Method 2:

1. Let us imagine that two sensory stimuli, namely stimulus 1 and stimulus 2 undergo associative learning. At a later time when stimulus 1 (cue stimulus) arrives, it is expected to induce the internal sensation of memory of the second stimulus 2. For this to happen, it is necessary that some changes should occur at the locations of convergence of stimulus 1 and stimulus 2 at the time of learning. (Note that hippocampus known as an area of the brain associated with learning and memory receives inputs from all the different sensory modalities after 3 to 5 orders of neurons from the sensory receptor level). Now, let us examine what changes should be occurring at the location of convergence between two sensory stimuli at the time of learning. What should be the critical change occurring during learning between the synapses activated by stimulus 1 and stimulus 2? Between what locations of the synapses that these changes should take place? The interaction should take place between those sub-synaptic locations that will enable retrieval of memory of the second stimulus when the first stimulus arrives and vice versa. In this regard, interaction taking place between the postsynaptic terminals of stimulus 1 and stimulus 2 is suitable. (This was arrived by examining different sub-synaptic areas to find properties that endow them to generate units of internal sensation by trial-and-error method. This is described in section II). The interaction between the postsynaptic terminals was named as inter-postsynaptic functional LINK (Fig.2). The term "functional" is used to indicate that the formation of the LINK is a function of the activities arriving at the postsynaptic terminals activated by stimulus 1 and stimulus 2 during associative learning. At the time of memory retrieval, reactivation of the inter-postsynaptic functional LINK is a function of arrival of activity, from either stimulus, at one of their corresponding postsynaptic terminals. The term LINK is written in capital letters to indicate that it is the key element of the hypothesis.

Different types of inter-postsynaptic functional LINKs formed during associative learning

The inter-postsynaptic functional LINKs formed during associative learning can be of different types:

a. Those that are formed by removal of water of hydration between the postsynaptic terminals, which will allow abutting of the membranes. This requires very high energy and will lead to a rapid reversal of the functional LINK. This can provide sufficient learning-induced changes that can last only for a short period of time responsible for working memory.

b. Strong interaction between the postsynaptic terminals can lead to reversible partial hemifusion between the postsynaptic terminals. This can explain the retention of learning-induced mechanism for more time.

c. Further interaction can lead to reversible complete hemifusion between the postsynaptic terminals that will enable its retention for much more time.

d. If the complete hemifusion can be retained for some time, it is likely that the stabilizing mechanisms can result in long-term maintenance of this.

Inter-LINKing spines are expected to belong to different neurons

At this juncture, it is paramount to understand the origin of the spines that are getting inter-LINKed. According to the studies based on synaptic plasticity thesis, either the spines of a single neuron cluster together at dendritic branches or the synapses at the spines to a single neuron make interactions (Govindarajan et al., 2006; Stuart and Spruston, 2015; Bloss et al., 2018), which are thought to be responsible for the integration of the inputs onto a single neuron.

In contrast to the above hypotheses, the present work approached the problem differently. The inter-LINK formed during associative learning is expected to generate first-person internal sensation at physiological timescales at the time of memory retrieval. Along with this, it is also expected to generate motor activity corresponding to the retrieved memory. This leads to the question, “To which neuron/neurons should the inter-LINKing spines belong, so that they can maintain specific outputs associated with each of the associatively learned sensory inputs?” The immediate answer is that they should belong to different neurons (Fig.3). Moreover, since the mean inter-spine distance is even larger than the mean spine diameter (Konur et al., 2003), the inter-LINKing postsynaptic terminals should belong to different neurons. This is expected to be the general rule. There could be exceptions; for example, when axonal terminals of newly formed granule neurons form synapses with a fixed number of dendritic spines of a CA3 neuron (Fig.4).

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Inter-postsynaptic functional LINKs can be viewed as biological equivalents of K-lines

K-lines were proposed as the key operational change occurring at the time of associative learning (Minsky, 1980) that is expected to provide the necessary function during memory retrieval. This proposal came as a result of attempts to understand natural intelligence that can be translated into engineered systems.

Stage II

In the next stage, the basic units of semblances occurring at the functionally inter-LINKed postsynaptic terminal are derived. Let us examine the effect of the arrival of the stimulus during memory retrieval. Let stimulus 1 arrive as a cue stimulus (Fig.5). It arrives at the synapse A-B. Postsynaptic potential at B propagates through the inter-postsynaptic functional LINKs and reach towards postsynaptic terminal D. As discussed in Method 1, the arrival of the stimulus 1 (cue stimulus) happens only infrequently. Therefore, when second postsynaptic terminal D is depolarized incidentally in the absence of the arrival of an action potential at its corresponding presynaptic terminal C, then postsynaptic terminal D is expected to get the cellular hallucination that it is receiving sensory inputs through its presynaptic terminal C, resulting in “semblance". This can induce units of virtual inner sensation of memories at the time of memory retrieval and can meet the expectations of a mechanism for memory (Minsky, 1980), if there is a specific operational logic at this location. Before examining the operational logic for the generation of internal sensations, we need to answer two questions. 1) How can a cellular hallucination (semblance) get induced at inter-LINKed postsynaptic terminal D that was previously activated by the item whose memory needs to get retrieved? 2) What is the sensory content of this hallucination?

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The propagation of potentials through the synapse A-B and the IPL B-D provide vector components that are responsible for contributing to the oscillating extracellular potentials (Fig.5B).

When the related learning events continue, one of the postsynaptic terminals that already took part in a previous learning event (either B or D in the Fig.5) will be used to form functional LINKs with the postsynaptic terminals of the neighboring synapses (seen as additional postsynaptic terminals on the right side of the postsynaptic terminal D in the left panel, Fig.6). As this process continues, it will result in the formation of islets of LINKed (LINKable/ re-activatible during retrieval) postsynaptic terminals (right panel, Fig.6).

It is expected that basic units of semblances take place at the functionally inter-LINKed postsynaptic terminal (see Fig.5). Here, we need to answer two questions. 1) How can a cellular hallucination (semblance) get induced at the inter-LINKed postsynaptic terminal D that was previously activated by the item whose memory needs to get retrieved? 2) What is the sensory content of this hallucination?

What is the logic behind the generation of cellular hallucination (semblance)?

