the IPLs that have received inputs from a limb remains stable in the brain, any reactivation of this by stimuli arriving to this set of IPLs through a different sensory input can evoke semblance of phantom limb or pain. This can possibly occur when the same nerve root in the proximal regions of the lost limb is stimulated. |
| 114 | Innate behavior (e.g. sucking reflex) that enables survival. | A mechanism evolving from heritable changes to explain innate behavior in response to a stimulus. | Associative sensory stimuli of different velocities propagate through pathways that converge at certain locations. IPL mechanisms at these locations generate inner sensations such as memory & also fire motor neurons for survival. When these associations from environment is important for survival, then adaptational changes will generate IPLs at the locations of convergence of sensory inputs. This can be viewed as an evolved mechanism. |
| 115 | Neurodegeneration resulting from repeated general anesthesia (Baranov et al., 2009). | Need an explanation why the repeated induction of a mechanism of loss of consciousness by anesthetics can lead to loss of spines and eventual loss of neurons. | Anesthetics arriving from ECM space first to the outer lipid membrane leads to asymmetry between the outer & inner leaflets of the lipid bilayer causing curving of membranes (Lipowsky, 2014). Lipophilic anesthetics get partitioned inside the hydrophobic lipid phase in the regions of membrane reorganization on the spines (lateral aspect). This results in dehydration of the inter-spine ECM space leading to large number of non-specific IPLs altering inner sensation of consciousness (Vadakkan, 2015). Conversion of IPLs to inter-neuronal inter-spine fusion leads to spine loss & neuronal death. |
| 116 | More years of education (increased number of associative learning events) reduces dementia risk (Maccora et al., 2020). | Should be able to explain whether surplus learning-induced changes are generated by prolonged learning events. | Associative learning events have several shared associative elements in them. This leads to formation of surplus number of IPLs by different learning events since new neurons get inserted into the circuitry and alters it at higher orders above the granule neuron layer of the hippocampus. Hence, surplus IPLs are formed in the cortex (Vadakkan, 2013; 2019), which can explain reduced dementia risk with more education. |
| 117 | Specific brain regions appear to be associated with specific functions based on the lesions/ lesion studies. | Need to provide a circuit-based explanation. | Sensory cortices receive inputs from specific sensory stimuli. These locations are expected to have IPLs necessary for perception. Hippocampus receives inputs from all the sensations. Converging inputs here form IPLs during associative learning. Cortical regions have sparse converging locations where IPLs form for specific learning associated changes. Thus, specific locations have specific functions. |
| 118 | Astrocytic pedocytes cover less than 50% of peri-synaptic area in nearly 60% of the synapses in the CA1 region of hippocampus (Ventura & Harris, 1999). | Hippocampal mechanism of learning & memory must explain the suitability of distribution of astrocytic processes. | Area of spines free of astrocytic pedocytes favor generation of inter-neuronal inter-spine interactions for IPL formation (Vadakkan, 2019). Astrocytic pedocytes can mop up neurotransmitter molecules spilled over from the synaptic cleft and recycle them to provide back to the neurons. |
| 119 | Present nervous systems have evolved over millions of years & are also the results of certain accidental coincidences. | It is expected to be possible to explain how the circuitry that provides all the features can be evolved through simple steps of variations and selection. | IPL formation & reactivation lead to sparking of the first-person inner sensations of features of a learned item in response to the arrival of fastest or first sensory cue stimulus (associatively learned). This started providing survival advantages to animals in a predator-prey environment. These beneficial features were selected such that organization of the neuronal processes continued to get maintained and conserved over time (Vadakkan, 2020). |
| 120 | Dye diffuses from one neuronal cell to another as the cortical neurons move from periventricular region towards their destination indicating formation of an inter-cellular fusion pore (Bittman et al., 1997). This occurred in all the cells. This is followed by death of nearly 70% of these cells and survival of the remaining 30% cells. | It is expected to become possible to explain how an event of inter-cellular fusion leads to selection of variants that acquire an ability to prevent further inter-cellular fusion. Since neurons cannot divide further (arrested in interphase), a transient stage of fusion is expected to trigger a "fusion prevention mechanism" in the surviving neuronal cells. It is also necessary to explain whether this mechanism has any role in the unique functional property of generation of first-person inner sensations in the nervous system. | Explained based on the semblance hypothesis (Vadakkan, 2020). Dye diffusion indicates formation of fusion pores between neuronal cells. The initial occurrence of inter-neuronal fusion could have taken place due to changes in membrane composition or lack of checkpoint mechanisms to arrest hemifusion from progressing to fusion. But the neuronal adaptations that it brought to arrest IPL changes beyond IPL hemifusion enabled the neuronal processes to generate IPLs. The functional advantages of generating first-person inner sensations provided exceptional survival advantages to the organisms. |
| 121 | Following the above stage where dye diffusion is observed, significant neuronal death (70%) (Blaschke et al., 1996) & spine loss (13 to 20%) are observed. | There is a high probability that the surviving cells have acquires an adaptation. | Explained based on the semblance hypothesis (Vadakkan, 2020). Following death of 70% cells, an adaptation occurring in the surviving cells most likely prevents any future coupling between neurons that may result in inter-neuronal fusion. This adaptation is suitable for maintaining IPLs for generating useful functions. |
| 122 | Aging is the most important risk factor for neurodegenerative disorders such as Alzheimer’s disease (Guerreiro & Bras, 2015). | It is necessary to explain loss of a specific mechanism or structural change occurring during aging responsible for age-related dementia. Dementia means both decline in memory & behavioral motor activity such as speech & motor actions. | Dye diffusion between neuronal precursor cells during one stage of development occurs in 100% of cells (Bittman et al., 1997). Death of up to 70% of these cells & survival of rest 30% of cells that become adult neurons indicates that an adaptation is triggered in the surviving cells that prevents any future inter-neuronal fusion events, spine loss & neuronal deaths. Age-related defects in this adaptation mechanism can lead to cell-cell fusion, cytoplasmic content mixing & neurodegeneration. This a possible explanation for age-related cognitive decline (Vadakkan, 2021). |
| 123 | Higher brain functions take place in a narrow range of frequency of oscillating extracellular potentials as evidenced by EEG (Rusalova, 2006). | To have oscillating extracellular potentials, there should be corresponding intracellular changes. In the cortex, neurons are arranged in six neuronal orders (layers). Neurons between these orders are connected by synapses. So, synaptic transmission is expected to take place perpendicular to the cortical surface. It is necessary to show changes that generate horizontal component of those oscillations. | Both the mechanisms for learning & memory retrieval are expected to contribute/depend on vector components to the oscillating extracellular potentials. What provides the horizontal component? Propagation of potentials across the IPLs that are formed between spines that belong to laterally located neurons have the ability provide the horizontal component for oscillating potentials. (Vadakkan, 2010; 2013). Note: Since neurons of all the orders have their apical terminal attached to the subpial region, spines that belong to neurons of different neurons also participate in IPL formation & contribute to the horizontal component of oscillations. |
