Semblance Hypothesis

FAQs

Why do we need a hypothesis?

We have not yet discovered the mechanism of operation of the nervous system that provides internal sensations of various higher brain functions such as perception, memory and consciousness. The main reason is due to the fact that only the owner of the nervous system has access to these internal sensations. So far we haven't made any direct attempts to explore its formation. Hypothesis development is essential to understand how internal sensations are induced in a system with nearly 1011 neurons and 1015 synapses. A single counter-example of proof against a hypothesis can then be used as sufficient reason to modify or reject it. According to Karl Popper, a philosopher of science, a hypothesis must be falsifiable; i.e. it must at least in principle be possible to make an observation that would disprove the proposition as false, even if one has not actually (yet) made that observation (Popper 1965). Once such an observation is made, it will lead to rejection of the hypothesis. However, even with the rejection of a hypothesis, we are likely to make some conclusions that will aid in the development of new and better hypotheses.

Nervous system is being studied by large number of faculties of sciences at various levels – biochemical, cellular, electrophysiological, systems, behavioural, imaging. In order to explain all these features, the solution must be a unique one. In this regard, a testable hypothesis is highly valuable. Even though the internal sensations cannot be directly examined, we can circumvent the difficulty. If a simple unique solution can be derived to explain all the findings made at various levels, then this solution must be right. This motivated developing a hypothesis for nervous system functions. The hypothesis can then be verified in biological systems by a) searching for the predictions that can be made from the hypothesis, b) examining comparable circuit features for different sensations in remote species of animals, and c) postdictive examination of findings. Once verified, it can be further studied by the gold standard test of replicating the mechanism in engineered systems. This approach will truly enable us to undertake a cost-effective research work in the right direction.

What function should we begin examining to build the hypothesis?

Memory is the best one to study. This is because we can 1) induce changes in the nervous system during associative learning that can be verified. 2) induce first-person internal sensation of retrieved memories at physiological time-scales. 3) carry out loss of function studies. 4) test whether the hypothesis can be extended to understand consolidation of memories, perception and consciousness. 5) replicate in engineered systems to test for the formation of the first-person inner sensation of memory. 6) use the very large amount of already collected data to verify the hypothesis being built at its various stages. For example, the following questions can be addressed. a) What parallel cellular changes are taking place during testing for long-term potentiation (LTP) with a regular stimulus and retrieval of memories? b) How LTP can get correlated with the surrogate markers of behavioural motor activities indicative of the induction of internal sensation of memory?

What is the difference between single synapse strengthening hypothesis and semblance hypothesis?

Hebbian plasticity hypothesis explains changes in the strengths of single synapses during learning (synaptic plasticity changes). It is not yet known how a cue stimulus propagating through its path utilizes the changes in synaptic strength to induce memory of the associatively learned second item. In this context, the present hypothesis was developed from asking the question "At the time of memory retrieval, when one of the sensory stimuli (the cue stimulus) moves through its pathway, how can it induce inner sensation of memory of the associatively learned sensory stimulus (that moved through a second pathway at the time of learning) along with behavioral motor activity reminiscent of the associatively learned second stimulus?"

Based on the semblance hypothesis, when an associative learning takes place between two sensory stimuli, there should be certain changes at the locations where these stimuli converge (for example hippocampus in spatial memory or amygdala in fear memory). This hypothesis examined the interaction between the synapses of the associatively learned stimuli at locations of their convergence. At a later time, when one of the stimuli (cue stimulus) arrives at the locations of convergence of the two sensory stimuli, the cue stimulus should be able to induce internal sensation of the memory of the associatively learned second stimulus. Therefore, semblance hypothesis focused on identifying the locus of interaction between the two neuronal pathways and more specifically, the sub-synaptic levels between which this interaction can lead to learning induced changes from which the cue stimulus can induce inner sensations of memory of the second stimulus. In summary, synaptic plasticity hypothesis examines single synapse strength changes; whereas, semblance hypothesis examines changes occurring between the synapses at the locations of their convergence.

What are the issues with studying neuronal firing (somatic spike) in understanding higher brain functions?

Neural network studies have been carried out for the last fifty years and are finding severe difficulties in solving the nervous system. The problems can be explained as follows.

1) Investigations during the last 15 years have shown that in addition to somatic spikes (neuronal firing or action potential), there are spiking potentials occurring at the dendrites (Antic et al. 2010; Moore et al. 2017). Spikes are the summated (summed up) potentials occurring at a localized region. The purpose of the somatic spike is to propagate the potentials towards all the axonal terminals of the neurons. However, we have to still discover the function of the dendritic spikes. Only by directing our studies to interconnect as many observations as possible, we will be able to find the functional attributes of dendritic spikes that will help us to solve the system. 

2) The number of input connections (postsynapses or postsynaptic terminals or dendritic spines) vary widely among the neurons. It ranges from one (passive conductance of potentials between the initial orders of neurons of the visual pathway) to approximately 5,600 (as in a monkey’s visual cortex) to 60,000 (as in a monkey’s motor cortex) (Cragg 1967). Most often, arrival of a tiny fraction of inputs is sufficient to fire a neuron. For example, a pyramidal neuron that receives tens of thousands of inputs can fire an action potential by spatial summation (summation at the same time) of 40 EPSPs at the axonal hillock that arrives from any combination of 40 inputs (Basic electrophysiology; Palmer et al. 2014). Please note that temporal summation of even less than 40 EPSPs can induce an action potential. The combinatorial probability of the number of sets of synapses whose activation can give rise to the firing of a neuron is enormously high. This makes an action potential non-specific with regards to its inputs.

