Rapid chain generation of interpostsynaptic functional LINKs can trigger seizure generation: Evidence for potential interconnections from pathology to behavior.

The experimental finding that a paroxysmal depolarizing shift (PDS), an electrophysiological correlate of seizure activity, is a giant excitatory postsynaptic potential (EPSP) necessitates a mechanism for spatially summating several EPSPs at the level of the postsynaptic terminals (dendritic spines). In this context, we will examine reversible interpostsynaptic functional LINKs (IPLs), a proposed mechanism for inducing first-person virtual internal sensations of higher brain functions concurrent with triggering behavioral motor activity for possible pathological changes that may contribute to seizures. Pathological conditions can trigger a rapid chain generation and propagation of different forms of IPLs leading to seizure generation. A large number of observations made at different levels during both ictal and interictal periods are explained by this mechanism, including the tonic and clonic motor activity, different types of hallucinations, loss of consciousness, gradual worsening of cognitive abilities, a relationship with kindling (which uses an augmented stimulation protocol than that used for inducing long-term potentiation (LTP), which is an electrophysiological correlate of behavioral makers of internal sensation of memory), effect of a ketogenic diet on seizure prevention, dendritic spine loss in seizure disorders, neurodegenerative changes, and associated behavioral changes. The interconnectable nature of these findings is explained as loss of function states of a proposed normal functioning of the nervous system.

A Derived Mechanism of Nervous System Functions Explains Aging-Related Neurodegeneration as a Gradual Loss of an Evolutionary Adaptation.

BACKGROUND: Solving the nervous system requires understanding how it generates inner sensations of "mind" within it. It was possible to derive a hypothesis of brain functions where the formation of a spectrum inter-postsynaptic (inter-spine) functional LINKs (IPLs) are the key structural changes responsible for encoding at the time of learning and are used for inducing the inner sensation of memory, both taking place at millisecond timescales. Since stages of ontogeny reflect possible stages of evolution, it is possible to examine whether IPLs have features of an evolved mechanism. OBJECTIVE: To examine whether 1) IPLs have features of an evolved mechanism, 2) significant neuronal death during ontogeny leads to evolutionary adaptations for preventing cell death among the surviving neurons, and 3) loss of these adaptations lead to cellular changes that can cause agingrelated neurodegeneration. METHODS: Key milestone changes of the ontogeny of the nervous system were examined to test whether they match with a feasible sequence of steps that lead to the formation of IPLs. RESULTS: Several developmental stages can explain a probable sequence of events that lead to IPL formation among synaptically-connected neurons. When internal sensations generated by the IPLs started providing survival advantage, evolution has started preserving the IPL circuitry. A stage of inter-spine fusion possibly leads to a) significant neuronal death during the early stages of development, and b) trigger an adaptation in the surviving cells to stabilize and prevent the IPLs from undergoing fusion. Since there are no irreversible steps for maintaining the stability of IPLs, agingrelated factors may destroy the adaptation mechanism and destabilize the IPLs predisposing them to cause neurodegeneration. CONCLUSION: The derived testable IPL mechanism that can explain nervous system functions is capable to have evolved. An adaptation to prevent IPL hemifusion from progressing to fusion is likely the last stage of nervous system evolution. Since the IPL mechanism is utilized during every event of learning, any aging-related factors that can weaken this adaptation can cause IPL fusion and lead to neurodegeneration.

Presynaptic and postsynaptic amplifications of neuropathic pain in the anterior cingulate cortex.

Neuropathic pain is caused by a primary lesion or dysfunction in the nervous system. Investigations have mainly focused on the spinal mechanisms of neuropathic pain, and less is known about cortical changes in neuropathic pain. Here, we report that peripheral nerve injury triggered long-term changes in excitatory synaptic transmission in layer II/III neurons within the anterior cingulate cortex (ACC). Both the presynaptic release probability of glutamate and postsynaptic glutamate AMPA receptor-mediated responses were enhanced after injury using the mouse peripheral nerve injury model. Western blot showed upregulated phosphorylation of GluR1 in the ACC after nerve injury. Finally, we found that both presynaptic and postsynaptic changes after nerve injury were absent in genetic mice lacking calcium-stimulated adenylyl cyclase 1 (AC1). Our studies therefore provide direct integrative evidence for both long-term presynaptic and postsynaptic changes in cortical synapses after nerve injury, and that AC1 is critical for such long-term changes. AC1 thus may serve as a potential therapeutic target for treating neuropathic pain.