| 124 | In prematurely born infants, the oscillating extracellular potentials in electroencephalogram (EEG) show discontinuity in the waveform (Selton et al., 2000). | It is necessary to explain a horizontal component formed during development as the brain matures. Since premature infants will not survive below certain age & since "brain death" is considered as "death", enabling extracellular potentials to oscillate in a narrow range of frequency is a vital requirement. | This can be explained in terms of formation of additional IPLs, by the arrival of large number of associative stimuli that provides lateral spread of potentials through them. Formation of recurrent collaterals, cortico-thalamic & thalamo-cortical pathways are also expected to contribute to the horizontal component (Vadakkan, 2021). |
| 125 | A comparatively longer duration for humans to achieve motor functions, after birth, compared to animals. | It is necessary to provide at least a framework of an explanation for this delay. This may also likely relate to the higher cognitive abilities of humans compared to animals. A mechanistic explanation is needed. | In humans, sufficient number of motor units (one motor neuron & the muscle fibers supplied by it) receive input signals through a more time-consuming process. One of the routes through which motor neurons receive potentials is through the IPLs. Large number of associative learning events can lead to the formation of more IPLs, which in turn enable generation of first-person inner sensations of more higher brain functions in humans compared to animals. Since more time will be needed for the formation of sufficient number of IPLs for potentials to reach motor units, it takes more time for humans to achieve full-fledged motor functions (Vadakkan, 2021). |
| 126 | Artificial triggering of spikes in one neuron in the cortex causes spikes in a group of neighboring neurons in the same neuronal order located at short distance (25–70µm) from the stimulated neuron (Chettih & Harvey, 2019). | It should be possible to explain a mechanism that can lead to lateral spread of firing between neurons of the same neuronal order within a short radius. Need an explanation for a mechanism through a path other than trans-synaptic route. | One explanation is propagation of depolarization across the IPLs between spines that belong to different neurons (Vadakkan, 2013). This also explains why only sparsely located neurons get fired, correlated in time. |
| 127 | The protein complexin blocks SNARE-mediated fusion by arresting the intermediate stage of hemifusion. Complexin is present in the spines. But docked vesicles are not found inside the postsynaptic terminals (spine) (in contrast to what is observed in the presynaptic terminals). | This leaves the question, "Which inter-membrane fusion is getting arrested by complexin?" It is necessary to explain an inter-membrane fusion process that can be mediated by SNARE proteins and blocked by complexin by arresting fusion at or before the intermediate stage of hemifusion in the spines. | SNARE proteins provide energy for bringing together membranes against repulsive charges and overcoming energy barrier between abutted membranes (Oelkers et al., 2016). They also generate force to pull together abutted membranes as tightly as possible (Hernandez et al., 2012). By initiating the fusion process by supplying energy (Jahn & Scheller, 2006), SNARE proteins can lead to the formation of characteristic hemifusion intermediates (Lu et al., 2005; Giraudo et al., 2005; Liu et al., 2008). Protein complexin present within the postsynaptic terminals (Ahmad et al., 2012) is known to interact with the neuronal SNARE core complex to arrest fusion at the stage of hemifusion (Schaub et al., 2006). These indicate possibility for inter-spine interactions mediated by SNARE and regulated by complexin. |
| 128 | There are hundreds of types of neurons in the cortex (Huntley et al., 2020; Mao & Staiger, 2024). | It is necessary to explain how these many different types of neurons can orchestrate a specific cortical function. | Based on the semblance hypothesis, what is important is the inter-neuronal inter-spine interaction to form IPls during learning & their reactivation to generate both semblances & motor effects. Different neurotransmitters can modulate postsynaptic potentiation of inter-LINKed spines, whereby modulating the qualia of semblances generated. |
| 129 | There are a very large number of types of neurons in the cortex (Huntley et al., 2020; Mao & Staiger, 2024). | It is necessary to explain how these many different types of neurons are maintained without causing any problems. Also explain advantages of their existence. | IPLs are expected to be formed between spines of different types of neurons including that of the inhibitory neurons. As nature of depolarization at the terminals varies, it can alter depolarization of inter-LINKed spines & the conformation of net semblance formed. This can fine tune the qualia of inner sensations (Vadakkan, 2021). |
| 130 | Transcriptomic analyses show heterogeneity of even adjacent neurons of the same type in the cortex (Kamme et al., 2003; Cembrowski et al., 2016). | This indicates that any mixing of the contents between these neurons is fatal to them. Hence, there will be a robust mechanism to prevent intercellular fusion. | Different mRNA profiles of adjacent neurons of even the same type indicate that any cytoplasmic content mixing will lead to homeostatic mechanisms such as spine or neuronal loss to prevent it from further progress (Vadakkan, 2016). This matches with the structural limitation of IPLs to only the stage of inter-membrane hemifusion. |
| 131 | Heterogeneity in clinical features & pathological changes in Alzheimer's disease (& other neurodegenerative disorders). | First, there will be a universal mechanism that involves different neuronal types. Secondly, many factors are likely involved in the operational mechanism. Pathological changes due to these factors should be able to explain heterogeneity. | A common mechanism is pathological conversion of normal maximum limit of hemifusion to pathological fusion. Clinical features depend on a) formation of non-specific IPLs at different locations, & b) locations of IPL fusion that can lead to spine loss & even neuronal death (Vadakkan, 2016). Hence the heterogeneity. |
| 132 | In excitatory neurons, spine depolarization can occur without any dendritic depolarization. Also, distal human dendrites contribute limited excitation to the soma even during the occurrence of dendritic spikes (Beaulieu- Laroche et al., 2018a; Beaulieu-Laroche et al., 2018b). | Why did such a mechanism get selected? What is the functional significance of depolarization of the spine head? Is there any link between depolarization of the spine heads, oscillating extracellular potentials & different brain functions? Are the spine heads involved in certain computations? | The IPL mechanism needs only depolarization of the spine heads for generating units of inner sensations. Even though lack of depolarization of the dendrites & lack of firing of the postsynaptic neurons can prevent motor outputs, it does not affect generation of semblance at the inter-LINKed spines. This matches with the ability to generate inner sensations without generating any corresponding motor actions.