Semblance is the mechanism by which virtual internal sensations are being created. Searching for a cellular location where such a mechanism can be formed resulted in arriving at the requirement for inter-postsynaptic functional LINK. In figure 5, when cue stimulus arrives at the postsynaptic terminal B and re-activates the inter-postsynaptic functional LINK, it activates the postsynaptic terminal D. What makes the postsynaptic terminal to have a cellular hallucination (semblance) that it is receiving activity from its own presynaptic terminal C? The logic can be explained as follows. By default, the postsynaptic terminal D is normally activated by its presynaptic terminal C. To make sure that this is the case, it appears that the Mother Nature has designed an excellent method. There is a continuous quantal release of neurotransmitter molecules from the synaptic vesicles of the presynaptic terminal C even during periods of rest (and sleep). These provide regular arrival of miniature potentials at the postsynaptic terminals. The combined effect of all these potentials is represented by the miniature excitatory postsynaptic potentials (mEPSPs or “minis”). The fact that it is not possible to completely block mEPSPs “even in experimental conditions” indicates that it is a highly conserved default operation of the nervous system. Another necessary condition is the maintenance of oscillatory neuronal activity. The finding that electrical stimulation of the visual cortex produces a visual percept (phosphene) only when high-frequency gamma oscillations are induced in the temporo-parietal junction (Beauchamp et al., 2012) emphasizes the role of oscillating neuronal activity as a system requirement for the semblance formation for creating internal sensations. The lateral spread of activity through the inter-postsynaptic functional LINKs can contribute towards the horizontal component of the oscillating potentials and the synaptic potentials between vertically oriented neurons in the cortex can provide the vertical component. Since inter-postsynaptic spread of potentials occurs perpendicular to the trans-synaptic spread of potentials, this general feature can explain the wave form of oscillating potentials in all other regions in the nervous system, especially where sensory inputs converge.

What is meant by tricking the inter-LINKed spine to hallucinate?

The inter-LINKed spine heads, like the heads of any other spines (postsynaptic terminals), are continuously being depolarized by quantally-released neurotransmitter molecules all the time, including during sleep. This sets the dominant state of the system that allows any laterally arriving depolarization through the IPL to trick the inter-LINKed spine to hallucinate that it is receiving sensory inputs from the environment through its presynaptic terminal. Are there any real-life examples for the occurrence of such a hallucination? This has been asked recently by few readers. Here are two examples and they highlight the importance of maintaining a dominant state to trick the system to hallucinate.

1. First example is the principle underneath the success of pick pocketers for successfully doing their job! When I was in grade six, we had to read from “The Adventures of Tom Sawyer” by Mark Twain. Young Tom Sawyer along with a group of boys got training to pickpocket. Here, Tom Sawyer had to dissuade the attention of the people by taking advantage of either introducing alternate sensory stimuli or wait for their natural occurrence so that he could take a wallet from someone’s pocket without their attention. Here is a modern version of pick pocketing (and how to avoid getting pick pocketed!). Watch the events of pick pocketing in this video to see how a regular background stimulus (stimuli arriving from regular movements while walking up or down the stairs) can trick someone to think that the stimuli during pick pocketing is perceived only as a normal stimulus (Video; Fig.7). In the video, we can see that pick pocketers are successful when the victim walks up or down the stairs.

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It can be noticed that the body movements that happen as one climbs up or walks down the stairs act as the new normal background sensations during which pick pocketers can trick one’s sensory system to perceive the pick pocketing only as the movement of one’s body as one climbs up or walk down the stairs. The thief is taking advantage of the new dominant state of the system where continuous new sensory stimuli of moving through the stairs to trick that system to pickpocket!

2. A second example is that of giving injections to animals. One of the tricks here is to first pat the location where one wants to inject (Fig.8) and then tap at that location with much more intensity several times before one can put the needle at that location. If you tap 10 times, you can successfully put the needle on the 11^th time without animal’s attention. You have to continue to tap again for another 10 times before you can put the needle for a second time at the same location without animal’s knowledge (Video - watch between 7 & 7.2 minutes). The bottom line is that to trick the system to hallucinate that it is only the tap and not the needle, you have to make the sensory stimuli arriving from "tapping" as the dominant normal state of the system. In this background state, you can successfully put the needle (trick the animal to sense that the needle is only another tap).

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The above two examples are not perfect. But they can give some good idea how a system can be tricked to hallucinate, provided you can maintain a dominant state. Now the question is how can the nervous system end up operating in this manner? If we look carefully, synapses are having quantal release from the presynaptic vesicles all the time, which depolarize the spine heads including that of the inter-LINKed spines. There are no toxins on the Earth that can completely block this quantal release (& we hope that we will not bring any toxins from any other planets or satellites to the Earth!!). In a system where the synaptic junctions are having continuous quantal release, accidental coincidence during the early evolutionary stages might have brought two spines (postsynaptic terminals) to abut each other and form an IPL during simultaneous arrival of two stimuli from an item. Later, arrival of one of the stimuli allowed propagation of the postsynaptic potentials to depolarize the inter-LINKed spine from a lateral direction, tricking this inter-LINKed spine to hallucinate that it is receiving sensory inputs from the environment through its presynaptic terminal. This possibly started providing survival advantage to the animal in instances when the fastest (light) or first (smell or sound from a curved location where light cannot curve) arriving stimulus reach the nervous system. This property continued to get modified over generations to form the operational mechanism of the nervous systems. Article

Also note the importance of maintaining a dominant state of the system for tricking the system to hallucinate about the sensory content of the associatively learned second item. In the above described case of injecting a horse, if you tap 10 times, you can successfully put the needle on the 11^th time without animal’s attention. You have to continue to tap at again for another 10 times before you can put the needle for a second time at the same location without animal’s knowledge. This means that you have to reset the background state to a state where you can trick the system to hallucinate that it is only the regular tap before giving the second injection. Even though, this is not a perfect example, it embraces the idea to certain extent. This has similarities to sleep in animals. During the evolution of the nervous system on Earth, where there is day and night, sleep provided much of the needed opportunity to put the system back to having a dominant state where depolarization of the spines heads by the continuous quantally-released neurotransmitter molecules became the dominant state of the system. This explains the substantive (not just indispensable) nature of sleep in maintaining the system. Article

What is the sensory content of the cellular hallucination (semblance)?

Cue stimulus activates postsynaptic terminal B that leads to re-activation of inter-postsynaptic functional LINK and activates the postsynaptic terminal D that was previously activated by the item whose memory is getting retrieved now (Fig.9). At postsynaptic terminal D, this leads to a semblance of activity arriving from the sensory receptors through neuron Z. Neuron Z is normally depolarized by activating a set of axonal terminals of the neurons in order 4 that synapse to neuron Z’s dendritic spines (postsynaptic terminals). The spatial summation of nearly 40 or the temporal summation of less than 40 EPSPs (from nearly 40 postsynaptic terminals (dendritic spines) out of the nearly 4×10⁴ postsynaptic terminals of each neuron) triggers an action potential at neuron Z’s axon hillock (Note that the number of postsynaptic terminals (dendritic spines) for a neuron varies. In the hippocampus, we expect that the excitatory neurons have postsynaptic terminals in the order of 10⁴). In the same way, the neurons in set {Y} in turn receive synaptic transmissions and spread of activity through functional LINKs from a set of neurons {X} in neuronal order 3. By continuing the extrapolation in a retrograde fashion towards the sensory level, it will be possible to determine the set of sensory receptors {SR} whose activation could theoretically cause the activation of postsynaptic terminal D.

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Dimensions of internal sensations resulting from the lateral activation of postsynaptic terminal D can be understood from the nature of the sensory stimulus that can activate sensory receptors in the set {SR}. It is likely that activation of subsets of a minimum number of sensory receptors from {SR} (example, {sr1}, {sr2}, and {sr3} (Figs.9&10) is sufficient to activate postsynaptic terminal D. Therefore, a hypothetical packet of minimum sensory stimuli called “semblion” capable of activating one of the above subsets of sensory receptors that can activate postsynaptic terminal D is hypothesized as the basic unit of internal sensation of memory.