From cells to sensations: A window to the physics of mind.

Principles of methods for studying particles and fields that cannot be sensed by third-person observers by routine methods can be used to understand the physics of first-person properties of mind. Accordingly, whenever a system exhibits disparate features at multiple levels, unique combination of constraints offered by them direct us towards a solution that will be the first principle of that system. Using this method, it was possible to arrive at a third-person observable solution-point of brain-mind interface. Examination of this location identified a set of unique features that can allow an associatively learned (cue) stimulus to spark hallucinations that form units of first-person internal (inner) sensations reminiscent of stimuli from the associatively learned second item in timescales of milliseconds. It allows us to peep into a virtual space of mind where different modifications and integrations of units of internal sensations generate their different net conformations ranging from perception to an inner sense of hidden relationships that form a hypothesis. Since sparking of inner sensations of the late arriving (when far away) or non-arriving (when hidden) features of items started providing survival advantage, the focus of evolution might have been to optimize this property. Hence, the circuity that generates it can be considered as the primary circuitry of the system. The solution provides several testable predictions. By taking readers through the process of deriving the solution and by explaining how it interconnects disparate findings, it is hoped that the factors determining the physics of mind will become evident.

A potential mechanism for first-person internal sensation of memory provides evidence for the relationship between learning and LTP induction.

Studies conducted to verify learning-induced changes anticipated from Hebb's postulate led to the finding of long-term potentiation (LTP). Even though several correlations have been found between behavioural markers of memory retrieval and LTP, it is not known how memories are retrieved using learning-induced changes. In this context, the following non-correlated findings between learning and LTP induction provide constraints for discovering the mechanism: 1) Requirement of high stimulus intensity for LTP induction in contrast to what is expected for a learning mechanism, 2) Delay of at least 20 to 30 s from stimulation to LTP induction, in contrast to mere milliseconds for associative learning, and 3) A sudden drop in peak-potentiated effect (short-term potentiation) that matches with short-lasting changes expected during working memory and occurs only at the time of delayed LTP induction. When memories are viewed as first-person internal sensations, a newly uncovered mechanism provides explanation for the relationship between memory and LTP. This work interconnects large number of findings from the fields of neuroscience and psychology and provides a further verifiable mechanism of learning.

Calcium calmodulin-stimulated adenylyl cyclases contribute to activation of extracellular signal-regulated kinase in spinal dorsal horn neurons in adult rats and mice.

The extracellular signal-regulated kinase (Erk) cascades are suggested to contribute to excitatory synaptic plasticity in the CNS, including the spinal cord dorsal horn. However, many of their upstream signaling pathways remain to be investigated. Here, we demonstrate that glutamate and substance P (SP), two principal mediators of sensory information between primary afferent fibers and the spinal cord, activate Erk in dorsal horn neurons of both adult rat and mouse spinal cord. In genetic knock-out mice of calcium calmodulin-stimulated adenylyl cyclase subtypes 1 (AC1) and 8 (AC8), activation of Erk in dorsal horn neurons were significantly reduced or blocked, either after peripheral tissue inflammation or by glutamate or SP in spinal cord slices. Our studies suggest that AC1 and AC8 act upstream from Erk activation in spinal dorsal horn neurons and the calcium-AC1/AC8-dependent Erk signaling pathways may contribute to spinal sensitization, an underlying mechanism for the development of persistent pain after injury.

Genetic reduction of chronic muscle pain in mice lacking calcium/calmodulin-stimulated adenylyl cyclases.