3) Thirdly, postsynaptic potentials contributing to both sub- and supra-threshold activation of a neuron do not contribute to the neuronal firing. Therefore, if there are mechanisms for inducing internal sensations occurring at the unaccounted synapses, they will get ignored if neuronal firing alone is examined. For example, let us take one pyramidal neuron (excitatory neuron) with 25,000 inputs (dendritic spines). If 3600 inputs (dendritic spines) are activated simultaneously (due to their synaptic activation) during an action, only one action potential will be elicited. Simultaneous arrival of 40 inputs at the axonal hillock is enough to induce that action potential. This means (3600 - 40) = 3560 EPSPs get wasted without having any functional use. Is this advantageous to the system? For the purpose of this discussion, let us assume that 40 EPSPs can fire a neuron. In this context, any set of inputs of less than 40 EPSPs that do not lead to the generation of action potential is also getting wasted. In what context evolution would have conserved this mechanism? The input redundancy may be a possible mechanism to achieve common set of outputs for operating the limited set of combinations of muscles in the body for achieving behavioral activities to survive in the environment. However, in the context that we are still searching for a mechanism of induction of first-person internal sensations, reminiscent of the external stimuli in their absence, it is required to examine possible mechanisms occurring at the input level. This is necessary to avoid ignoring any valuable operational mechanism occurring at the input level.

4) Postsynaptic potentials induced at the dendritic spines located at remote locations on the dendritic tree (for example, pyramidal neurons with long apical dendritic tree) has to travel long distances to reach towards the axon hillock to summate above the threshold for triggering the action potential. They degrade significantly as they reach the axon hillock (Spruston 2008). Therefore, contributions of these potentials to neuronal firing get reduced and vary depending on the distance they have to travel and the dendritic diameter. This naturally leads to the question "Why would these potentials get conserved?" Except in conditions where they contribute to the nth EPSP required to trigger the action potential, it is very likely that they are providing functions independent of the neuronal firing. Therefore, we have to think about a mechanism other than neuronal firing.

5) Since EPSPs get degraded as the distance from the dendritic spine to the soma increases, in reality EPSPs from more than 40 dendritic spines will be needed to fire a neuron. For example, let us assume that inputs from 100 spines need to arrive at the axon hillock for one event of firing of a given neuron. Let us also assume that this pyramidal neuron has 30,000 dendritic spines (inputs or postsynaptic terminals). If EPSPs arriving from nearly 100 of its dendritic spines can fire that neuron, then nearly [3x104! ÷ (100! x (3x104! – 100!))]  4.68x10289 sets of combinations of inputs can fire that neuron. If we consider that a pyramidal neuron has only 3,000 dendritic spines, then the set of combinations will reduce to 1.04x10189. This means that a gigantic number of combinations of inputs can cause the same neuronal firing. Therefore, when we see a neuron firing (somatic firing or somatic spike) (in vivo, at physiological conditions), it is not at all specific with respect to its inputs.  

6) Many times, several neurons are held at subthreshold activation. It means that they will be receiving less than 40 postsynaptic potentials all the time, just short of few potentials for triggering an action potential (neuronal firing). Neurons located at higher orders than those that are firing in an oscillating fashion (reasons for these oscillating type of neuronal firing need explanation, especially the horizontal component of the oscillations – which are explained by the present hypothesis) are mostly held at a range of subthreshold values. For example, 38 or 39 inputs arriving at higher order neurons will not lead to the firing of those neurons. These sub-threshold-activated neurons require only 1 or 2 inputs to cause their firing. Therefore, when we see these neurons firing, these neuronal firings have to be interpreted completely differently.

All the above findings show that studies using neuronal firing and networks of firing-neurons do not examine specific mechanisms that are likely to take place at the level of the inputs (dendritic spines). In addition, when it comes to the need for explaining the first-person internal sensations of higher brain functions, the current studies examining the third-person observations are a dimension away (third-person v/s first-person) from where we need to reach.

So what does a neuronal firing mean with respect to its inputs? From the above paragraphs, we have seen examples of conditions in which a neuron held at its baseline state can get fired by either 3600 inputs or just 1 input. In what context evolution would have conserved this mechanism? It may be a possible mechanism to achieve common set of outputs for operating the limited set of combinations of muscles in the body for achieving behavioral activities to survive in the environment. In the context that we are still searching for a mechanism of induction of first-person internal sensations, reminiscent of that are induced by the external stimuli (in the latter's absence), it is required to examine possible mechanisms occurring at the input level.  In the context of input redundancy in firing a neuron, this will avoid ignoring any valuable operational mechanism occurring at the input level. This will allow us to address the question from the previous subtitle "Where is the ideal location for convergence to occur that will allow the cue stimulus to induce internal sensation of the associatively learned second stimulus?" without ignoring the specificity of inputs brought by the cue stimulus. It is reasonable to expect interactive changes occurring at the input levels of the neurons at locations of convergence of associatively learned stimuli. This is examined in the new hypothesis.

What are the current challenges in memory research and how can we overcome them? 