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As the cue stimulus passes through different functional LINKs, it evokes a large number of semblances as explained above. Once these possible semblions are identified, their integration can be carried out to obtain a net semblance that matches the sensory characteristics of the item whose memory is retrieved. Attempts to match the different integration products from the semblions with that of the sensory stimuli from the item whose memories are retrieved will lead to the discovery of the algorithm for neural computations for memory retrieval. The net semblance can exceed more than the threshold without any effect on the retrieved memory. As the functional LINKs get re-activated during memory retrieval, the expected spread of excitatory postsynaptic potential (EPSP) that occurs through some of these functional LINKs can be crucial in adding to the existing sub-threshold EPSP at the axonal hillocks of some neurons that are routinely activated by the oscillatory neuronal activities in the hippocampus and cortex as well as from baseline sensory activities arriving at many neurons. Since the number of functional LINKs continues to change (due to continued associative learning) over the lifespan of the nervous system, the characteristic features of the semblions are also expected to change gradually. This will lead to gradual changes in the net semblances for memory. Related learning can increase the number of LINKed postsynaptic terminals and increase semblance for memory. Absence of retrieval of a specific memory, lack of repetition of learning or lack of related learning will reduce the number of re-activatible inter-postsynaptic functional LINKs and will reduce semblance for retrieval of a specific memory. Along with the induction of semblances, the reactivation of inter-postsynaptic LINKs can also provide additional potentials to the inter-LINKed postsynaptic terminal that can lead to firing of the latter’s neuron if it is kept at a subthreshold activated level (Fig.11).

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What is the nature of inter-postsynaptic functional LINK?

Different mechanisms for the formation of inter-postsynaptic LINKs are possible and are required to explain the formation of internal sensations of other higher brain functions that operate at different time-scales. These different types of inter-postsynaptic LINKs with varying half-lives are suitable to explain perception, working, short- and long-term memories. A description of some of them is given in Fig.12.

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Are there any experimental evidence supporting the presence of the inter-postsynaptic functional LINK?

New technologies are required to test for the presence of the close contact between the membranes by hydration exclusion (Fig.12B) in vivo. Another mechanism of inter-postsynaptic functional LINK is the reversible inter-postsynaptic membrane hemi-fusion. If this is correct, then examination of the membrane bilayers at locations where postsynaptic areas are close together is an opportunity to test the hypothesis. It is also true that at locations where (sensory) inputs converge, the extracellular matrix space is very minimal as observed by routing electron microscopic (EM) examination of these regions. At these locations, abutted postsynaptic membranes are expected to be seen. However, there are some hurdles. First, the membrane hemi-fusions are reversible. However, locations within the hippocampus that has already undergone many associative learning, stabilization of these hemi-fused areas (most probably by the insertion of trans-membrane proteins) are expected. Secondly, only a very small area of membrane hemi-fusion is required for the functional effect of the formation of inter-postsynaptic functional LINK. Since the area of the postsynaptic membrane surface that has to be examined for such small areas of membrane hemi-fusion is very large, dedicated EM studies by taking serial sections spanning an entire postsynaptic terminal is required.

Alternatively, examination of a large number of electron microscopic pictures of the hippocampal regions taken for other purposes can be tried. The limitation of this is the lack of resolution of the electron microscopic pictures to visualize the membrane double layer. In a recent EM work (Fig.13) with good resolution, it is possible to observe closely abutted areas, suggesting that they may lack inter-membrane extracellular matrix space. Since dehydration during the tissue processing contribute to these observations, inter-membrane close contacts with hydration exclusion need to be verified using new in vivo techniques. In the above figure, another finding is very striking. There are areas of two layers of hemi-fused membrane for short distances instead of four layers of the two abutting postsynaptic membranes. These are very unlikely to be caused by rotation of the membranes or changes during processing of the tissue. These short spans of reduced number of layers is what is expected by the hemi-fusion process and provide support for the hypothesis until further verifications are carried out. Multiple fused spine heads on a single spine neck seen on dendritic excrescences at the CA3 dendritic tree (Amaral and Dent, 1981; Chicurel and Harris, 1992; Frotscher et al., 1991) is a possible structural modification evolving from long-standing inter-postsynaptic functional LINKs.

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Why didn't we discover these IPLs until now?

First, there was no reason to search for a mechanism of exclusion of water of hydration at the inter-neuronal inter-spine regions that are activated during associative learning. Secondly, no dedicated studies were carried out to image the lipid bilayers of an entire dendritic spine and its interactions with the abutting spines that belong to different neurons to examine the formation and reversal of inter-postsynaptic functional LINKs by a) exclusion of water of hydration between them, b) formation of inter-spine partial and complete hemifusion, and c) formation of inter-spine fusion in pathological conditions. Though sound simple, this is a huge undertaking with many challenges. Since the IPLs are expected span a length of only nearly 10nm length, ultra-structural details of entire spine membranes are necessary.

It seems that all the above steps used third-person observations. Where is the examination from a first-person frame of reference?

In Figure 9, the steps needed in finding out the sensory content of the cellular hallucination induced at the postsynaptic terminal D involves examination form a first-person frame of reference. It requires searching backwards from the postsynaptic terminal D towards the sensory receptor level to find out the subset of minimum sensory receptors whose stimulation can activate the postsynaptic terminal D. The minimum sensory stimuli required to activate this subset of sensory receptors constitute the semblion, which is the basic unit of internal sensation. The backward extrapolation from the postsynaptic terminal D towards the sensory receptor level to find out the packets of sensory stimuli is an implicit process taking place during the internal sensations of all the higher brain functions. In this examination, we observe the packets of sensory stimuli (content of the unit of internal sensation) from a first-person frame of reference.

How can we explain long term potentiation (LTP) in terms of the semblance hypothesis?

For a more detailed description, see published article

The semblance hypothesis was derived to explain plausible synaptic changes occurring during learning suitable for evoking virtual inner sensation of a sensory stimulus during memory retrieval. The operational principle of the formation of semblances resulting in memories is completely different from that of LTP; however, the formation of inter-postsynaptic LINKs can be viewed as a common denominator in both semblance hypothesis and LTP induction (has yet to be confirmed). Explanation of semblance formation through inter-postsynaptic membrane functional LINKs can fill the gaps in our findings of the correlation between memory and LTP and can explain why it has led to a large number of debates. One general argument is that any hypothesis of memory should be able to explain the relationship between LTP and the surrogate behavioral motor activity indicative of memory retrieval.