BACKGROUND: The Ca2+/calmodulin-stimulated adenylyl cyclase (AC) isoforms AC1 and AC8, couple NMDA receptor activation to cAMP signaling pathways in neurons and are important for development, learning and memory, drug addiction and persistent pain. AC1 and AC8 in the anterior cingulate cortex (ACC) and the spinal cord were previously shown to be important in subcutaneous inflammatory pain. Muscle pain is different from cutaneous pain in its characteristics as well as conducting fibers. Therefore, we conducted the present work to test the role of AC1 and AC8 in both acute persistent and chronic muscle pain. RESULTS: Using an acute persistent inflammatory muscle pain model, we found that the behavioral nociceptive responses of both the late phase of acute muscle pain and the chronic muscle inflammatory pain were significantly reduced in AC1 knockout (KO) and AC1&8 double knockout (DKO) mice. Activation of other adenylyl cyclases in these KO mice by microinjection of forskolin into the ACC or spinal cord, but not into the peripheral tissue, rescued the behavioral nociceptive responses. Additionally, intra-peritoneal injection of an AC1 inhibitor significantly reduced behavioral responses in both acute persistent and chronic muscle pain. CONCLUSION: The results of the present study demonstrate that neuronal Ca2+/calmodulin-stimulated adenylyl cyclases in the ACC and spinal cord are important for both late acute persistent and chronic inflammatory muscle pain.

Presynaptic regulation of the inhibitory transmission by GluR5-containing kainate receptors in spinal substantia gelatinosa.

GluR5-containing kainate receptors (KARs) are known to be involved in nociceptive transmission. Our previous work has shown that the activation of presynaptic KARs regulates GABAergic and glycinergic synaptic transmission in cultured dorsal horn neurons. However, the role of GluR5-containing KARs in the modulation of inhibitory transmission in the spinal substantia gelatinosa (SG) in slices remains unknown. In the present study, pharmacological, electrophysiological and genetic methods were used to show that presynaptic GluR5 KARs are involved in the modulation of inhibitory transmission in the SG of spinal slices in vitro. The GluR5 selective agonist, ATPA, facilitated the frequency but not amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) in SG neurons. ATPA increased sIPSC frequency in all neurons with different firing patterns as delayed, tonic, initial and single spike patterns. The frequency of either GABAergic or glycinergic sIPSCs was significantly increased by ATPA. ATPA could also induce inward currents in all SG neurons recorded. The frequency, but not amplitude, of action potential-independent miniature IPSCs (mIPSCs) was also facilitated by ATPA in a concentration-dependent manner. However, the effect of ATPA on the frequency of either sIPSCs or mIPSCs was abolished in GluR5-/- mice. Deletion of the GluR5 subunit gene had no effect on the frequency or amplitude of mIPSCs in SG neurons. However, GluR5 antagonist LY293558 reversibly inhibited sIPSC and mIPSC frequencies in spinal SG neurons. Taken together, these results suggest that GluR5 KARs, which may be located at presynaptic terminals, contribute to the modulation of inhibitory transmission in the SG. GluR5-containing KARs are thus important for spinal sensory transmission/modulation in the spinal cord.

Substantive nature of sleep in updating the temporal conditions necessary for inducing units of internal sensations.

Unlike other organs that operate continuously, such as the heart and kidneys, many of the operations of the nervous system shut down during sleep. The evolutionarily conserved unconscious state of sleep that puts animals at risk from predators indicates that it is an indispensable integral part of systems operation. A reasonable expectation is that any hypothesis for the mechanism of the nervous system functions should be able to provide an explanation for sleep. In this regard, the semblance hypothesis is examined. Postsynaptic membranes are continuously being depolarized by the quantally-released neurotransmitter molecules arriving from their presynaptic terminals. In this context, an incidental lateral activation of the postsynaptic membrane is expected to induce a semblance (cellular hallucination of arrival of activity from its presynaptic terminal, which forms a unit for internal sensation) of the arrival of activity from its presynaptic terminal as a systems property. This restricts induction of semblance to a context of a very high ratio of the duration of the default state of neurotransmitter-induced postsynaptic depolarization to the total duration of incidental lateral activations of the postsynaptic membrane. This requirement spans within a time-bin of a few sleep-wake cycles. Since the duration of quantal release remains maximized, the above requirement can be achieved only by ceiling the total duration of incidental lateral activations of the postsynaptic membrane, which necessitates a state of sleep.

The functional role of all postsynaptic potentials examined from a first-person frame of reference.