Memories are virtual internal sensations at the time of memory retrieval. The behavioral motor activities observed along with it should be considered as surrogate markers indicative of memory retrieval. Strong correlation between the experimental finding of long term potentiation (LTP) and the surrogate behavioral motor activities at the time of memory retrieval have been observed. However, alone, LTP has certain limitations. LTP takes at least 30 seconds (Gustafsson and Wigström, 1990) and even more than a minute to reach it peak level of induction, which does not match with the physiological time-scales of changes occurring during associative learning. LTP was reported as lacking sufficiency to be the mechanism of memory storage (Shors and Matzel, 1997; Martin et al., 2000; Piorazi and Mel, 2001). Furthermore, several reported correspondences of LTP temporal phases do not correspond with that of memory phases (Abbas et al., 2015). In spite of these, the correlation between the behavioral markers of memory with LTP (excluding the time-scale issues) has some hidden facts that can provide a valuable piece of the puzzle towards understanding the cellular changes occurring during associative learning. In this context, it becomes necessary that the true mechanism of formation of first-person internal sensation of retrieved memories should be able to explain how LTP is related to memory.

Challenges in understanding the mechanistic changes during associative learning that enables cue-induced internal sensation of retrieved memory and its related effects on the observations in the field of psychology have been discussed (Gallistel and Balsam, 2014; Edelman, 2012). The challenges become manageable when the frame of reference of examination of the higher brain functions is changed from the third-person to the first-person.

What are the general requirements of a hypothesis of memory?

It should theoretically be able to explain the following features.

- Retrieval of memory at physiological time-scales

- Provision for unlimited memory life-times (Rubin and Fusi, 2007)

- Ease of learning a related task

- Disuse reduction in memory

- Instant access to very large memory stores (Abbott, 2008)  

- Should have provision for a mechanism for retaining specificity of memory retrieval                                              

- Functional integration and operation of hippocampal new neurons in learning and memory and its possible role in consolidation of memory

- Transfer of the basic units of memory for a different learning and retrieval event (Dahlin et al., 2008)

- Ability to explain the observed correlation between LTP and behavior motor activities indicative of formation of inner sensation of memory

- Ability to explain observations of sufficient memory retrieval from the cortex even when the hippocampus is removed

- Ability to explain internal sensation of perception at least as a framework

- Ability to explain internal sensation of consciousness at least as a framework

- Mechanism within the system to generate hypothesis (Abbott, 2008)

- Ability to explain some of the features of mental disorders (disease processes often help to understand the normal operational mechanism)

A hypothesis that can provide a broad framework incorporating the above features needs to be built and tested theoretically followed by experimental approaches to confirm the basic structural changes taking place both during associative learning and memory retrieval.

Explain semblance hypothesis in simple words?

Since the nature of retrieved memory changes as we keeping changing the cue stimulus from a general one to specific ones, it indicates that units of internal sensation that are induced keep changing as the cue stimulus changes. These rapid changes occurring at physiological time scales require explanation for a feasible cellular mechanism that can induce internal sensations. The induced first-person internal sensation is virtual in nature. Therefore, the aim of the semblance hypothesis is to derive a mechanism for such a function. The derived mechanism for inducing units of internal sensation should operate by a simple mechanism that can be applied universally to explain internal sensation of different higher brain functions.

The derivation of the hypothesis has two major stages. Each stage consists of a series of steps that are numbered.

Stage I

1. For the purpose of derivation of the hypothesis, memory is viewed as a virtual inner sensation of a sensory stimulus since the sensory inputs from the item memorized is not present during the retrieval of memory.

2. We store thousands of memories. A specific internal or external cue stimulus is required to retrieve a specific memory.

3. In the classical Pavlovian experiments, the conditioned and unconditioned stimuli were very distinct items reaching different sensory systems. Associated learning need not have to always take place between different sensory stimuli. Associative learning can occur between different stimuli arriving at the same sensory system that can activate different sets of sensory receptors.

4. Let us now conduct an imaginary experiment. Let us look at a violet-colored pen. While looking at it, let us assume that a specific set of 105 synapses (out of the total 1015 synapses in our brain) were activated at different orders of neurons (1st order being the order close to the sensory level). If we can specifically stimulate the set of those specific 105 synapses, it is assumed that we are likely to memorize/ imagine/ visualize that violet-colored pen.

5. How can we activate a specific set of 105 synapses out of the total 1015 synapses? Saying in a different way, how can we selectively activate each of those 105 specific synapses from a set of 1015 synapses for retrieving the memory immediately after associative learning? If we know how we can activate one of those 105 specific synapses that identify the item to be memorized, then we can extend the same mechanism to all the 105 synapses. (The chance of activating highest number synapses among the set of 105 synapses is maximum immediately after associative learning and can explain working memory).

6. Alternatively, we can address the issue in a modified way. What is the minimum requirement that satisfies activation of a synapse? Activation of the postsynaptic terminal (dendritic spine) can be taken as the equivalent of activating a synapse since the activation of a postsynaptic terminal requires the arrival of an action potential at its presynaptic terminal.

7. Since there is no sensory stimulus available from the item to be memorized, we cannot anticipate any action potential reaching at the presynaptic terminal. Therefore, we need to activate the postsynaptic terminals of the synapses that represent the learned item without any action potential reaching their presynaptic terminals during memory retrieval.