Previous experiments have shown that spatial learning becomes impaired after saturation of LTP (Moser et al., 1998). Later experiments have shown specific interrelationship between LTP and surrogate markers of memory retrieval (Whitlock et al., 2006). In this work it was shown that one-trial inhibitory avoidance learning in rats produced the same changes in hippocampal glutamate receptors as the induction of LTP with high-frequency stimulation. This study showed that learning-induced synaptic potentiation occludes high-frequency stimulation-induced LTP. Based on the findings in this work, a plausible explanation for the relationship between LTP and memory through the semblance hypothesis can be done as follows.

a. Learning first, followed by LTP induction:

According to the semblance hypothesis, prior learning events in a caged environment would have already made many islets of LINKed postsynaptic terminals (dendritic spines) in the hippocampi of the rats. Since associative learning opportunities are finite during caged life, we can expect a slow expansion (by LINKing more postsynaptic terminals with additional related learning events) of discrete islets of LINKed postsynaptic terminals as the rats grow up. When rats undergo avoidance learning (a novel instance of associative learning), we can expect the formation of functional LINKs between two or more islets of functional LINKs that are already present in the animal. Even though this is particularly important in this experimental context, it will also hold true in any novel associative learning.

In experiments using inhibitory avoidance testing (Whitlock et al., 2006), not all the recording electrodes recorded an increase in field excitatory postsynaptic potential (fEPSP) slope, indicating that ionic changes at the locations of the tips of these electrodes (CA1 dendritic tree) required to produce an increase in the fEPSP slope did not take place. However, among those electrodes that recorded an increase in fEPSP slope after inhibitory avoidance learning, a sufficient number of Shaffer-CA1 synapses were potentiated. Let I and II stand for two islets of functionally LINKed postsynaptic terminals that were already present in the animal before the avoidance learning session. During learning, it is likely that LINKs were formed between the islets (islets of LINKed postsynaptic terminals) I and II. This will generate a sudden increase in the size of an islet of LINKed postsynaptic terminals to nearly twofold, forming a mega-islet of LINKed postsynaptic terminals (Fig.14).

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Activation of a postsynaptic terminal of this mega-islet of LINKed postsynaptic terminals can cause spread of depolarization between its postsynaptic terminals. Since a subset of postsynaptic terminals in the mega-islet already LINKed to one of the dendritic spines (postsynaptic membrane) on the dendritic tree of one CA1 neuron, multiple EPSPs from this subset will reach the main dendrite of a CA1 neuron simultaneously. This results in a summated EPSP at this dendritic location sufficient to produce a corresponding increase in current sink in the extracellular matrix. Immediately following the associative learning event, a proportion of sensory inputs reaching the animal for a long duration of time is likely to activate the postsynaptic terminals of this mega-islet, leading to prolonged activation of the main dendrites of the above CA1 neuron (until the CA1 neuron begins homeostatic mechanisms to reduce this prolonged and increased EPSP generation). The extracellular signal recorded from the apical dendrites of a population of pyramidal neurons in the stratum radiatum of the CA1 region in response to Schaffer collateral stimulation, namely the fEPSP, will now show an increase in amplitude and contribute to an increase in fEPSP slope for a long duration of time (LTP). This learning-induced LTP can occlude further LTP induction.

b. LTP induction first, followed by learning:

The occlusion process explained in the study (Whitlock et al., 2006) can be considered a bidirectional process, meaning that the induction of LTP in a sufficient number of synapses that are involved in inhibitory avoidance learning will prevent consequent avoidance learning. It is likely that hundreds of axons of the CA3 neurons in the Schaffer collateral pathway are activated by high-frequency stimulation (LTP induction), activating the postsynaptic terminals (dendritic spines) of a CA1 neuron. During this process, many postsynaptic terminals can get functionally LINKed due to the simultaneous activation of closely placed postsynaptic terminals by high-frequency stimulation (assuming that sufficient oxygenation state is present during this process). Some of these LINKs will occur between the islets of already LINKed postsynaptic terminals, leading to the generation of mega-islets. Following this, the activation of one or more postsynaptic terminal by a regular stimulus (not high frequency) can lead to the spread of depolarization between the postsynaptic terminals within the mega-islet. Since one or a small subset of postsynaptic terminals in the mega-islet originates from the dendritic tree of a single CA1 neuron, multiple EPSPs from these postsynaptic terminals can reach one dendrite of a CA1 neuron simultaneously. This results in an increase in the EPSP at these dendritic locations, leading to LTP. This artificially-induced LTP can occlude further learning-induced LTP.

If we can artificially induce LTP in a large number of fibers that includes those that are critical for the learning, then the animal may not be able to successfully retrieve specific memories after a new associative learning using those synapses following the LTP induction. This means that the animal cannot retrieve the specific memories; i. e., when a cue stimulus tries to retrieve a memory using these synapses, the induced depolarization spreads across all those postsynaptic terminals that are LINKed by the LTP induction. The retrieval using a specific cue now induces synaptic semblances at all those LINKed postsynaptic terminals in the mega-islet, some of which were LINKed non-specifically during LTP induction. Activation of those non-specific postsynaptic terminals will also lead to the activation of non-specific neurons, leading to the induction of non-specific network semblances that are not related to the learned item. In other words, the expected specificity of semblance for the learned item gets diluted by the large amount of non-specific semblances, preventing specific memory retrieval.

The following diagram (Fig.15) demonstrates the similarities between the cellular processes in LTP following induction and internal sensation of retrieved memory following associative learning.

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The hypothesis has used one key assumption that internal sensation is induced at a specific location by a specific mechanism. Why should this be correct?

In order to build a hypothesis, some assumption has to be made in the beginning. If one assumption can consistently substantiate all the nervous system functions, then the probability for that assumption to be correct is high. This is similar to solving a system of linear equations having a unique solution. When only one variable remains unknown, then using its different relations with other variables the value of the unknown variable can be found mathematically. Alternatively, one is allowed to assign different values that unknown variable and use trial and error methods to solve the system. Similarly, in the case of a biological system where only one variable of internal sensation remains unknown, large number of known variables and their relationships with the unknown variable can be used by trial and error methods to solve the system. In deriving semblance hypothesis, induction of semblances as a system property was assumed to take place at the inter-LINKed postsynaptic terminal (dendritic spine) by the reactivation of the inter-postsynaptic functional LINK due to compelling reasons such as 1) some form of depolarization is always taking place at the postsynaptic terminal continuously, 2) the miniature EPSP generation cannot be blocked completely by any natural or synthetic chemicals on earth, 3) the formation of the inter-postsynaptic LINK can be achieved as a function of simultaneous activation of the abutted postsynaptic terminals during associative learning, 4) induction of semblance can then be derived as a function of lateral activation of the inter-postsynaptic LINK, 5) presence of different types of inter-postsynaptic functional LINKs having different life spans is suitable to explain how changes generated by learning can last for different durations, 6) it is possible to stabilize the functional LINK, providing ability to retain ability to retrieve memory of associatively learned items or events for different duration of time, 7) the lateral spread of activity through the inter-postsynaptic functional LINK contributes to the horizontal component of the oscillating potentials which is a requirement for inducing the system property of internal sensations, 8) semblance is a virtual property that suits to explain the virtual internal sensations of various higher brain functions, 9) semblance is a first-person property induced within the system towards which only the owner of the nervous system has access. All these fitting conditions make induction of semblance as an appropriate assumption. The possibilities for a spectrum of changes that can be formed during the generation of inter-postsynaptic LINK (see Fig.12) and their maintenance for a wide range of time periods shows the exact features that one would expect from the basic operational mechanism. Inter-postsynaptic functional LINK mechanism can operate in agreement with all the constraints offered by the findings listed in the Table 1 on the front page of this web site. Due to these reasons, the hypothesized mechanism is likely to be correct. 