|
| 133 | The histological features of amyloid (senile) plaques & neurofibrillary tangles observed in Alzheimer's disease & in a spectrum of neurodegenerative disorders are also observed in normal aging (Anderton, 1997). | A mechanistic explanation for how & why intracellular neurofibrillary tangles & extracellular plaques that are key pathological features in neurodegenerative disorders are observed in normal aging (but without symptoms). | The formation of extracellular plaques can reduce the number of specific IPLs formed during learning, which are necessary for generating specific memories. People with large number of surplus specific IPLs will be able to afford to lose a subset of those IPLs. However, those with only borderline number of IPLs (just enough to generate specific memories) will be affected by the accumulation of amyloid plaques in the ECM space. |
| 134 | Therapeutic agents developed for treating seemingly unrelated neurological diseases such as seizure disorders, Parkinson's disease, spasticity, & hallucinations can alleviate different headache pains. | Explanations for mechanisms of different disorders & the operational mechanism of the system should provide interconnected explanations for the effectiveness of therapeutic agents in different headaches. | By inhibiting voltage-gated sodium channels, it reduces neuronal excitability & prevent rapid IPL formation preventing seizures, prevents IPL formation between spines of spiny neurons of basal ganglia, reduce inputs via IPLs to upper motor neurons reducing spasticity, reverse/inhibit IPLs inhibiting/reducing inner sensation of headache pains. |
| 135 | Since learning is expected to generate certain new circuit connections, the circuit elements (like on a printed circuit board (PCB)) must remain separate from each other. | Properties of both neuronal membranes and extracellular matrix should match with the new circuit connections, functional properties imparted by them and their reversal. | Even though extracellular matrix space seems negligible between the membranes, hydration layer between the lipid membranes shows high energy barrier in artificial systems (Rand & Parsegian, 1984; Martens & McMahon 2008; Harrison, 2015). |
| 136 | "Representational drift" - meaning that when a brain function is repeated, set of neurons that fire changes with time (Schoonover et al., 2021; Marks & Goard, 2021; Deitch et al., 2021). | In the case of memory, it is necessary to show either a) redundancy in its operational mechanism, or 2) surplus operational units, subset of which integrate to provide memory. | Correlation between a brain function & neuronal firing will be true for those neurons that are being held at sub-threshold activation state & receive additional potentials through learning generated IPLs. Repetition of associations of overlapping features in future learning events propagating through a circuitry that inserts new neurons along its path will generate new set of IPLs. Hence, when a brain function is repeated, it fires new set of neurons (Vadakkan, 2019). |
| 137 | Ability to induce robust long-term depression (LTD) in the spinous region of medium spiny neurons (MSNs) of nucleus accumbens (NAc) of naïve animals. | It is necessary to explain LTD as an active process & not merely reversal of a mechanism for LTP (Dong et al., 2015). Since it takes minutes to induce LTD, it is necessary to explain it as a time-dependent mechanism (Thomas et al., 2001; Brebner et al., 2005). It is also necessary to show that energy applied at the spinous region leads to depression of potentials at the recording electrode placed at the postsynaptic region or on MSN soma. | IPL formation between a spine of a MSN that synapse with excitatory inputs and another spine of a second MSN that synapses with inhibitory inputs leads to the generation of depression of net potentials. The net result of many of such IPLs can cause depression of the net potentials recorded by the recording electrode. This can explain LTD (Vadakkan, 2021). |
| 138 | Following stimulation, there is a time delay to observe LTD (Thomas et al., 2001; Brebner et al., 2005) comparable to the time delay observed in the induction of LTP (Gustafsson & Wigström, 1990; Escobar & Derrick et al., 2007). | A time-dependent cellular change is taking place during the delay period following LTD stimulation. | Like LTP, LTD induction also results from the formation of IPLs. Since energy is needed for spine expansion that can facilitate IPL formation between spines that synapse with excitatory and inhibitory inputs, spine expansion also needs time to take place. |
| 139 | Similar to LTP, LTD in NAc is also NMDA receptor-dependent (Lüscher & Malenka, 2012). | LTD induction takes place through activation of NMDA receptors of glutamatergic synapses. It is necessary to explain how NMDA receptor activation leads to both LTP & LTD. | Excitatory synaptic function is necessary for spine expansion and IPL formation between spines that belong to different MSNs in the NAc region. Since dopaminergic terminals that synapse on to the spines that receive excitatory inputs, it is reasonable to infer that spines of excitatory synapses are the major partner of the IPLs (Vadakkan, 2021). |
| 140 | When rewards or conditioned stimuli that predict reward are presented, dopamine neurons in the VTA increase their firing (Schultz, 1998; Roitman et al., 2004) releasing dopamine in their terminals that synapse with spines of MSNs in NAc. | Dopamine produces certain changes at the spines of MSNs that synapse with excitatory inputs. | Dopamine is known to cause spine expansion (Yagishita et al., 2014). Expanding spines can augment IPL formation and retain the formed IPLs for a long period. Since some of the spines involved in IPL formation synapse with excitatory inputs and some with inhibitory inputs, the net effect in the presence of dopamine is augmentation of depression (Vadakkan, 2021). |
| 141 | Drugs of abuse such as cocaine increase dopamine levels in the NAc (Lüscher & Malenka, 2011). | Dopamine has certain actions in the NAc to cause addiction that leads to its abuse. | Dopamine leads to spine expansion, formation of IPLs that leads to inner sensation of pleasure. Continued exposure can lead to spine loss & dependency on cocaine to maintain normal comfort level (Vadakkan, 2021). |
| 142 | Exposure to cocaine leads to attenuation of postsynaptic potentials in MSN spines of NAc (Beurrier & Malenka, 2002). | It is necessary to show how dopamine released due to the action of cocaine acts on spines of MSNs that synapse with excitatory inputs & results in attenuation of postsynaptic potentials. | Dopamine is known to cause spine expansion (Yagishita et al., 2014). Spine expansion speeds up IPL formation with a spine that receive inhibitory input, altering the conformation of semblance at this location to generate inner sensation of pleasure (Vadakkan, 2021). |
| 143 | Dopamine attenuates postsynaptic potentials elicited by stimulation of different excitatory inputs to NAc shell region (Park et al., 2008). | Action of dopamine on spines of MSNs that synapse with excitatory inputs attenuates postsynaptic potentials when these excitatory inputs are stimulated through a mechanism. | Attenuation of postsynaptic potentials by dopamine can be explained in terms of expansion of the spine head to which the dopaminergic terminal synapses to & that spine in turn form an IPL with another spine that is synapsing with an inhibitory input (Vadakkan, 2021). |
| 144 | In response to natural rewards & cocaine exposure, a major set of MSNs in NAc show depression of firing rate (Carelli, 2002; Ishikawa et al., 2009; Kourrich & Thomas, 2009). | Rewards and drugs cause release of dopamine from VTA. It is necessary to show how dopamine’s action on spines of MSNs that synapse with excitatory inputs result in reduced firing rate of MSNs. | Due to the reasons mentioned in the above row, as postsynaptic potentials reduce firing rate also reduces (Vadakkan, 2021). |
| 145 | Dopamine reduces excitability of MSNs in NAc in vitro (O'Donnell & Grace, 1996). | It is necessary to show how the action of dopamine on the spines of MSNs that synapse with excitatory inputs results in inhibition of MSNs. | Dopamine augments IPL formation between two spines - one synapsing with an excitatory input & another synapsing with an inhibitory input. Hence, the net effect results in inhibition of the excitatory output (Vadakkan, 2021). |