8. The above arguments get further support by the fact that lateral entry of activity of certain areas of the brain either artificially or by pathological conditions can induce virtual internal sensations in the form of hallucinations with a compelling sense of reality (Selimbeyoglu and Parvizi, 2010).

9. Activation of a postsynaptic terminal without the arrival of an action potential at its presynaptic terminal (at the synaptic level) can represent the idea of evoking a virtual sensation of a sensory stimulus (at the systems/behavioral level). In other words, the cue stimulus is expected to activate a specific set of postsynaptic terminals that can evoke virtual sensation of a sensory stimulus. Immediately after the learning, can the cue stimulus activate the postsynaptic terminals of the synapses of the path through which the learned item would travel?

10. At this point, we come across with two key questions. 1) Can we activate the postsynaptic terminal of a synapse in the absence of the arrival of an action potential at the presynaptic terminal? 2) How can we choose to activate those 105 specific postsynaptic terminals from the total 1015 synapses for specific activation immediately after associative learning? What we have is a specific cue stimulus that activates a specific set of cue-specific synapses. We can now arrive at a simple question at the synaptic level: “How can we activate a specific set of 105 postsynaptic terminals that would otherwise be activated by the item whose memory is to be retrieved in the presence of the activation of the specific set of synapses by the cue stimulus?

11. Let us assume that the cue stimulus evokes activation (depolarization) of the postsynaptic terminals through which activity from the learned item pass through. Then, it is reasonable to argue that some of the synapses through which activity spreads from the cue stimulus should be physically close enough to some of the postsynaptic terminals through which activity from the learned item passed through (for derivation of the hypothesis, physical proximity is used; mechanism other than physical proximity may operate). A mechanism should exist that can cause spread of activity from the synapses of the cue stimulus to the postsynaptic terminals of the item whose memories are retrieved (Figure 1).

                                                                                
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Figure 1. Illustration of the hypothesized depolarization spread during retrieval. During retrieval, the cue stimulus reaching presynaptic terminal A depolarizes its postsynaptic membrane B, and the depolarization spreads to postsynaptic membrane D. This can only happen, provided there is a functional LINK between the postsynaptic terminals B and D. Therefore, we can assume that a functional LINK is required to be formed between postsynaptic terminals B and D during learning.

12. Since physical closeness between the postsynaptic terminals B and D is expected, it can be assumed that for associative learning to occur, the sensory inputs from the cue stimulus and the item whose memory is to be retrieved should inevitably converge at some brain locations. (Note: The hippocampus, identified as a location important for learning and memory, receives inputs from all the sensory systems). What should be the critical change occurring during learning between the synapses activated by the cue stimulus and the item whose memory is retrieved? Between what locations of the synapses that these changes should take place? Since neurotransmission is a unidirectional process, activation of the postsynaptic terminal can be viewed as equivalent to activation of the synapse. Therefore, the interaction taking place between the postsynaptic terminals may fulfill the requirements. Moreover, for the specific mechanism of induction of internal sensations (sembalnce), an interaction between the postsynaptic terminals is required (please see the semblance formation part). Therefore, during learning a functional LINK is established between the postsynaptic terminals of the cue stimulus and the item to be learned (Figure 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 the cue stimulus and the postsynaptic terminal activated by the item to be learned during associative learning. The reactivation of the inter-postsynaptic functional LINK is a function of arrival of activity at either one of the postsynaptic terminals at the time of memory retrieval. The term LINK is written in capital letters to indicate that it is the key element of the hypothesis and that we have to explore it further to discover its exact nature. The building units formed by inter-postsynaptic functional LINK has the advantage that as the features of the cue stimulus changes, the postsynaptic terminals activated through the functional LINKs changes and the retrieved memory is also changed.     

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Figure 2. Illustration showing the hypothesized functional LINK formed between the two postsynaptic membranes B and D during associative learning.

13. During learning, co-activation of synapses from the learned item and the cue stimulus needs to induce specific changes that will later allow the cue stimulus alone to evoke activation of the set of postsynaptic membranes that belong to the learned item. This leads to the generation of the semblance hypothesis. A unit of memory, in the presence of an internal or external cue stimulus, results from the ability to induce specific postsynaptic events at the synapses of the neurons from the learned item without the requirement of action potentials reaching their presynaptic sides.

14. The inter-postsynaptic functional LINKs formed during associative learning could be of different types:

a.
Those that are formed by removal of water of hydration between the postsynptic terminals, which will allow abutting of the membranes. This requires very high energy and will lead to 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 postsyaptic terminals. This can explain 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 retension 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.

15. Inter-postsynaptic functional LINK may be viewed as biological parallels of
K-lines proposed by Marvin Minsky (Minsky, 1980) who was the founder of MITs Artificial Intelligence program.

16. Let us examine the effects of propagation of depolarization through the inter-postsynaptic functional LINKs. As discussed before, activity arriving at the postsynaptic terminals of the synapse activated by the cue stimulus will propagate through the inter-postsynaptic functional LINK to the second postsynaptic terminals that will otherwise be activated by the learned item (Figure 3). The arrival of the cue stimulus and the reactivation of inter-postsynaptic functional LINK happens only occasionally. Therefore, when the second postsynaptic terminal is depolarized incidentally in the absence of the arrival of an action potential at its corresponding presynaptic terminal, then this second postsynaptic terminal gets the illusion of an action potential reaching at its presynaptic side, resulting in “synaptic semblance". This induces the unit of virtual inner sensation of memories at the time of memory retrieval.

