One Unknown
The primary objective of the semblance hypothesis has been met: the space of viable mechanisms has been sufficiently constrained to a single remaining unknown—the IPL mechanism. It needs to be tested and verified.
IPLs must be able to form and get reactivated in millisecond time-scales
When presented with a set of colors, each paired with a corresponding image, most individuals can successfully encode two or more pairings within one second, suggesting that associative learning can occur on a sub-second timescale. The learning-induced changes resulting from these rapid associations can later be used to retrieve the corresponding memories.
What are the potential candidate mechanisms?
ECM acts as a buffer zone for ions, facilitating ion flux across membranes during the propagation of depolarization. It acts as an insulating medium that prevents any ephaptic connections between spines that remain abutted. Breaking this insulating barrier in millisecond timescales is the anticipated mechanism for the IPL mechanism. The following are the candidate mechanisms that can be tested.
1. Ultrafast IPL formation mechanism
Will update soon.
2. Removal of hydration layer between abutted spines
The most notable feature of the ECM in the cortex is the extremely thin space it occupies (see Fig. 14). It serves a critical role as a robust insulating medium, due to the high energy required to establish electrical connectivity (Rand and Parsegian, 1984; Cohen and Melikyan, 2004; Martens and McMahon, 2008; Harrison, 2015) between neuronal processes by displacing fluid ECM between them. The high energy requirement for establishing physical interactions between lipid membranes ensures that there will be no non-specific interactions leading to electrical continuity between neuronal processes. This also suggests that learning must trigger a biological mechanism to overcome the high energy requirement within milliseconds. This provides a functional advantage. If learning induces lipid membrane changes on millisecond timescales that overcome the energy barrier, establishing inter-neuronal electrical continuity could become a powerful learning mechanism.
Studies using artificial membranes (Leikin, 1987) suggest that the area of inter-spine hemifusion is likely limited to approximately 10 nm² or less. Astrocytic pedicels are present at only about 50% of synapses, and they occupy only 50% of the perisynaptic space (Ventura & Harris, 1999). Despite this limitation, the remaining surface area of the ECM where IPLs can be established is vast, which greatly benefits the system’s operation.
3. Partial and complete inter-spine membrane hemifusion
a) Role of SNARE and complexin proteins
Experimental evidence points to the role of SNARE proteins and complexin (see Vadakkan, 2019) may be able to overcome the energy barrier between abutted membranes. SNARE proteins are known to provide energy to bring membranes together, overcoming repulsive charges and addressing energy barriers related to curvature deformations during hemifusion between abutted membranes (Oelkers et al., 2016). They also generate the force needed to pull the membranes together as tightly as possible (Hernandez et al., 2012). By initiating the fusion process and supplying the necessary energy (Jahn and Scheller, 2006), SNARE proteins facilitate the formation of characteristic hemifusion intermediates (Lu et al., 2005; Giraudo et al., 2005; Liu et al., 2008). These properties underscore the significance of SNARE proteins in forming hemifusion intermediates between the lateral regions of spine heads. SNARE proteins are present in the postsynaptic region (Ref). Additionally, the protein complexin, present within postsynaptic terminals (Ahmad et al., 2012), is known to interact with the neuronal SNARE core complex to halt fusion at the hemifusion stage (Schaub et al., 2006). Since SNARE-mediated vesicle fusion at the presynaptic terminals occurs in milliseconds, it is anticipated that SNARE-mediated IPL formation will follow a similar timescale.
How to test them? As animals have already learned many items and events in their environment associatively, it is reasonable to expect several stable hemifused regions between spines at locations of stimulus convergence, making them detectable.
Empirical Validation
This framework calls for targeted experimental investigation to determine whether such IPLs exist and whether they uniquely satisfy the full set of constraints across cellular, electrophysiological, and systems-level domains.
Summary pdf
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 anesthetic agents
12. Conditioned learning explained using a video