| 146 | Synchronization of membrane potential states in a population of NAc neurons (Goto & O'Donnell, 2001). | It is necessary to show how membrane potential states in a population of NAc neurons get synchronized. It is necessary to provide an explanation how spines of the MSNs in NAc that receive excitatory input & spines that receive inhibitory inputs together exhibit synchronization of membrane potentials. | Inhibitory inter-neurons that are electrically connected with each other through gap junctions are known to make oscillations. The islets of inter-LINKed spines are also expected to contribute vector components towards generating oscillating extracellular potentials. Based on the semblance hypothesis, these oscillations are responsible for binding units of inner sensations. |
| 147 | Similar to LTP, LTD in the hippocampal synaptic areas is implicated in different types of learning (Kemp & Manahan-Vaughan, 2004; Dong et al., 2013; Dong et al., 2015). | It is necessary to explain the similarity between correlation between LTP induction & learning with that of the LTD induction & learning. | Based on the semblance hypothesis, associating two sensory stimuli in learning requires formation of IPLs. Since spines that receive inhibitory inputs are present on the MSNs, IPLs formed between spines receiving excitatory & inhibitory inputs can exhibit LTD. Since IPL formation is the basis of learning, irrespective of the strength of net postsynaptic potentials, semblance formed on the inter-LINKed spines generates inner sensation of memory (Vadakkan, 2021). |
| 148 | Impaired ability to induce LTD at the input synaptic region of MSNs of NAc in “addicted” state (Kasanetz et al., 2010). | It is necessary to explain how the initial use of drugs leads to LTD. Then it is necessary to show how "addicted" state leads to an impaired ability to induce LTD. | Initially, IPL formation between spines synapsing to excitatory and inhibitory inputs leads to depression of postsynaptic potentials showing LTD. Later, when more spines are lost in the "addicted state", more amount of drug will become necessary even to generate normal conformation of semblance at those location to maintain internal sensation of normal comfort (Vadakkan, 2021). |
| 149 | Inner sensation of pleasure is correlated with specific NAc properties, which is reflected by the ability to induce LTD at the input regions of MSNs of NAc. | It is necessary to provide interconnected explanations for 1) ability to induce robust LTD in NAc from naïve animals, 2) impaired ability to induce LTD in “addicted” state, 3) attenuation of postsynaptic potentials by cocaine, & 4) reduced firing of MSNs in response to cocaine/dopamine. | Inner sensation is explained in terms of the conformation of semblances generated at the inter-LINKed spines. At the IPLs between a spine that receive excitatory input & another receiving inhibitory input, the inner sensation is expected to be that of pleasure (Vadakkan, 2021). |
| 150 | Controversial views (pdf) expressed by Camillo Golgi against Ramón y Cajal's interpretations of results obtained from modified Golgi staining protocols. | The chemistry behind the modification of original Golgi staining protocol must be able to provide reasons for this controversy. Such an explanation is expected to become possible when we understand the operational mechanism of the brain. | Golgi used one oxidizing agent to pre-treat brain tissue before the staining reaction, whereas Cajal used an additional oxidizing agent for the same step. It shows that increasing oxidation state restricts the spread of Golgi chemical reaction between neurons by blocking certain channels between them. Since blood oxygenation level dependent (BOLD) signals occur in specific brain regions peaking around 4 seconds after learning (Monti et al., 2010; Murayama et al., 2010) & since most working memories are lost with time, it is possible to infer that oxygen reverses learning-induced channels. Since this gate should not allow mixing of cytoplasmic contents between neurons, it matches with the properties of IPLs with inter-membrane hemifusion as their structural upper bound (Vadakkan, 2022). |
| 151 | Formation of new neurons in the hippocampus | The operational mechanism should be able to explain functional advantage provided by insertion of new neurons. | Both input and output connections of new neurons will continuously alter the existing circuitry. Repetition of same associative learning will create new IPLs at higher neuronal orders increasing number of sparse storage mechanisms (Vadakkan, 2011). Since every associative learning event has a certain subset of commoon components, each learning continues to generate more IPLs for a given association. |
| 152 | A combination of both loss of spines and formation of new spines during learning (Frank et al., 2018). | There must be a mechanism that leads to loss of spines during learning. Formation of new spines should accomplish something new that can facilitate further learning. | The structural upper bound of permitted inter-membrane interaction for IPL formation is inter-membrane hemifusion, which is an intermediate stage of membrane fusion. Several factors can overcome the checkpoint needed to arrest the changes at the stage of hemifusion, leading to fusion. Neuronal cells will respond to this by removing those fused spines, which can explain spine loss during learning. |
| 153 | Permanent changes in the motor response to a single stimulus occur due to repeated exposure to that stimulus & are called non-associative form of learning. | It is necessary to provide a mechanism how permanent changes in the motor responses occur due to repeated exposures. | Any stimulus from the environment is a high-dimensional sensory input consisting of many newly associated components in it that can lead to formation of IPLs. During the time in between repeated exposures to this stimulus, it has to propagate through newly incorporated new neurons in the circuit. This leads to the formation of new IPLs in response to the same stimulus at the higher neuronal orders. Repetition of learning stabilizes these IPLs resulting in permanent changes in motor response to a single stimulus. |
| 154 | Prevalence of dendritic spikes on the dendrites of place cells (CA1 neurons) in behaving mice predicts spatial precision (Sheffield & Dombeck, 2015). | It is necessary to explain how spatial inputs lead to dendritic spikes. | Large EPSPs in a dendritic spike indicate arrival of addition of several EPSPs on the dendrite. Arrival of several EPSPs via IPLs to reach an islet of inter-LINKed spine is feasible. Spatial stimuli reaching an islet of inter-LINKed spines leading to summation of EPSPs in the islet & generates a dendritic spike. |
| 155 | Both consolidation for long-term memory (Flexner et al., 1967; Davis & Squire, 1984) and late-phase LTP in in vitro slices (Krug et al., 1984; Huang et al., 1996) are protein synthesis dependent. However, after protein synthesis inhibitor exposure to the consolidated memory engram cells, direct optogenetic activation of these cells retained the ability to retrieve specific memory (Ryan et al., 2015). | It is necessary to show the presence of a protein synthesis independent functional engram cell-specific connectivity mechanism to explain how memories are retained. It is necessary to show that a non-protein mechanism is responsible for long-term maintenance of memories. | Based on the semblance hypothesis, during learning, an IPL is generated between the spines of different output engram neurons. The results of the experiment (Ryan et al.,2015) show that IPLs are not made of proteins. Based on the semblance hypothesis, learning generates IPLs by inter-spine membrane interactions leading up to the stage of inter-membrane hemifusion. |
| 156 | Compared to the set of neurons that fire when exposed to one of the associatively learned stimuli before learning, additional neurons are fired when an animal is exposed to the same stimulus after learning. This is documented in the lateral amygdala in fear conditioning experiments (Schoenbaum et al., 1998; Tye et al., 2008). | New paths orginate during learning. It is ncessary to provide a location and mechanism for these paths. | Based on the semblance hypothesis, IPLs are formed during learning. After learning, one of the associatively learned stimulus will propagate through the IPLs and provide addtional potentials to some of the neurons that will allow them to cross the threshold for firing. This explains how additional neurons fire when the animal is exposed to the same stimulus after learning. |