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Figure 3. During retrieval, the cue stimulus reaching presynaptic terminal A depolarizes its postsynaptic membrane B, re-activates the inter-postsynaptic functional LINK. In this manner, depolarization spreads to postsynaptic membrane D evoking cellular illusion at the postsynaptic terminal D of an action potential reaching at its presynaptic terminal C. This is named synaptic semblance.

17. When the related learning events continue, one of the postsynaptic terminals (either B or D in the figure 3) 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, Figure 4). As this process continues, it will result in the formation of islets of LINKed (LINKable/ re-activatible during retrieval) postsynaptic terminals (right panel, Figure 4).

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Figure 4. Left panel: Illustration showing LINKable postsynaptic terminals. Multiple postsynaptic terminals (dendritic spine heads) belonging to dendrites of different neurons can become functionally connected to each other upon coincident activation. Only two presynaptic terminals (A and C) and two postsynaptic terminals (B and D) are marked. Assume that there are nearly one hundred postsynaptic terminals arranged in a horizontal plane. The dotted line shows a cross-section across the postsynaptic terminals and used in the right panel.

Right panel: A hypothetical cross-sectional view of LINKed postsynaptic terminals of the synapses in one horizontal plane in a brain region (see the horizontal dotted line across the postsynaptic membranes in the left panel); in this illustration, we imagine that all the postsynaptic membranes are in the same plane. Postsynaptic membranes are shown in small dark circles (broken arrow). When learning occurs, functional LINKs between simultaneously activated postsynaptic terminals can be established. Continued learning using any of those synapses will increase the number of interconnected postsynaptic membranes forming islets of functionally LINKed postsynaptic terminals (solid arrow). Multiple LINKs between the postsynaptic terminals in an islet can cause the spread of excitatory postsynaptic potential (EPSP) across the islet. The individual islets are expected to be functionally separate from each other.

To which neurons do the postsynaptic terminals that inter-LINK belong to?

Since the mean inter-spine distance is even larger than the mean spine diameter (Konur et al., 2013), the inter-LINKing postsynaptic terminals should belong to different neurons. This is also essential to maintain the specific outputs associated with each of the associatively-learned sensory inputs. This is expected to be the general rule. There could be exceptions; for example, when granule neuron axonal terminals continuously form synapses with the dendritic spines of a CA3 neuron.

Stage II

In the next stage, the basic units of semblances occurring at the functionally inter-LINKed postsynaptic terminal are derived (Figure 5). Activation of the postsynaptic terminal B leads to re-activation of inter-postsynaptic functional LINK and activates the postsynaptic terminal D. At the postsynaptic terminal D, this leads to semblance of activity arriving from neuron Z in the neuronal order 5. Neuron Z is normally depolarized by activating a set of axonal terminals of the neurons in order 4 (in Figure 5) 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 (Number of postsynaptic terminals (dendritic spines) for a neuron varies widely. For example, the early orders of neurons in the retina has only few postsynaptic terminals; however, in the hippocampus we expect that the excitatory neurons to have postsynaptic terminals in the order of 104). Let the set of all combinations (for the spatial summation of EPSPs) and permutations (for the temporal summation of EPSPs) of the neurons in neuronal order 4 whose activity through both normal synaptic transmission and spread of activity through the functional LINKs ((A) and (B) respectively (in the inset of Figure.5).

In the same way, the neurons in set {Y} in turn receive synaptic transmissions and spread of activity through the 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 neuron Z. Dimensions of internal sensations resulting from the activation of neuron Z will be related to a 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} in Figure 5) is sufficient to activate postsynaptic terminal D (or neuron Z). 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 (or neuron Z) is derived. This is hypothesized as the basic unit of internal sensation of memory.

                                             
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Figure 5. Schematic representation of sensory elements induced during the activation of a synapse or a neuron. The gray circles represent neurons. The numbers on the left side of the neuronal orders denote their position in relation to the sensory receptors. Neuron Z is shown in neuronal order 8. During memory retrieval, a cue-stimulus (marked by asterisk) reaching presynaptic terminal A depolarizes its postsynaptic membrane B and the resulting EPSP at postsynaptic terminal B re-activates the functional LINK that activates postsynaptic membrane D (Mechanisms other than depolarization are also considered (Vadakkan, 2010)). When postsynaptic membrane D is depolarized, it evokes the cellular hallucination of an action potential reaching its presynaptic terminal C. This is called synaptic semblance. Note that presynaptic terminal C belongs to the neuron Z. Either synaptic semblance occurring at the postsynaptic terminal D or random activation of neuron Z produces the hallucination that it is receiving inputs from the set of neurons {Y} that synapse to it. The set of neurons {Y} are activated by the activation of the set of neurons {X}. The set of neurons {X} in turn are activated by the set of neurons in the neuronal order above it. (Recurrent collaterals and projection neurons can also activate a higher order neuron. For simplicity these are not shown). Continuing this extrapolation towards the sensory level identifies a set of sensory receptors {SR}. It can be seen that stimulation of subsets of sensory receptor sets {sr1}, {sr2}, and {sr3} from the set {SR} may be capable of independently activating neuron Z. The dimensions of hypothetical packets of sensory stimuli capable of activating the sensory receptor sets {sr1}, {sr2}, and {sr3} are called semblions 1, 2 and 3 respectively. These semblions are viewed as the basic building blocks of the virtual internal sensations of memory. A cue stimulus can cause postsynaptic terminal D to hallucinate about any of the semblances 1, 2, 3 or an integral of them. Activation of the postsynaptic terminal D or the neuron N by the cue stimulus or the artificial activation of neuron Z can lead to the virtual internal sensation of semblions 1, 2, 3 or an integral of them. The method of integrating the semblions that match can with the internal sensations induced by the cue stimulus with that of the item whose memory is retrieved can be determined by computational studies. Inset: Circles represent the soma of neurons. (A) A dendritic spine (postsynaptic terminal) of a neuron receives synaptic transmission. (B) Another of its dendritic spine receives activity through a functional LINK. Straight arrows show normal spread of activity. Dotted arrows show the direction of extrapolation of semblance (From Vadakkan, 2011).