This work has explained induction of units of internal sensation of memory. How can it explain perception and consciousness?

Learning and memory were examined due to the advantages of examining them. Changes can be induced during learning and these changes are expected to be used to induce memories. Since these expected changes can be hypothesized, they can be tested to verify the hypothesis. This led to the derivation of inter-postsynaptic functional LINK formation and induction of units of internal sensations at the inter-LINKed spines as the basic operations. It is reasonable to expect that the basic mechanism of induction of units of internal has shared properties with the internal sensations of both perception and consciousness. Slight modification of the process of induction of units of internal sensations is expected to occur both during perception and in the operational mechanism of consciousness. In the case of perception, a real time process of induction of units of internal sensations has to be explained that can explain the large number of known properties of perception. This was carried out to explain visual perception (Vadakkan, 2015c). In the case of consciousness, it has to explain a) why a large number of units of internal sensations are getting induced while the animal is at rest, b) what is the net semblance formed by these units of internal sensations, and c) how it forms a background matrix upon which internal sensations in response to specific cue stimuli can be efficiently induced (Vadakkan, 2010).

What is the basic logic behind this work?

Let us imagine that there is a solvable system of linear equations. This means that there are few equations that contain several variables and these equations form a system, meaning that they are all interrelated. If we know the values of all the variables except one, then we will be able to find out the value of that unknown variable using simple mathematical method. But if we examine very carefully, we will see that the relationship of the unknown variable with the known variables within the equations can guide us to understand what the value of that unknown variable is. The above relationships are constraints that allow us to understand the value of the unknown variable. So, instead of using mathematical methods, we can also find the value of the unknown variable by trial and error method.

In a similar manner, the nervous system has a very large number of variables that are observed as different findings at various levels (molecular, cellular, inter-cellular, electrophysiological, systems, behavioral, and imaging). We already know all those findings and we have made large number of correlations between several findings already. Now we have one unknown variable, which is the generation of internal sensations within the mind. We are afraid to use it, since we don’t know how it is getting generated. Let us now use this variable in our findings. Here is an example. In addition to observing the behavior alone, let us include the fact that during memory retrieval there is an internal sensation of memory. Now, internal sensation is the only unknown variable within a large number of findings within the system. Now, we can use trial and error methods by using all the constraints offered by findings from different levels (Given in Table 2 on the Home page) to arrive at the mechanism of generation of internal sensations. The only difficulty is that we need to examine a very large number of observations from different levels to arrive at the solution and fine-tune it. Semblance hypothesis has used this method.

Are there any convincing evidence to show that this hypothesis is correct?

For a system that generates first-person internal sensations that are not accessible to third-person observers, it is necessary to use methods used in mathematics and physics to understand a phenomenon that is not sensible to our sensory systems. In this regard, the present work has derived a solution for the system using the underlying principle of finding a solution for a system of linear equations, which is also in agreement with the principle of unification. The resulted solution was used to triangulate (Munafò and Smith, 2018) findings from different levels. The derived solution is now is a position to explain the first-principle behind its operations.

Foremost, present hypothesis has viewed memories in their true sense as first-person internal sensations. The derived solution was found to have background properties for the induction of units of virtual internal sensations. The continuous depolarization of the spine heads (by both quantal release and EPSPs induced by intermittent arrival of action potentials at their presynaptic terminals by sensory stimuli from environment) sets the background state. Associative learning between two stimuli is expected to generate an inter-postsynaptic (inter-spine) LINK (IPL) between the spines that belong to two different neurons. In the above-explained background state, if one of the stimuli (cue stimulus) can incidentally reactivate the IPL, then it is expected to spark a cellular hallucination (semblance) at the inter-LINKed spine of receiving stimulus from the second stimulus. This matches with the expectation of a mechanism for cellular hallucination within the nervous system for explaining memory (Minsky, 1980). This is expected to provide a mechanism for the generation of virtual, first-person internal sensation of memory at physiological time-scales. We can make an extrapolation from the inter-LINKed spine towards the sensory receptors to identify the minimum sensory stimuli required to activate that inter-LINKed spine, which forms units of internal sensation. The combination of a) unique background state of the system, b) possibility for the formation of IPLs with mechanisms that can have different life spans, c) the suitability of the location of IPL that can allow the cue stimulus to reactivate it, d) observation of a suitable mechanism for the induction of virtual first-person internal sensation at physiological time-scales, and e) the perpendicular direction of propagation of potentials through the synapses and IPLs that can contribute vector components to the oscillating extracellular potentials whose frequency within a specific range controls the operation of the system matches with the expectations of a system that generates mind. This coincidence of multiple features provides the most convincing evidence.

Now, if we look at the above mechanism carefully, we can see that the ability to induce cellular hallucination (that constitutes first-person internal sensation) mandates that the dominant state of the system should be that the depolarization of the inter-LINKed spine head occurs with the arrival of activity from its presynaptic terminal. Therefore, lateral activation by the cue stimulus that depolarizes the inter-LINKed spine head from a lateral direction tricking the system to induce cellular hallucination at the inter-LINKed spine that constitutes memory should only occur for a limited duration of time. In other words, when the system keeps the arrival of depolarization from the presynaptic terminal as the dominant feature, then any incidental (or less duration) activation arriving through the IPLs will induce the cellular hallucination. If the ratio of the above two states is high, then the efficiency to trick the system to hallucinate in response to a lateral activation (which constitutes components memory) by a cue stimulus is easy. Since the quantal release that occurs all the time is at a saturated phase, then the system needs to control the duration of lateral activation. After a certain period of time, the system has to enter into a state of sleep (that prevents lateral activations by cue stimuli) following which the system resets itself back to the above dominant state. This provides an explanation for the substantive nature of sleep to the extent that the system will cease to function if it is not allowed to sleep for a few days. This provides another convincing evidence.