| 157 | Fear learning generates local connectivity between LA neurons (Abatis et al., 2024). Electrophysiological studies show that stimulation of one LA neuron causes arrival of depolarization to a minor fraction of LA neurons in the immediated neigbhorhood. | After cued fear conditining (CFC), many LA neurons achieve functional connectivity between them. It is necessary to explain the route through which depolarization can occur from one LA neuron to the next. It should be a learning induced connectivity mechanism that occurs in millisecond timescales. Hence, it must be a non-synaptic mechanism. | Based on the semblance hypothesis, inter-neuronal and intra-neuronal inter-branch inter-spine interactions (called IPLs) constitute the engram changes during associative learning. When more than two spines are LINKed in this manner, it leads to the formation of islets of inter-LINKed spines (IILSs). Artificial stimulation one LA neuron will cause back propagation of potentials along its dendritic tree branches towards the spines that can propagate to the rest of the inter-LINKed spines within different IILSs & propagate towards the latter's postsynaptic LA neuronal soma causing some of these LA neurons to fire. |
The following are findings related to long-term potentiation (LTP), an electro-physiological finding that shows numerous correlations with the ability to learn. But a few of its features (e.g. high intensity stimulation, time scales of seconds instead of milliseconds, & sudden drop in peak-potentiated effect (short-term potentiation)) needed explanations to substantiate causation for the ability to learn & memorize. Amongst all, LTP remains the single most finding that provided maximum number of constraints to test the semblance hypothesis. Note: To reach interconnected explanations, sometimes it was necessary to re-interpret the findings from different laboratories and provide alternate explanations different from those of the authors (Please note: I regard this inevitability as an unpleasant, but crucial step in this process). | |||
| 158 | Experimental finding of long-term potentiation (LTP) has shown several correlations with behavioral motor actions that are surrogate markers of memory retrieval. | It must be possible to explain how cellular changes during LTP induction and learning are correlated & how this is related to the ability to retrieve memory. | High energy applied during LTP stimulation leads to the formation of large number of non-specific IPLs responsible for LTP. 1) More the abutted spines at locations of convergence of sensory stimuli, more the ability to learn, and 2) Application of high energy leads to increased formation of non-specific IPLs responsible for LTP (Vadakkan, 2019). |
| 159 | Learning takes place in milliseconds, whereas LTP induction takes at least 20 to 30 seconds (Gustafsson & Wigström), 1990), and even more than a minute (Escobar et al., 2007). | Cellular changes during learning are expected to get scaled-up during LTP induction in a time-dependent manner. Need to explain a time-consuming cellular change for this. | High energy delivered by LTP stimulation protocols leads to spine expansion & formation of large number of non-specific IPLs. This opens several channels through which potentials arrive at the recording electrode, showing a potentiated effect. Long duration of persistence of IPLs explains the long-term nature of LTP (Vadakkan, 2019). |
| 160 | Blockers of membrane fusion blocks LTP (Lledo et al., 1998). | Need to explain the cellular location where they act & explain how they block LTP. | Huge energy applied during LTP stimulation is expected to cause inter-neuronal inter-spine fusion. When blockers of membrane fusion are used, this will not take place, preventing LTP induction (Vadakkan, 2019). |
| 161 | Loss of spines during LTP induction (Yuste & Bonhoeffer, 2001). | A mechanistic explanation is needed for loss of spines when high energy is applied during LTP stimulation. | High energy applied during LTP induction leads to formation of large number of non-specific IPLs and IPL fusion. IPL fusion leads to triggering mechanisms to stop cytoplasmic content mixing. Removing spines by the neuron will prevent further damage to that neuron. |
| 162 | CA2 region of hippocampus is resistant to LTP induction. Removal of peri-neural net proteins from this region allows LTP induction. | The cellular mechanism responsible for LTP induction must be able to explain how peri-neural net proteins block LTP. This can provide hints for a structural explanation of LTP. | Based on semblance hypothesis, anything that prevents formation of IPLs blocks induction of LTP. Perineural net proteins around the spine head region (Dansie & Ethell, 2011) provides an explanation (Vadakkan, 2019). |
| 163 | Hippocampus having convergence of all the sensory inputs has shown maximum strength of LTP. It is possible to induce LTP of different strengths at different locations where inputs converge. | It should be possible to provide an explanation why LTP strength is high at locations where more inputs converge. | Based on the semblance hypothesis, more IPLs are expected to form at locations where more inputs converge (Vadakkan, 2010; 2013). At locations where more IPLs are present, it is possible to generate proportionately more non-specific IPLs responsible for LTP induction (Vadakkan, 2019). |
| 164 | LTP is associated with enlargement of spine heads (Lang et al., 2004). LTP on single spines show spine enlargement (Matsuzaki et al., 2004). | It is necessary to an explanation how enlargement of spines leads to LTP that can explain all the features of LTP and its correlation with the ability to learn in an interconnected manner. | Spine enlargement favors IPL formation. In the presence of high energy of LTP stimulation, large number of non-specific IPLs are formed, which will allow a regular stimulus to propagate through multiple channels to summate and arrive at the recording electrode (Vadakkan, 2019). |
| 165 | LTP, kindling, and seizures are strongly interrelated. | A structure-function-pathology relationship exists that must provide interconnecting explanations. | Explained as formation of non-specific IPLs in response to high energy stimuli and pathological conditions causing membrane instability, increased neuronal excitability and ionic changes in terms of alterations of IPLs proposed by the semblance hypothesis (Vadakkan, 2019). |
| 166 | LTP induction is associated with AMPA receptor sub-unit redistribution into the cytoplasm of the spine head region (Shi et al., 1999; Passafaro et al., 2001). | To provide a mechanistic explanation for inter-neuronal inter-spine interaction during IPL formation, it is necessary to show that vesicles containing AMPA receptors move laterally within the spines. | It was shown that exocytosis of vesicles containing AMPA receptor sub-units is associated with their lateral movement during LTP (Park et al., 2006). |
| 167 | LTP stimulation needs high energy (either in the form of high frequency or high intensity stimulation). | Need an explanation how this high energy is used to make cellular changes to generate LTP. Correlation between the ability to learn and the strength of LTP that can be induced necessitates an explanation for LTP as a scaled-up change that occurs during learning. | It was possible to explain LTP as a scaled up change occurring during learning by the formation of large number of non-specific IPLs between the stimulating and recording electrodes (Vadakkan, 2019). This requires high energy since hydration layer between the spine membranes is expected to need high energy for its removal for the formation of an IPL. This can be inferred from experiments using artificial membranes (Rand & Parsegian, 1984; Martens & McMahon, 2008; Harrison, 2015). |