As the cue stimulus passes through different functional LINKs, it evokes large number of semblances as explained above. Once these possible semblions are identified, their integration can be carried out to obtain net semblance that matches the sensory characteristics of the item whose memory is retrieved. Attempts to match the different computational 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 life-span 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 subthreshold activated level (Figure 6).

                                

Figure 6. Diagram showing the formation of internal sensations and fine control of the motor activation by a cue stimulus. Oscillating neuronal activity results in the activation of many downstream neurons. They can be kept tonically inhibited under resting conditions (not shown) to subthreshold levels such that they can be disinhibited at the arrival of one or a few excitatory postsynaptic potentials (EPSPs). There were two associative learning events that occurred previously with the cue stimuli. The first one was with items 1 and 2. After this first step of associative learning, the cue stimulus was retrieving memories of items 1 and 2. Note the reactivation of a sparse inter-postsynaptic functional LINK in the cortex. Along with retrieving memory of the second item, cue stimulus also evokes a motor response using the motor neuron. At a later time, the same cue stimulus had undergone a second associative learning event with item 3. Following this second learning event, the cue stimulus evoked internal sensations (semblances) of learned items 1, 2 and 3. However, as the semblance for item 3 was evoked, it also resulted in an inhibition of the motor activity (note the output from postsynaptic terminal D3 providing inhibitory potentials to the upper motor neuron). This type of an event is an example of the behavioral inhibition occurring at the frontal cortices. Complexities of the internal sensations can be based on the nature of the cue stimulus, previous associative learning, and the type of the nervous system. Reward-induced associative learning may be facilitated by dopamine-induced enlargement of dendritic spines (Yagishita et al., 2014) that promotes possible inter-postsynaptic membrane hemifusion and its stabilization for a long period of time. Also note that the cue stimulus reactivates inter-postsynaptic functional LINKs at other cortical areas to evoke memories for learned item 1. Since the inter-postsynaptic functional LINKs are transient and need reinforcement for long-term persistence, the induction of a minimum number of inter-postsynaptic functional LINKs alone may not maintain the effect of learning for a long period of time. In the hippocampus, the reactivation of inter-postsynaptic functional LINKs in response to spatial stimuli is expected to induce semblances for memories associated with that space and the EPSPs arriving through the inter-postsynaptic LINK induce firing of subthreshold-activated CA1 neurons (place cells). This explains how spatial memories are associated with place cell firing. Formation of circuits in this manner can explain the induction of internal sensations along with simultaneous behavioral motor action. Note the formation of a sparse inter-postsynaptic functional LINK at the cortex, which can contribute to specificity of retrieved memory (for a more complex path of its formation, see figure 9 in Vadakkan, 2015b). EPSP: excitatory postsynaptic potential. (n)th EPSP: the last EPSP necessary to achieve threshold EPSP to generate an action potential. Each motor action will evoke certain sensory stimulus in the form of proprioception that will act as a feedback stimulus to the system confirming that the motor action was executed. N: Excitatory neuron; IN: Inhibitory neuron. A and C: Presynaptic terminals; B and D: Postsynaptic terminals. Red line between B and D: Inter-postsynaptic LINK. (+) stimulation; (-) inhibition (Modified from Vadakkan KI, Reviews in the Neurosciences, 2015).

What is the logic behind induction of semblances?

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 3, when cue stimulus arrives at the postsynaptic terminal B and re-activate 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, 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 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 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 occur 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 the nature of inter-postsynaptic functional LINK?

Different mechanisms for the formation of inter-postsynaptic LINKs are possible and are required to explain 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 are given in Figure 7.