When assigning a central role to the neuronal firing, a large number of incoming postsynaptic potentials not utilized during both supra- and subthreshold neuronal activations are not given any functional significance. Local synaptic potentials at the apical dendrites get attenuated as they arrive at the soma to nearly a twentieth of what a synapse proximal to the soma produces. Conservation of these functions necessitates searching for their functional roles. Potentials induced at the postsynapses of neurons of all the neuronal orders activated by sensory inputs carry small bits of sensory information. The activation of these postsynapses by any means other than the activation from their corresponding presynaptic terminals, that also contribute to oscillating potentials, induce the semblance of the arrival of activity from their presynaptic terminals. This is a candidate mechanism for inducing the first-person internal sensory elements of various higher brain functions as a systems property. They also contribute to the firing of subthreshold-activated neurons, including motor neurons. Operational mechanism of inter-postsynaptic functional LINKs can provide necessary structural requirements for these functions. The functional independence of the distal dendritic compartment and recent evidence for in vivo dendritic spikes indicate their independent role in the formation of internal sensory elements. In these contexts, a neuronal soma is flanked by a large number of quasi-functional internal sensory processing units operated using very little energy, even when a neuron is not firing. A large number of possible combinations of internal sensory units explains the corresponding number of specific memory retrievals by the system in response to various cue stimuli.

Neurodegenerative disorders share common features of "loss of function" states of a proposed mechanism of nervous system functions.

Neurodegenerative disorders are highly heterogeneous for the locations affected and the nature of the aggregated proteins. Nearly 80% of the neurodegenerative disorders occur sporadically, indicating that certain factors must combine to initiate the degenerative changes. The contiguous extension of degenerative changes from cell to cell, the association with viral fusion proteins, loss of dendritic spines (postsynaptic terminals), and the eventual degeneration of cells indicate the presence of a unique mechanism for inter-cellular spread of pathology. It is not known whether the "loss of function" states of the still unknown normal nervous system operations can lead to neurodegenerative disorders. Here, the possible loss of function states of a proposed normal nervous system function are examined. A reversible inter-postsynaptic functional LINK (IPL) mechanism, consisting of transient inter-postsynaptic membrane (IPM) hydration exclusion and partial to complete IPM hemifusions, was proposed as a critical step necessary for the binding process and the induction of internal sensations of higher brain functions. When various findings from different neurodegenerative disorders are systematically organized and examined, disease features match the effects of loss of function states of different IPLs. Changes in membrane composition, enlargement of dendritic spines by dopamine and viral fusion proteins are capable of altering the IPLs to form IPM fusion. The latter can lead to the observed lateral spread of pathology, inter-neuronal cytoplasmic content mixing and abnormal protein aggregation. Since both the normal mechanism of reversible IPM hydration exclusion and the pathological process of transient IPM fusion can evade detection, testing their occurrence may provide preventive and therapeutic opportunities for these disorders.

Selective contribution of Egr1 (zif/268) to persistent inflammatory pain.

UNLABELLED: The zinc finger transcription factor Egr1 is critical for coupling extracellular signals to changes in cellular gene expression. Expression of Egr1, as well as other immediate early genes, is up-regulated in response to a number of noxious stimuli. Activity-dependent activation of Egr1 has been reported in forebrain regions, including the anterior cingulate cortex (ACC), after peripheral injury. However, no study has reported a direct contribution of Egr1 to behavioral nociceptive responses. Here, we use Egr1 knockout mice to show that Egr1 is selectively required for behavioral responses to persistent inflammatory pain. Behavioral responses to peripheral inflammation were significantly reduced in Egr1 knockout mice, whereas responses to acute noxious stimuli were normal. In addition, inflammation triggered an up-regulation of Egr1 expression in the ACC of wild-type mice. Last, synaptic potentiation induced by theta (theta) burst stimulation in the ACC was significantly reduced or blocked in Egr1 knockout mice. Our study suggests that the transcription factor Egr1 plays a selective role in nociceptive behavioral responses to persistent inflammatory pain but not to acute noxious stimuli. PERSPECTIVE: Chronic pain diminishes the quality of life. Here, we show that the immediate early gene Egr1 plays a role in chronic inflammatory, but not acute, pain. Egr1 knockout mice showed reduced nociceptive behaviors to persistent inflammatory pain and inflammation increased Egr1 expression in the anterior cingulate cortex of wild-type mice.

A framework for the first-person internal sensation of visual perception in mammals and a comparable circuitry for olfactory perception in Drosophila.