| 168 | LTP requires a specific postsynaptic fusion protein SNARE (Jurado et al., 2013). | It is necessary to provide a suitable property of this protein in terms of its ability to elicit LTP. | SNARE protein has the ability to bring together repulsive membranes & overcome energy barriers related to curvature deformations during hemifusion (Martens & McMahon, 2008; Olkers et al., 2016). SNARE protein generates force for pulling the abutted membranes together as tightly as possible (Hernandez et al., 2012). t-SNARE protein syntaxin generates local membrane traffic in spines and directs membrane fusion (Kennedy et al., 2010). |
| 169 | It was possible to induce LTP after blocking NMDA receptors by increasing postsynaptic Ca2+ via voltage-sensitive calcium channels. | A mechanistic explanation is necessary to provide an inter-connected explanation how it was possible to induce LTP by stimulating postsynaptic terminals (spines) alone. | Formation of large number of inter-spine LINKs during LTP induction derived by the semblance hypothesis provides a suitable explanation (Vadakkan, 2019). |
| 170 | Blockade of exocytosis of AMPA receptor containing vesicle cause severe reduction in LTP (Kennedy et al., 2010; Ahmad et al., 2012). | To provide an inter-connected explanation, it is necessary to have a logical explanation how exocytosis of AMPA receptor containing vesicles is associated with IPL formation. | Tetanic stimuli that induce LTP lead to both AMPA receptor insertion & generalized recycling of membrane segments from endosomes that contain GluR1 AMPA receptor sub-units (Park et al., 2006). Vesicle membrane segments contribute to reorganize the lateral spine membrane that can lead to the formation of IPLs. |
| 171 | Surface expression of any AMPA receptor subunit is sufficient for inducing LTP (Granger et al., 2013). | To provide an inter-connected explanation, it is necessary to have a logical explanation how surface expression of AMPA receptors subunits is associated with IPL formation. | Tetanic stimuli that induce LTP lead to both AMPA receptor insertion & generalized recycling of membrane segments from endosomes that contain GluR1 AMPA receptor sub-units (Park et al., 2006). Vesicle membrane segments contribute to reorganize the lateral spine membranes that can lead to the formation of IPLs. |
| 172 | Potentials from the recording electrode following LTP stimulation does not show a ramp-like increase before reaching its peak. | Sudden rise to peak-potentiated effect following a delay needs a suitable explanation. | Initial formation of small islets of inter-LINKed spines that finally coalesce to form a large islet will lead to a sudden occurrence of a mega-summation of several small summated potentials (Vadakkan, 2019). |
| 173 | Persistence of potentiated effect for long duration, which led to the name LTP. | Need a matching mechanistic explanation for the long duration of potentiated effect once LTP is induced. | High energy of LTP stimulation is likely to cause membrane fusion at regions of IPLs. It is difficult for these multiple regions to reverse back. This contrasts with the few nanometers at which IPLs are expected to form during natural learning. Hence, in the latter case, most of them reverse back. |
| 174 | LTP induction is associated with lateral movement of vesicles containing AMPA receptor sub-units (Makino & Malinow, 2009). However, high energy stimulation alone can surpass the above requirement (Herring & Nicoll, 2016). | It is necessary to provide a suitable explanation for a) what is the function of the vesicles? b) how can application of high energy overcome this requirement? (Note: This is a unique condition. Only when we reach the correct solution, it will become possible to arrive at a suitable explanation.) | Lateral movement of vesicles can contribute membrane segments at the lateral regions of spines (Park et al., 2006) and facilitate IPL formation. IPL formation requires overcoming a high energy barrier (Rand & Parsegian,1984; Martens & McMahon, 2008; Harrison, 2015). High energy stimulation alone can achieve inter-cellular fusion (for e.g. in hybridoma production (Zimmermann & Vienken, 1982). |
| 175 | Sudden drop in peak-potentiated effect, called short-term potentiation (STP) (Racine et al., 1983). | It is necessary to explain what reverses back immediately after a peak potentiation is reached. At least one factor is getting reversed back very quickly. | Hydration exclusion from the space between the membranes is a high energy requiring process and hemifusion state is highly reversible (Chernomordik & Kozlov, 2008). Hence, immediately following LTP induction, several IPLs tend to reverse back responsible for sudden drop in potentiated effect (Vadakkan, 2019). |
| 176 | Synapses and synaptic transmission are necessary for LTP induction when stimulating from the pre-synaptic side. | An operational mechanism that can operate concurrent with synaptic transmission is necessary to explain LTP. | Formation of large number of non-specific IPLs is associated with normal operation of the synapses and are necessary for IPL formation during learning (Vadakkan, 2019). |
| 177 | Non-Hebbian plasticity changes are observed during LTP induction (Schuman & Madison, 1994; Bonhoeffer et al., 1989; Kossel et al., 1990; Engert & Bonhoefferet, 1997). | It is necessary to explain why synapses that are not stimulated also get involved during LTP induction. | When a group of spines expands, it will compress the extracellular matrix around them and the abutted spines across them that are not stimulated by LTP. This can lead to formation of IPLs with those spines and explain the finding of non-Hebbian plasticity (Vadakkan, 2019). |
| 178 | Field EPSP amplitude is increased (200%) more than EPSP amplitude (60%) recorded from a single CA1 neuron after LTP induction (Abbas et al., 2015; Holmes & Grover, 2006). | An explanation is necessary for the difference in the amplitudes of EPSPs in these two cases. | Since the recording electrode is in the ECM in field recording, it reflects arrival of large number of potentials through a large number of IPLs around it. when one CA1 neuron is recorded, potentials can arrive through the IPLs generated by its spines (Vadakkan, 2019). |
| 179 | Property of cooperativity in LTP induction. Only a fixed fraction of stimulated presynaptic terminals directly synapse with the CA1 neuron from which recording is carried out. Unless certain cooperative property is present, this will not occur. | Need an explanation for a cooperative function that allows potentiated effect to be recorded from the recording electrode. Since blocking NMDA receptors using Mg2+ alone could not prevent this (Kauer et al., 1988) other routes are involved. | Based on the semblance hypothesis, formation of large number of non-specific IPLs between the lateral portions of abutted spines provide routes through which a regular stimulus can reach the recording electrode after LTP induction. This can be viewed as a cooperative function (Vadakkan, 2019). |
| 180 | Property of associativity in LTP induction. It is potentiation of a weak input if it is activated along with a strong tetanus at a separate location, but as a converging input (Levy & steward, 1979). | It is necessary to explain what is connected during this procedure that will later allow the weak input to bring potentiated effect at the recording electrode. | The convergent nature of the inputs allows separate islets of inter-LINKed spines from the weak and strong stimuli to become connected through the formation of IPLs between them. This will allow both islets to get connected with that of the recording CA1 neuron. Hence, a weak input will be able to propagate through multiple channels and arrive at the recording electrode in a summated form (Vadakkan, 2019). |
181 | Property of input specificity in LTP induction (Andersen et al., 1977). A strong stimulus can induce LTP, whereas a weak stimulus will not. Weak inputs that are active only at the arrival of strong stimulus share the potentiation induced by the strong stimulus. | A mechanistic explanation for a process that requires simultaneity of stimulation of both the weak and strong stimuli is needed. | Simultaneous application of the strong and weak stimuli at optimal distances will be necessary to generate IPLs between the separate islets of inter-LINKed spines that these stimuli generate if they are stimulated independently. Note that IPL formation requires removal of hydration layer between abutted spines, which is a high energy requiring process (Rand and Parsegian, 1984; Martens and McMahon, 2008; Harrison, 2015). |