                                                     AI from neuroscience

Figure 7. Different types of reversible inter-postsynaptic functional LINKs. a) Two abutted synapses A–B and C–D. Presynaptic terminals A and C are shown with synaptic vesicles (in blue color). Action potential arrives at presynaptic terminal A releasing a volley of neurotransmitters from many synaptic vesicles inducing an excitatory postsynaptic potential (EPSP) at postsynaptic terminal B. The waveform represents the direction towards which the EPSP propagates. From the presynaptic terminal C, one vesicle is shown to release its contents to the synaptic cleft. This quantal release is a continuous process (even during rest) providing very small potentials to postsynaptic membrane D. Postsynaptic terminals B and D have membrane-bound vesicles marked V inside them. These vesicles contain glutamate receptor subtype 1 (GluA1). Activity arriving at the synapse can lead to exocytosis of GluA1 receptor-subunits and expansion of the postsynaptic membrane. During exocytosis, the vesicle membrane is added to the postsynaptic membrane at locations of exocytosis making this region of the membrane highly re-organizable. This matches with the location where α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor subunits were shown to concentrate at the extra-synaptic locations extending at least 25 nm beyond the synaptic specialization (Jacob and Weinberg 2014). Note the presence of a hydrophilic region separating postsynaptic terminals B and D. When action potential arrives at the presynaptic terminal, it activates synapse AB and an EPSP is induced at postsynaptic terminal B. The hydrophilic region prevents any type of interaction between postsynaptic terminals B and D. Very high energy is required for excluding the inter-postsynaptic hydrophilic region (Martens and McMahon 2008). b) Membrane expansion can provide sufficient energy to exclude the inter-postsynaptic hydrophilic region allowing close contact between the postsynaptic membranes at this region. Action potential arriving at synapse AB reactivates the inter-postsynaptic functional LINK formed by close inter-postsynaptic contact and spreads to postsynaptic terminal D. an membrane segment marked in Turkish blue shows area where membrane reorganization occurs. c) Diagram showing formation of a partial inter-postsynaptic membrane hemifusion following anesthesia. Note the interaction between the outer layers of membranes of the postsynaptic terminals. Depending on the lipid membrane composition and the type and concentration of anesthetics, the process of close contact between the membranes described in above section (b) can get converted to a partial hemifusion state. d) Stage of partial hemifusion can progress to complete hemifusion. Any transmembrane protein inserted to the hemifused segment can maintain the inter-postsynaptic functional LINK for long periods of time. e) Hemifusion can advance to a complete fusion state depending on several factors. Fusion of the postsynaptic terminals (dendritic spines) between two different neurons can lead to cytoplasmic content mixing and cytotoxic cell response. These include dendritic spine loss and eventually triggering of apoptosis leading to neurodegenerative changes (Figure modified from Vadakkan KI (2015a, b).

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 (Figure 7B) 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 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 (Figure 8) 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.

                                                                        AI from Neurons

Figure 8. This figure is Figure 4D from Burette A.C, Lesperance T, Crum J, Martone M, Volkmann N, Ellisman M.H, and Weinberg RJ (2012) Electron Tomographic Analysis of Synaptic Ultrastructure. Journal of Comparative Neurology 520 (12): 2697-2711. This figure is modified by inserting a red arrow. The red arrow points towards a likely inter-postsynaptic area with only 2 layers of membrane instead of the expected 4 layers. Even though tissue distortions during tissue processing and folded membrane are possibilities, such changes that can span for distances of only 100 nm is very unlikely. This observation indicates the possibility that it is an area of inter-postsynaptic membrane hemi-fusion. It needs further dedicated studies for verification. The green arrow points to a likely location where the close contact between membranes is visible. Since some of the cell processes are likely astrocytic pedocytes, dedicated studies are required to verify these observations. Scale bar = 100nm.

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

In Figure 5, 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?

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 correlation between memory and LTP and can explain why it has led to 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 inter-relationship 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 reasoning 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 as explained in figure 1. 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 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 two-fold, forming a mega-islet of LINKed postsynaptic terminals (Figure 9).

                                                                                      Neurons, synapses and AI

Figure 9. Illustration explaining the basis of long term potentiation (LTP) based on the present hypothesis. Illustration shows potential LINKable site between islets of postsynaptic terminals (dendritic spines) (please see the figure 4 for details of the islets; they are visualized by hypothetical cross-sectional view through functionally LINKed postsynaptic terminals) that belong to two different CA1 neurons. During an associative learning, LINK formed between the postsynaptic terminals (marked with asterisks) of islets 1 and 2 (large circles) can lead to the formation of a mega-islet that can continue to contribute to the LTP recorded from the recording electrode as explained in the text. Position of the stimulating electrode is at the Schaffer collaterals. Shaffer collateral from the CA3 neurons synapse to the dendritic spines (postsynaptic terminals) of the CA1 neurons. Many of these postsynaptic terminals are functionally LINKed to form islets in an animal (see figure 4 for details of the islets of functional LINKs). Here two such islets I and II (large circles) are shown. One of the postsynaptic terminals from each of the islets I and II is shown to continue towards the soma of the CA1 neurons. Activation of any one of the postsynaptic terminal within an islet will result in EPSP spread towards the somas of the CA1 neuron. The islets are formed between postsynaptic terminals that are concurrently activated during previous associative learning. During an associative learning of a novel item or during induction of LTP (note the position of the stimulating electrode is at the Schaffer collaterals), a new functional LINK may form between the postsynaptic terminals (marked asterisks) of islets I and II. This can lead to the formation of a mega-islet combining the two islets. This can contribute to the LTP recorded from the recording electrode as explained in the text.

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 field EPSP, 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 terminals 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 non-specifically LINKed during the 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 retrieva
l.

The following diagram (Fig. 10) demonstrates the similarities between the cellular processes in LTP following induction and internal sensation of retrieved memory following associative learning.