Perception is a first-person internal sensation induced within the nervous system at the time of arrival of sensory stimuli from objects in the environment. Lack of access to the first-person properties has limited viewing perception as an emergent property and it is currently being studied using third-person observed findings from various levels. One feasible approach to understand its mechanism is to build a hypothesis for the specific conditions and required circuit features of the nodal points where the mechanistic operation of perception take place for one type of sensation in one species and to verify it for the presence of comparable circuit properties for perceiving a different sensation in a different species. The present work explains visual perception in mammalian nervous system from a first-person frame of reference and provides explanations for the homogeneity of perception of visual stimuli above flicker fusion frequency, the perception of objects at locations different from their actual position, the smooth pursuit and saccadic eye movements, the perception of object borders, and perception of pressure phosphenes. Using results from temporal resolution studies and the known details of visual cortical circuitry, explanations are provided for (a) the perception of rapidly changing visual stimuli, (b) how the perception of objects occurs in the correct orientation even though, according to the third-person view, activity from the visual stimulus reaches the cortices in an inverted manner and (c) the functional significance of well-conserved columnar organization of the visual cortex. A comparable circuitry detected in a different nervous system in a remote species-the olfactory circuitry of the fruit fly Drosophila melanogaster-provides an opportunity to explore circuit functions using genetic manipulations, which, along with high-resolution microscopic techniques and lipid membrane interaction studies, will be able to verify the structure-function details of the presented mechanism of perception.

A pressure-reversible cellular mechanism of general anesthetics capable of altering a possible mechanism for consciousness.

Different anesthetics are known to modulate different types of membrane-bound receptors. Their common mechanism of action is expected to alter the mechanism for consciousness. Consciousness is hypothesized as the integral of all the units of internal sensations induced by reactivation of inter-postsynaptic membrane functional LINKs during mechanisms that lead to oscillating potentials. The thermodynamics of the spontaneous lateral curvature of lipid membranes induced by lipophilic anesthetics can lead to the formation of non-specific inter-postsynaptic membrane functional LINKs by different mechanisms. These include direct membrane contact by excluding the inter-membrane hydrophilic region and readily reversible partial membrane hemifusion. The constant reorganization of the lipid membranes at the lateral edges of the postsynaptic terminals (dendritic spines) resulting from AMPA receptor-subunit vesicle exocytosis and endocytosis can favor the effect of anesthetic molecules on lipid membranes at this location. Induction of a large number of non-specific LINKs can alter the conformation of the integral of the units of internal sensations that maintain consciousness. Anesthetic requirement is reduced in the presence of dopamine that causes enlargement of dendritic spines. Externally applied pressure can transduce from the middle ear through the perilymph, cerebrospinal fluid, and the recently discovered glymphatic pathway to the extracellular matrix space, and finally to the paravenular space. The pressure gradient reduce solubility and displace anesthetic molecules from the membranes into the paravenular space, explaining the pressure reversal of anesthesia. Changes in membrane composition and the conversion of membrane hemifusion to fusion due to defects in the checkpoint mechanisms can lead to cytoplasmic content mixing between neurons and cause neurodegenerative changes. The common mechanism of anesthetics presented here can operate along with the known specific actions of different anesthetics.

A supplementary circuit rule-set for the neuronal wiring.

Limitations of known anatomical circuit rules necessitate the identification of supplementary rules. This is essential for explaining how associative sensory stimuli induce nervous system changes that generate internal sensations of memory, concurrent with triggering specific motor activities in response to specific cue stimuli. A candidate mechanism is rapidly reversible, yet stabilizable membrane hemi-fusion formed between the closely apposed postsynaptic membranes of different neurons at locations of convergence of sensory inputs during associative learning. The lateral entry of activity from the cue stimulus-activated postsynapse re-activates the opposite postsynapse through the hemi-fused area and induces the basic units of internal sensation (namely, semblions) as a systems property. Working, short-term and long-term memories can be viewed as functions of the number of re-activatible hemi-fusions present at the time of memory retrieval. Blocking membrane hemi-fusion either by the insertion of the herpes simplex virus (HSV) glycoproteins or by the deposition of insoluble intermediates of amyloid protein in the inter-postsynaptic extracellular matrix (ECM) space leads to cognitive impairments, supporting this mechanism. The introduction of membrane fusion blockers into the postsynaptic cell cytoplasm that attenuates long-term potentiation (LTP), a correlate of behavioral motor activities in response to memory retrieval, provides further support. The lateral spread of activity through the inter-postsynaptic membrane is capable of contributing to oscillating neuronal activity at certain neuronal orders. At the resting state these oscillations provide sub-threshold activation to many neurons at higher orders, including motor neurons maintaining them at a low initiation threshold for motor activity.