| 182 | Learning can be occluded after LTP induction and vice versa (Moser et al., 1998; Whitlock et al., 2006). | It is necessary to provide a mechanistic explanation for a shared mechanism following LTP induction and learning. | LTP induction leads to the formation of a large number of IPLs in a localized area. Hence, learning following LTP induction will not to be able to generate new IPLs at that location. As the cue stimulus propagates (during memory retrieval) through the large number of non-specific IPLs formed by LTP induction, it generates a large number of non-specific semblances. This explains reduced memory observed in those experiments. |
| 183 | Dopamine augments both (motivation-promoted) learning (Bromberg-Martin et al., 2010) and LTP (Otmakhova & Lisman, 1996). | It is necessary to show that both learning and LTP have a shared common mechanism and dopamine operates to augment both learning and LTP by the same mechanism. | Augmentation of both motivation-enhanced learning and LTP can be explained in terms of enlargement of spines caused by dopamine (Yagishita et al., 2014) that can augment IPL formation. |
| 184 | Most learning changes are short-lasting, capable of generating only working memories. But LTP is long lasting (hours). | It is necessary to find a mechanistic explanation for rapidly reversing learning changes and why the scaled-up learning change in LTP is resistant to reverse back. | Most IPLs are reversible since their formation during learning by exclusion of hydration layer between spine membranes is a high energy requiring process. In contrast, LTP stimulation uses very high energy during which physiological IPL changes are expected to progress to membrane fusion that offer resistance to reversal. |
| 185 | Inhibitors of NMDA receptors do not reverse late LTP maintenance (Day et al., 2003). | Need to explain a change that is maintained during late stage of LTP, which cannot be revered by inhibiting NMDA receptors. | Since IPL changes between lateral margins of spines that belong to different neurons already occurred during LTP induction, NMDA receptor inhibition will have no role in LTP maintenance. Moreover, IPL fusion changes produced by LTP induction are highly resistant to getting reversed back. |
| 186 | LTP decay and memory loss are mediated by AMPA receptor endocytosis (Dong et al., 2015). | It is necessary to explain how AMPA receptor endocytosis can reverse LTP induced changes. | Endocytosis of AMPAR subunits that uses membrane segments from the lateral spine region is expected to reduce spine size & lead to reversal of the IPLs. This can explain LTP decay. |
| 187 | Autophagy results in memory destabilization and erasure of auditory fear memory associated with AMPAR endocytosis (Shehata et al., 2018). | It is necessary to provide a mecahnistic explanation how autophagy leads to loss of memory. | GluA2-dependent AMPAR endocytosis is a prerequisite for autophagy to affect memory destabilization (Shehata et al., 2018). Endocytosis removes membrane segments from the spine head region causing decrease in spine size and reversal of existing IPLs. This can explain loss of memory. |
| 188 | Contextual fear conditioning recruits newly synthesized GluA1-containing AMPAR into the spines of the hippocampal memory-ensemble cells in a learning-specific manner (Matsuo et al., 2008). | A mechanistic explanation of how GluA1 subunit insertion into the spines facilitates learning. | GluA1- AMPARs are located nearly 25nm from the synaptic margins ( Jacob & Weinberg, 2015). This matches with the lateral spine head region at which IPLs are expected to form. Bringing these subunits in vesicles to the membranes will lead to insertion of some of the vesicle membrane segments to the lateral spine head region facilitating IPL formation. |
| 189 | GluA1 subunits have a main role in directing AMPA receptors to the surface, which is correlated with LTP and fear memory (Rumpel et al., 2005). | A mechanistic explanation how GluA1 subunit insertion into the spines facilitates both LTP & learning (& also memory). | GluA1- AMPARs are located nearly 25nm from the synaptic margins ( Jacob & Weinberg, 2015) that are lateral spine head regions at which IPLs are expected to form. Since these subunits are brought to the surface by vesicles, it promotes incorporation of membrane segments to this region & facilitate IPL formation. Based on the semblance hypothesis, the latter is the basis for both learning and LTP induction. |
| 190 | Increase in the size of mEPSP (miniature EPSP) after LTP induction (Manabe et al., 1992). | mEPSP is thought to be influenced by an increase in the number or function of AMPA receptors (Malenka & Nicoll, 1999). It is necessary to show the source for increased AMPA current. | Recording electrode is electrically connected with neighboring spines through IPLs. This allows arrival of current from neighboring spines which mostly belonging to different neurons, which mostly belonging to different neurons, showing increase in the size of mEPSP. |
| 191 | Several delayed changes that occur following LTP induction have shown correlations with learning & memory (e.g. CaMKII phosphorylating AMPA receptor subunits (Lisman et al., 2012). | It is necessary to explain how delayed changes following LTP are correlated with animals' ability to learn. | A downstream cascade of biochemical changes within the neurons can be viewed as steps to prepare the spines both to maintain the already formed IPLs and to generate new IPLs during subsequent learning events. |
| 192 | LTP induction is known to modify specific sets of place cells. Specifically, LTP in hippocampal pathways abolish existing place fields & create new place fields (Dragoi et al., 2003). | It is necessary to provide a mechanistic explanation of how changes brought about by LTP induction affect firing of place cells (CA1 neurons in the hippocampus). | Formation of a large number of new IPLs induced by LTP can lead to the spread of potentials through these IPLs and result in firing of additional postsynaptic CA1 neuron (Vadakkan, 2016). |
| 193 | Small spines were found to be preferential sites for cellular changes causing LTP induction (Matsuzaki et al., 2004). | It is necessary to explain what particular feature of small spines in contrast to large spines lead to LTP induction. | Large spines are likely to have already formed IPLs with their abutted spines. Hence, they are unlikely to form additional IPLs during LTP induction. In contrast, small spines have the ability to expand in response to LTP stimulation and form several new IPLs responsible for the potentiated effect. |
| 194 | Associative LTP can be induced more easily in new granule neurons (Schmidt-Hieberet al., 2004). | It was explained in terms of a reduction in the threshold for inducing LTP. It means that new neurons are devoid of certain channels. It is necessary to show that LTP is able to introduce these channels on them. | This can be explained in terms of the formation of several IPLs between the spines of new granule neurons (compared to the old ones) with the spines on the pre-existing islets of inter-LINKed spines of existing granule neurons (Vadakkan, 2016). |
| 195 | Fear conditioning induces associative LTP in the amygdala (Rogan et al., 2007; McKernan & Schinnick-Gallagher, 2007). | Provide an explanation how learning causes a potentiated effect at the MGN-LA synaptic area. In other words, show how fear conditioning alters auditory CS-evoked responses in LA in the same way as LTP induction. | Based on the semblance hypothesis, LTP can be explained by the formation of a large number of IPLs between a set of spines through which high energy current flows (Vadakkan, 2019). Here, spines of both different LA neurons & different branches of the same LA neuron (since the output function is the same - foot shock) undergo form IPLs. |