                                   Comparison between LTP and memory

Figure 10. Illustration showing the structural mechanism of formation of internal sensation of memory and its relationship with a possible mechanism of LTP. (A) During memory retrieval, a cue-stimulus reaching presynaptic terminal A depolarizes its postsynaptic terminal B, re-activates the hemi-fused inter-postsynaptic membrane and activates postsynaptic terminal D, evoking a cellular illusion of an action potential reaching latter's presynaptic terminal C. In normal conditions, an action potential reaches presynaptic terminal C when the CA3 neuron is activated. Sensory identity of the semblance of activity occurring at the postsynaptic terminal D consists of inputs from the set of neurons {Y} that synapse to the CA3 neuron. The set of neurons {Y} are normally activated by inputs from a set of lower order neurons {X}. The set of neurons {X} in turn are activated by a further large set of its lower order neurons {W}. Continuing this extrapolation toward the sensory level identifies a set of sensory receptors {SR}. {sr1}, {sr2}, and {sr3} are subsets of {SR} and are capable of independently activating the CA3 neuron. Hypothetical packets of sensory stimuli activating sensory receptor sets {sr1}, {sr2}, and {sr3} are called semblions 1, 2, and 3, respectively. The activation of the postsynaptic terminal D by the cue stimulus can lead to the virtual internal sensation of semblions 1, 2, 3 or an integral of them. A CA1 neuron (place cell in the context of spatial memory) is shown to receive sub-threshold excitatory postsynaptic potential (EPSP) from oscillating neuronal activities of its lower order neurons. Cue stimulus-induced activation of postsynaptic terminal D reaches the soma of its neuron in the CA1 region. If the CA1 neuron receives a baseline summated EPSP short of one EPSP to trigger an action potential, then the additional EPSP arriving from the postsynaptic terminal D can add to sub-threshold EPSP, inducing an action potential in the CA1 neuron, resulting in its concurrent activation during memory retrieval; this CA1 neuron will not otherwise be activated in the absence of prior associative learning. This can explain place cell (CA1neuron) firing occurring concurrently with spatial memory retrieval. Bottom Panel: Cross-section through the postsynaptic terminals showing a newly formed functionally LINKed postsynaptic terminals B and D during associative learning. Three other islets are also shown. (B) Stimulation of the Schaffer collateral induces LTP by inducing postsynaptic membrane hemi-fusion between postsynaptic terminals that belong to islets of postsynaptic terminals B-D and F-H-J-L forming a mega-islet B-D-F-H-J-L. A regular stimulus at the stimulating electrode has now an increased probability of reaching the recording electrode through the large number of hemi-fused postsynaptic membranes within the large mega-islet, showing a potentiated effect when recorded from the CA1 neuron. Neuronal orders from 1 to 6 are numbered from the sensory receptors. Bottom Panel: Cross-section of an area containing the newly formed mega-islet of functionally LINKed postsynaptic terminals B-D-F-H-J-L formed during LTP induction. Two other islets are also shown. {SR}, Set of sensory receptors; {sr}, subset of sensory receptors. If LTP-induced mega-islets include postsynaptic terminals B and D, it reduces the specificity of retrieved memories in retrieving memories since spread of activity through different non-specific postsynaptic terminals of the islet induces non-specific semblances (From Vadakkan (2012).

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 the assumption to be correct is high. 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 provides suitability to explain different higher brain functions with varying duration of their existence, 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. These fitting conditions make induction of semblance as an appropriate assumption. In fact, the anatomical location consisting of the postsynaptic terminals with the inter-postsynaptic LINK is an ideal plot. When examination of various nervous system functions were continued, it was possible to observe very large number of well-fitting findings such as the following.  

    Operates in unison with synaptically-connected neurons

     Testable mechanism that can induce virtual internal sensations

     Retrieval of memory takes place at physiological time-scales

     Specificity for retrieved memory in response to a specific cue stimulus

     Explains working, short and long-term memory as part of the same mechanism

     Has provision for forgetting

     Dependent on the extracellularly recorded oscillating potentials

     Explains motivation-induced increase in learning due to dopamine’s effect

     Has the ability to store very large number of memories

     Can explain how memory can be retrieved after very long period of time after the learning

     Explains how locations of memory storage can be changed to explain consolidation of memory

     Explains a framework for the system to make a hypothesis

     Provides mechanism for internal sensation of sensory perception

     Explains how place cell fire in the presence of a spatial stimulus

     Ability to initiate motor activity with only an intention to move

     Explains innate behavior for survival of the animal. For example, for sucking, swallowing

     Loss of function explains pathologies

      a)  Dementia occurring secondary to various aetiologies

      b)  Neurodegeneration

      c)  Hallucinations in psychiatric disorders

     Explains how dopamine can induce hallucinations

     Explains a cellular mechanism for long-term potentiation (LTP)

     Explains how the system operates with very low energy expenditure

     Provided a framework for consciousness

     Provided an explanation how consciousness is correlated with oscillating potentials

     Provided a feasible mechanism of action of anesthetic agents that blocks consciousness

     Explains how dopamine that can enlarge dendritic spines reduce requirement for anesthetics

     Inter-postsynaptic functional LINKs match with K-lines proposed (Minsky, 1979)

    Testable both in biological and engineered systems

 

    The ability to explain the above features, some of them at at least in the form of well-supported frameworks increases the probability that the original assumption is likely correct.

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