A structure-function mechanism for schizophrenia.

THE MULTIPLE ETIOLOGIES OF SCHIZOPHRENIA PROMPT US TO RAISE THE QUESTION: what final common pathway can induce a convincing sense of the reality of the hallucinations in this disease? The observation that artificial stimulation of an intermediate order of neurons of a normal nervous system induces hallucinations indicates that the lateral entry of activity (not resulting from canonical synaptic transmission) at intermediate neuronal orders may provide a mechanism for hallucinations. Meaningful hallucinations can be de-constructed into an organized temporal sequence of internal sensations of associatively learned items that occur in the absence of any external stimuli. We hypothesize that these hallucinations are autonomously generated by the re-activation of pathological non-specific functional LINKs formed between the postsynaptic membranes at certain neuronal orders and are examined as a final common mechanism capable of explaining most of the features of the disease. Reversible and stabilizable hemi-fusion between simultaneously activated adjacent postsynaptic membranes is viewed as one of the normal mechanisms for functional LINK formation and is dependent on lipid membrane composition. Methods of removing the proteins that may traverse the non-specifically hemi-fused membrane segments and attempts to replace the phospholipid side chains to convert the membrane composition to a near-normal state may offer therapeutic opportunities.

The nature of "internal sensations" of higher brain functions may be derived from the design rules for artificial machines that can produce them.

Modeling various neuronal functions in search of emergent properties may achieve success when the gold standard of replicating the models in physical systems starts exhibiting some of these properties. Since very large number of functions can be modeled and need testing, we suggest an alternate method of examining higher brain functions: seeing them as internal sensations formed from their hypothetical basic units. Here, we explain the need to replicate the natural mechanism using electronic circuits, discuss some of the technical aspects and introduce some concepts for searching for properties of internal sensations evolving from them.

Processing Semblances Induced through Inter-Postsynaptic Functional LINKs, Presumed Biological Parallels of K-Lines Proposed for Building Artificial Intelligence.

The internal sensation of memory, which is available only to the owner of an individual nervous system, is difficult to analyze for its basic elements of operation. We hypothesize that associative learning induces the formation of functional LINK between the postsynapses. During memory retrieval, the activation of either postsynapse re-activates the functional LINK evoking a semblance of sensory activity arriving at its opposite postsynapse, nature of which defines the basic unit of internal sensation - namely, the semblion. In neuronal networks that undergo continuous oscillatory activity at certain levels of their organization re-activation of functional LINKs is expected to induce semblions, enabling the system to continuously learn, self-organize, and demonstrate instantiation, features that can be utilized for developing artificial intelligence (AI). This paper also explains suitability of the inter-postsynaptic functional LINKs to meet the expectations of Minsky's K-lines, basic elements of a memory theory generated to develop AI and methods to replicate semblances outside the nervous system.

A possible mechanism of transfer of memories from the hippocampus to the cortex.

The mechanism of time-dependent transfer of memories from the hippocampus to the cortex associated with the memory consolidation process still remains unknown. By visualizing memory as the virtual sensation of sensory stimuli, it has become possible to conceptualize memory as an integral of semblances induced at the postsynapses in the absence of the activation of their corresponding presynapses. This is hypothesized to be possible during memory retrieval by the re-activation of functional LINKs formed between the postsynapses during learning. On occasions of repetition of learning, related learning and unrelated learning, stimulation of the sensory receptor pairs used in the original learning event activates new hippocampal neurons incorporated in the circuitry and induces formation of new functional LINKs in the cortex. Since the virtual sensory units of semblances provide provisions for the formation of similar net semblance from different sets of postsynapses of origin both independently and cumulatively, locations of their formation appear transferable. When semblances from the cortex alone become sufficient to contribute to a specific memory, after a certain period of time from the initial learning, removal of the hippocampus gives an impression of (an apparent) transfer of memories from the hippocampus to the cortex.