The above derived mechanism agrees with all the constraints offered by the very large number of observations from different levels (please refer to Table 2 in the Home page). Now, some of the convincing evidences that were found during continued examination of this hypothesis are the following. a) Most learning-induced changes will reverse back quickly as the animal moves through the environment, explaining working memory. The proportion of what remains is very less and they remain for varying periods of time for short- and long-term memories. In this regard, we expect that most of the learning-induced mechanism should be able to reverse back quickly. It should leave a small proportion of learning-induced changes to last for varying periods of time. So if we have arrived at the actual mechanism, then we should be able to observe changes to explain the above. By examining Figure 12 in this page, it can be seen that the formation of inter-postsynaptic functional LINKs by exclusion of water of hydration (Fig.12B) requires huge amount of energy and it reverses back quickly. Only a small proportion of these LINKs can form partial and complete hemifusions (Fig.12C,D) and will last for different periods of time. This forms a perfect fit with what we expect from learning-induced changes. This perfect fit shows that this mechanism is inevitable. b) As a continuation of what we found just now, there should be a mechanism for stabilization of learning-induced changes for a long period of time. Since the stage of complete hemifusion (Fig.12D) can be stabilized by different methods, it provides a suitable mechanism. In addition, when the newly formed inter-LINKed spines become part of an islet of inter-LINKed spines, it will be able to get both activated more frequently enabling its long-term maintenance. c) Furthermore, since dopamine cause spine enlargement (Fig.12E), it augments inter-postsynaptic functional LINK formation and its stabilization. This can result in retention of memories for a long period of time. This is another example for a perfect fit. d) Several correlations were found between the ability to learn and induce LTP. The derived mechanism has explained all those correlations and in addition explained some of the remaining uncorrelated observations in the field. This ability of the derived work provides further convincing evidence. e) Ability to provide a framework of a mechanism for perception, explaining various features of visual perception and finding a comparable circuitry for olfactory perception in a remote species Drosophila provides another convincing evidence. f) Ability to provide a framework for internal sensation of consciousness and how anesthetic agents can lead to loss of consciousness provides another evidence. g) Ability to explain a large number of common features of neurodegenerative disorders as a loss of function of the normal operational mechanism is another convincing evidence.

What are the key features of the testable circuit?

Functions of the brain include receiving sensory information, conscious interpretation of some of them, behavioral motor activities in response to them based on previous associative learning, and storing some of the newly received information. What type of a functional map of the nervous system can incorporate these functions? Why have we not succeeded in understanding the nervous system yet? What are we missing here? Once we understand the circuitry, it is necessary to explain a large number of functions within the system at different levels. What type of a circuit map can provide all these different types of observed features within the nervous system?

One of the essential features of the brain function is the formation of first-person inner sensations of higher brain functions (e.g. perception, memory, and consciousness) as a first-person property. Studying this property requires a completely new approach separate from current anatomical, molecular biological and electro-physiological approaches; but at the same time adhering to latter's basic principles. In order to understand what approaches need to be taken, it is required to build a hypothesis that can explain both first-person internal sensations and third-person findings from various levels. Since most of the higher brain functions are first-person internal sensations within the mind, the main emphasis while searching for the circuit properties should be given to explain it. In other words, the working hypothesis should have bridges from cellular and electro-physiological properties to that of the virtual internal sensation.

Once a hypothesis is built, it requires to be tested by three essential steps. First, test whether the hypothesis can explain what we have already discovered in various faculties of brain sciences. Luckily, the nervous system is complex enough that we can ask many questions to verify the validity of the hypothesis. Secondly, the new features in the hypothesis can be tested and its predictions can be verified. The third step is to address the issue of the first-person properties of brain functions. We need to carry out the gold standard test of replicating the mechanism in engineered systems to confirm the findings. This is necessary since the higher brain functions of the mind that are first-person properties require this step to convert internal sensations to appropriate read-outs so that we experimenters (third-persons) can understand them. Can we bypass this third step? The only alternative is theoretical. If the hypothesis can explain a very large number of disparate findings from multiple levels of the system, then this can be taken as sufficient evidence.

Semblance hypothesis was proposed towards achieving the above goals. It has provided explanations for various electro-physiological, behavioral and systems findings from different faculties of brain sciences. The essential feature of the hypothesis is the proposal of inter-postsynaptic functional LINK (IPL). An examination of the possible nature of this was then carried out. From examining disease processes that can alter the IPLs, it was possible to arrive at a reasonable conclusion that IPL is a candidate mechanism. This can be tested in animals and human samples. Its formation and functional role can be tested both during associative learning and its experimental correlate of the induction of long-term potentiation (LTP). By including IPLs and their functional role, we can obtain a new brain circuitry, which is explained in the following two figures (Fig.16).

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The brain activity map that is built of the basic units presented here can explain the large number of nervous system functions (see Table 2 on the Home page) that are observed by different faculties of brain science. The basic cellular operating principle for the first person internal sensations of all the higher brain function should be sharing a common cellular mechanism. This will allow the common feature of induction of internal sensations in these higher brain functions. Inter-postsynaptic functional LINKs and the induction of semblance is capable of providing adequate mechanistic cellular features. Since the expected solution that can explain a wide range of findings at several levels is expected to be a unique one, the proposals made by semblance hypothesis can be considered for verification by testing the predictions made by the hypothesis and replicating the mechanism in engineered systems.

What are the implications of this work?

This work informs that the nervous system has two types of circuitry that operate in unison with each other. 1) A functional circuitry that operates through the formation, reactivation and reversal of IPLs. 2) A structural circuitry that operates through the synapses. Since firing of a single neuron can occur when it receives a fraction of its inputs (see section titled "What are the issues with studying neuronal firing (axonal spike) in understanding higher brain functions?" above), several neurons are kept at sub-threshold activation level under the influence of inhibitory neurons (Hangya et al., 2014; Karnani et al., 2014). In this context, the arrival of a small fraction of potentials through the IPLs will be able to fire some of those neurons for effective downstream end organ activation. Based on the IPL mechanism, internal sensations of various higher brain functions take place at the inter-neuronal inter-spine level. From the derivation of the mechanism, we have seen that integration of units of internal sensations induced at specific sets of inter-LINKed spines are essential for the generation of specific internal sensations associated with all the above higher brain functions. This is also essential to understand the internal sensations of various higher brain functions that include motivation, memory, perception, consciousness, aversion, reward, pleasure, anxiety, stress, fear, intentionality, hunger, thirst, and pain. By artificially altering neuronal firing at the neuronal orders at a level lower than that of the inter-LINKed spines, the internal sensations of most of the higher brain functions can be altered. But to understand the mechanism of generation of internal sensations of a higher brain function, we need to test the hypothesis of induction of units of internal sensations by the IPL mechanism and their integratation.

Why should this hypothesis be correct?

Science always seeks the truth. In order to understand certain phenomenon, it is necessary to examine it from multiple angles and make sure that our understanding is correct by all means. By keeping replication of the mechanism in an engineered system as the gold standard proof, the present work has kept the highest standard possible to undertake such an inquiry. Such an approach is expected to make one ask all possible questions in advance that will significantly reduce the probability of failure. The present work has used all the freedom it was necessary to put the pieces of the puzzle together.

When we say that we do not understand the brain, what we really meant are two things. a) We cannot inter-connect findings from different levels, and b) we do not understand how the first-person internal sensations in the mind are being generated. So our task is to find out the still undiscovered key operational mechanism for the generation of internal sensations that is also expected to inter-connect findings from different levels. In this context, we can use all the observations that we have already made from various levels and list the constraints offered by all of them (Given in Table 2 on the Home page). From those constraints, it is clear that the basic operational mechanism has to operate within the limited amount of freedom that it has. In other words, the constraints dictate what the solution is. The constraints offered by Nature are the guideposts that we can use to reach the solution. Wherever we reach, it should be the solution. So, we need to use all these constraints together and reach at the solution. Since a) the present work strictly adhered to these principles all throughout, b) large number of constraints were used to arrive at the solution, and c) large number of constraints were used to verify the solution, the derived solution is expected to be correct. The solution is expected to be a very unique one. At the same time, it is also expected to be a simple solution and universally present in all species of animals. The derived mechanism matches with these qualities. Now, we can further verify the hypothesis by asking more questions. Making attempts to disprove the hypothesis is part of this process. These can be continued until we become totally satisfied.