| 196 | Dendritic spikes mediate a stronger form of LTP that requires spatial proximity of associated synaptic inputs (Hardie & Spruston, 2009). Dendritic spike is a mechanism for co-operative LTP (Golding et al., 2002). Dendritic spikes are necessary for single-burst LTP (Remy & Spruston, 2007). | One of the requirements of LTP is postsynaptic depolarization that can result from large EPSPs that trigger dendritic spikes (Hardie & Spruston, 2009). Dendritic spikes generate a stronger form of LTP than alternative methods (Hardie & Spruston, 2009). In these contexts, it is necessary to show the source from which potentials arrive to generate large EPSPs. | Simultaneous arrival of input signals to two or more synapses whose spines (postsynaptic terminals) are inter-LINKed will lead to summation of EPSPs resulting in large EPSPs recorded from any single postsynaptic terminal (Vadakkan, 2016). |
| 197 | A modified fear conditioning study using two associative learning events with one common stimulus where inputs are synapsing on to one type of output neuron (Lateral amygdala (LA) neurons (Abdou et al., 2018). Stimulation of autophagy in LA neurons following one learning erased its memory. Optical LTP allowed anisomycin treated mice to completely recover amnesia. | It is necessary to explain how stimulation of autophagy within the postsynaptic LA neurons erases memory of a specific associative learning through inputs arriving through axonal terminals that synapse on to the LA neurons. The mechanism of storage is not reversible by protein synthesis inhibitor. Hence, a non-protein involved mechanism needs to be explained. | Based on the semblance hypothesis, during learning an IPL is generated between the spines of different LA neurons (Fig.19 in FAQ). When the motor output function is the same, then IPL can be formed between spines that belong to different branches of the same LA neuron (Fig.2 of the Home page). Stimulation of autophagy in LA neurons will cause increased endocytosis, removing membrane segments from the lateral spine head region. This will reduce the size of the spines sufficiently to reverse the learning generated new IPLs. After introduction of autophagy there will be recycling of membrane segments back to the spine heads to a certain extent to cause many spines to get abutted back. Optical LTP provides huge energy to the input terminals sufficient to generate IPLs in abutted spines. It also leads to spine expansion favoring IPL formation. |
| 198 | In the above study (Abdou et al., 2018) using modified fear conditioning experiments, optical LTD caused loss of a memory of a specific learning. Optogenetic stimulation of axonal terminals of AC & MGN neurons did not cause freezing in LTD induced animals. | Optical LTD does erases specific associative learning change. This should be such a change that cannot be reinstated by optical stimulation of the axonal terminals of AC & MGN neurons. | Modest depolarization used in LTD cause AMPAR endocytosis (Malenka,1994). Endocytosis removes membrane segments from the lateral spine head regions causing reversal of formed IPLs. This leads to loss of memory of a specific event. Ordinary stimulation of input terminals will not be able to cause memory retrieval due to the absence of IPLs since a) LTD is usually long lasting keeping the reversed IPLs in baseline non-LINKed states, & b) ordinary optogenetic stimulation has no sufficient energy for spine expansion to the level necessary for IPL formation. |
IPL: Inter-postsynaptic functional LINK; ECM: Extracellular matrix; NAc: Nucleus Accumbens; MSNs: Medium spiny neurons; FLE: Flash lag effect. Foot note 1: If we provide a set of colors and picture against each color and ask people to learn the association in one second, most people will be able to learn two or more associations during this period. This means that associative learning can take place in milliseconds. What type of a change can occur in less than one second? | |||
Table 2. Features of the system from different levels that need to be explained independently and by an inter-connectable manner using a derived solution. In other words, these constraints permit us to ask the question, "What should be the foundational operation that can satisfy all these constraints?" Even though several possibilities can be excluded (for example, biochemical reactions that occur slower than the physiological timescales of milliseconds during which learning takes place (using which memory needs to be retrieved) that can help exclude candidacy of several biochemical intermediates such as storage molecules), a systematic approach is necessary to find the correct solution. Please note that the listed findings are so disparate, and the constraints offered by them are so strong that there can only be one unique solution. In other words, this unique solution for the system should be compatible with all the previous experimental observations. Constraints provided by each of the observations help to narrow down the possibilities to arrive at the solution. A subset of the above list of observations can be used to derive the solution and the rest of the features can be used to verify whether the derived solution is correct or not. Please note that we cannot arrive at a solution using a few mathematical equations. Once we have a unitary solution, we need to search for the principle of their integration where mathematics is expected to have a role. | |||
A complete understanding of the operational mechanism leading to the first-person properties will only be achieved by carrying out the gold standard test of its replication in engineered systems. Even though replication of motor activities (such as speech) to produce behaviorally equivalent machines may seem adequate, the work will not be complete until first-person properties of the mind are understood. Engineering challenges with this approach include devising methods to convert the first-person accessible internal sensations to appropriate readouts. Experiments to translate theoretically feasible mechanisms of its formation both by computational and engineering methods are required. Feasibility to explain various brain functions both from first-person and third-person perspectives qualifies it as a testable hypothesis. The present work resulted from curiosity to understand the order behind the seemingly complex brain functions. In this attempt, I have used some freedom to seek a new basic principle in order to put the pieces of the puzzle together. This work wouldn't have become possible without a large amount of research work painstakingly carried out by many researchers over several years. Even though the present hypothesis is compatible with experimental data from different levels, it must be considered unproven until we complete its verification.
Video presentations
1. A testable hypothesis of brain functions
2. How to study inner sensations? Examples from mathematics
4. List of third-person findings and the derivation of the solution for the nervous system
6. Induction of units of inner sensation
8. Potential mechanism for neurodegeneration
9. LTP: An explanation by semblance hypothesis
10. A framework for consciousness
11. A potential mechanism of anaesthetic agents
12. Conditioned learning explained using a video
The challenge: "What I cannot create (replicate), I do not understand" – Richard Feynman. The rigor with which we should try to solve the nervous system must be with an intention to replicate its mechanism in an engineered system. Everything else will follow.
The reality: We are being challenged to find a scientific method to study the unique function of the nervous system - how different inner sensations are being generated in the brain concurrent with different third person observed findings. We cannot directly study them using biological systems. But we can use all the observations to try to solve the system theoretically, followed by verifying its predictions.
The optimism: “What are the real conditions that the solution must satisfy?” If we can get that right, then we can try and figure out what the solution is" – Murray Gell–Mann
The expectation: We are likely able to solve the mechanism of the nervous system functions in multiple steps. First, using constraints offered by all the observations, it is necessary to derive a solution (most likely a first principle) that can unify those observations. This can be followed by further verification by triangulation methods and examining comparable circuitry in different animal species. Once identified and verified, we can expect to replicate the mechanism in engineered systems.
The advice: "Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less." Marie Curie
The hope: We will give everything we can. Together we will explore it!