Give an example of a molecular evidence to suggest that this hypothesis must be correct?

I would like to quote the following words by Richard Feynman here. "When you have put a lot of ideas together to make an elaborate theory, you want to make sure, when explaining what it fits, that those things it fits are not just the things that gave you the idea for the theory; but that the finished theory makes something else come out right, in addition." This is an essential step to verify that we made a new discovery. If the semblance hypothesis is correct, then we should start observing new evidences that we never thought of while developing the hypothesis. I have explained many such examples. Here is a molecular example. In Figure 8, mechanism of IPL formation and maintenance is explained. IPL formation starts by interaction between the outer layer of the cell membranes of spines that belong to different neurons. This interaction can be stabilized by different mechanisms. If this is possible, then there should be molecular evidence to suggest such a mechanism is possible at suitable time-scales that matches with all the observed functions.

Membrane fusion is a high energy requiring process and the events have to overcome a high-energy barrier (Rand and Parsegian, 1984; Harrison, 2015). It is known that membrane fusion is facilitated by the action of certain specific intracellular proteins (Kozlovsky et al., 2004; Martens and McMahon, 2008). SNARE (soluble NSF (N-ethylmaleimide sensitive fusion protein) attachment protein receptor) proteins are known to provide energy for bringing together membranes until repulsive charges and overcome energy barrier related to curvature deformations during hemifusion between abutted membranes (Martens and McMahon, 2008; 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 and Scheller, 2006), SNARE proteins can lead to the formation of characteristic hemifusion intermediates (Lu et al., 2005; Liu et al., 2008). These properties of SNARE proteins highlight the functional significance of them to form hemifusion intermediates between the lateral spine head regions of spines. These intracellular factors can contribute to a short-lasting inter-spine membrane interaction leading to the generation of a short-lived IPL. Since mean inter-spine distance is more than mean spine head diameter (Konur et al., 2003), inter-neuronal inter-spine hemifusion is the best suitable type of inter-spine interaction.

SNARE proteins in the presynaptic terminals are largely studied. However, its presence within the dendritic spines shows that they have some functions here. All the properties of SNARE proteins described in the above paragraph show how it can contribute to the formation of hemifusion between the dendritic spines that belong to two different neurons. The specific property that SNARE proteins can form characteristic hemifusion intermediates (Lu et al., 2005; Liu et al., 2008) highlights the important functional property of this protein. Additional evidence includes the following. After the formation of IPLs in milliseconds of time during associative learning, they are expected to be reinforced by several delayed mechanisms. Since SNARE proteins are known to mediate fusion of intracellular vesicles containing AMPARs (a-amino-3-hydroxy-5-methyl-isoxazole propionic acid subtype of glutamate receptors) with the spine membrane (Lu et al., 2001; Kennedy et al., 2010), it forms a highly suitable mechanism that favor addition of membrane segments of the vesicles to the lateral spine head regions for the formation and maintenance of inter-spine hemifusion intermediates. In one previous study, it was found that fear conditioning drives AMPARs into postsynaptic regions of a large fraction of neurons in the lateral amygdala (Rumpel et al., 2005) after three hours. This study also found that memory is reduced if synaptic incorporation of AMPARs was blocked in as few as 10 to 20% of lateral amygdala neurons. Presence of AMPA GluR1 subunits at the lateral spine head region up to 25nm away from the synaptic cleft border (Jacob and Weinberg, 2014) indicates that this is the most probable region where AMPA GluR1 subunit vesicle exocytosis takes place. It also matches with the expectation of the location where inter-spine fusion can take place. These molecular events were not thought of at the time of derivation of this hypothesis. In fact, many of the findings were made only recently.

What are the odds of coming up with a correct hypothesis?

This was a question asked by one of my colleagues. I realize that this will also be a question arising in the minds of the readers. From a statistical point of view, the odds of coming up with a random hypothesis which is correct are very less. The reality is that I took hypothesis building as a hobby. I learned how to build a hypothesis and verify whether it can substantiate nervous system functions from different levels. I used to keep one hypothesis at a time. When I kept them for sufficient duration, I started finding weaknesses in them for providing sufficient logical rigor for a mechanism of nervous system functions. From each failure I learned a lesson, which helped me to build better ones. Interestingly, each of my subsequent hypotheses lived longer than the previous ones. Eventually, I reached my fifth hypothesis, which I kept for nearly a year before I abandoned it. It was based on charge transfer along the DNA molecules. I kept lot of hope & it made sense since neurons do not divide. But it failed in many aspects. Semblance hypothesis was the sixth hypothesis.

Was it possible to reach the details of the solution easily?

Even though the basic outline of the hypothesis and the concept of inter-postsynaptic functional LINK (IPL) became possible in early 2007, it took nearly four more years to identify the hidden mechanism that sparks the units of internal sensation at the IPL. Since the nervous system operates (for e.g. both learning and memory retrieval take place) only a narrow range of frequency of oscillating extracellular potentials, it is essential that the operational mechanism should have features to support this. Since the synaptic transmission in one direction and the propagation of depolarization across the IPLs that occurs in a perpendicular direction to this can provide the vector components to the oscillating extracellular potentials, it became very clear that the IPL mechanism is a highly suitable candidate. So I pursued to find a mechanism that can spark internal sensations at the inter-LINKed spine when a cue stimulus arrives. I was sure that I was "missing the trees for the forest" at that time. So my mind wandered around that location for months. When I published the article on consciousness in 2010, I was not aware the IPL mechanism. But, I was certain that a mechanism must be there. I was certain that it should be a simple mechanism since the system was evolved naturally. I was also certain that it will be capable of evading our attention so easily that I must search for it from different angles. So, I continued to search for a simple mechanism that can operate at time-scales of milliseconds. It was only by the end of 2010, I got the operational mechanism that can spark units of internal sensations. Immediately, I published the concept in early 2011 in the paper that explained "Processing semblances...". So, it took nearly four years. It was not easy! But it was worth pursuing!

What if this hypothesis is wrong?

This is a normal feeling following the development of any hypothesis. But if the hypothesis is correct, then the degree of this feeling will reduce with time. This is because there are a large number of ways by which the hypothesis can go wrong and there is only one unique way in which it can be correct. The major task of developing a hypothesis is to figure out the correct solution so that it can explain all the functions observed at various levels. In this approach, there are two major categories of mistakes that can occur and are the following. 1) Let us imagine that the nervous system consists of a large jigsaw puzzle in multiple dimensions and that we are trying to solve it using its parts. The most important thing is that we need to collect all the pieces of the puzzle from multiple levels and bring them on to the table. Since we will only solve for what we have on the table, missing some pieces from few levels can lead to a wrong hypothesis. 2) Secondly, let us imagine that we have brought all the pieces of the puzzle and they are of the same color (can be identified only by their shape, making the puzzle solving more difficult). So, direct matching of the pieces is the only way to confirm whether we are putting the pieces of the puzzle correctly. In this exercise, we may be able to put together a large number of pieces correctly, until we find that the remaining pieces won’t fit into the remaining slots (Hope every one of us had this experience). A good jigsaw puzzle will lead to these situations. Now, we need to dismantle everything and start building it again. Is this hypothesis reaching a stage described as above? Did it bring all the parts onto the table for assembling? Since this hypothesis has incorporated as many pieces of the puzzle as possible from multiple levels (by making sure that no non-redundant findings are left out) and was guided by the tight constraints offered by all those findings (given in Table 1 on the front page), these possibilities are expected to be very less. But, there is still a possibility that it is wrong. This is the reason why there is an open invitation to everyone for falsifying this hypothesis. When we make an observation that cannot be explained in terms of the present hypothesis, then we should consider it wrong. At that time, we should be able to build another hypothesis with more compelling explanations and inter-connectable features. It is also possible that someone can show that the present work is fundamentally wrong. But, it has not happened yet.

What is the motivation behind this work?

1. Nervous system generates first-person internal sensation in the mind, which is virtual in nature. These inner sensations then drive motor outputs in the form of speech and behavior that can be sensed by a third person. Examination of these third person findings alone is not sufficient to understand the system. It will need to acquire knowledge about a) how first-person internal sensations are induced, and b) how they are connected to the motor actions.

2. It is reasonable to expect that there is a solution. The reality is that we have difficulties in understanding it. Our minds can be trained to operate based on Bayes' rule. However, for solving difficult problems, we need to prepare our minds to go against all the priors. We can achieve this only by searching for totally new possibilities by ignoring all the priors. We need to look at the problem afresh similar to an outsider looking into the problem. It is a risky endeavor by all means. First, it will be very difficult to obtain funding to undertake such a work. Secondly, a work done in the absence of funding will be perceived as of low value. Thirdly, it has to face difficulties even from the very stage of publication. Is it worth taking the risk? Since we can use a large number of constraints from our previous findings to guide us towards finding the solution, we have a great opportunity to find the solution. If the constraints can guide us to reach a testable solution, then we should consider this as a potential solution and start taking steps to verify the predictions provided by the solution.

3. Let us imagine that we were able to derive a solution X. This solution should be in agreement with everything that we have already observed. If X can explain all the features of the system at various levels (in principle), then we should be prepared to accept its candidacy as a testable mechanism.

4. The virtual nature of internal sensations indicates that we should prepare ourselves to arrive at a first-principle that can provide testable predictions.

5. Based on the successful studies that allowed us to understand various phenomena in nature, the solution of the nervous system is expected to be a simple one. It is also expected to have features that continuously evaded our attention.

In order to solve the system (for all the levels), we need to use constraints obtained from multiple levels. This is a time consuming process that requires a large number of trial and error methods in the initial stage. In the absence of long-term unrestricted funding, it will not be possible to make serious attempts to solve the system. On the other hand, the large number of neurological and psychiatric patients needs urgent help. Without knowing the normal operating mechanism, it is not possible to design therapeutic methods for either prevention or treatment of several disorders. In fact, it is this context that motivated to undertake this work.

What is the main conclusion of the present work?

Semblance hypothesis has made a testable theoretical finding of a primary neuronal circuitry that resides within the synaptically-connected circuitry and has been evading our attention until now. This is the inter-postsynaptic functional LINK (IPL)-mediated circuitry described in the present work. In addition, the present work also derived a mechanism for the induction of units of internal sensation when IPLs are reactivated. According to the present work, the reactivation of IPLs provides vector components of the oscillating extracellular potentials whose frequency is tightly related to the efficiency of the system to induce internal sensations. An investigation to verify the presence of a spectrum of changes responsible for IPLs and the induction of internal sensations is needed.

What do we need to do in our experiments to verify the present work?

Current experiments are only examining single spines of neurons in to understand higher brain functions (by examining behavioral markers indicative of the generation of internal sensations of those brain functions. We find enlargement of spines and reduction in size or their elimination in experiments. We then start making correlations between these single spine changes with behavior. We fail to examine the interaction between the spine under examination and the spines in the neighboring region that belong to different neurons and how it can influence the internal sensation generated during those higher brain functions. If we look at any electron microscopic picture from cortical regions (for example, in this page see figure 9), the extracellular matrix space between abutted spines is very negligible. Since average inter-spine distance between spines on a dendritic branch is greater than the average spine diameter (Konur et al., 2003), the spines of a neuron are most likely abutted with spines that belong to other neurons. Undertaking studies by looking at how two abutted spines that belong to different neurons are interacting during a higher brain function such as learning at physiological time-scales of milliseconds will facilitate understanding of the inter-postsynaptic LINKs (IPLs) and their functions as explained in the present work. Only changes occurring at matching time-scales of learning or memory retrieval will be relevant. We cannot correlate any late occurring changes with the higher brain functions that generate internal sensations at time-scales of milliseconds.

Why do we need a first-person neuroscience?

Brain is an organ where first-person inner sensations of the mind are being generated. We have no previous experience in dealing with a system that generates first-person properties. It is a real challenge. If it is not for this challenge, many of us who work towards understanding the brain would not have been studying brain in the first place. We like to take these challenges, fail and fail again and eventually we hope one day we will become successful. In this context, we need to be very hard on the problem at hand and we need to face all the realities. Current third-person studies and efforts to use the results of such studies have shown us that we have to find the right tract. A typical example is news that is heartbreaking. During the last ten years, a large number of pharmaceutical companies moved away from drug development for neurological and psychiatric disorders (Wegener and Rujescu, 2013; Burke, 2014; Mehta et al., 2017). What is the reason? It is most likely that they have lost confidence in investing because many of the drug trials failed. For the community, it is a great loss since we have to live without having effective medications either to prevent or to reverse pathological changes in these disorders.

At this juncture, we are forced to ask, “Is there a possible reason why these drug trials constantly fail?” "What do we need to do?" A close examination shows that the studies of the higher brain functions and their dysfunctions are being carried out using surrogate markers such as speech output and behavioral motor actions for making conclusions. We are not attempting to understand the mechanism that operates to generate first-person inner sensations of memory. This is due to the lack of a scientific method to explore the first-person inner sensations of the higher brain functions. In order to design treatment methods to stop the loss of higher brain functions (e. g. memory problems) or alternations of higher brain functions (e.g., hallucinations), an exact science to explain a mechanism by which the first-person internal sensations are getting induced needs to be developed. Fixing the problems will become possible only when we truly understand the normal operational mechanism. In this context, it is necessary to develop specialized methods to explore and understand how first-person internal sensations are induced within the system. This can be best accomplished by having a dedicated first-person neuroscience. The main differences between current third-person neuroscience studies and a future first-person neuroscience studies are given the following table (Table 1).