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What constitutes the code whereby the brain
stores and recalls emotive memory? We suggest that neural recall is based on
the “tripartite” interactions of three physiologic compartments:
· Neurons
- networked, sparse ensembles.
· Neural
Extracellular Matrix (nECM) - A hydrogel with a polysaccharide
lattice surrounding neurons.
· Dopants
(metals and neurotransmitters (NTs)) - ejected from vesicles. The nECM performs
as a “memory material” wherein a neuron imprints incoming cognitive information
as a c dopant code comprising trace metals and NTs (which elicit physiologic as
well as emotive effects).
To “write”, the neuron ejects vesicles
containing dopants into the surrounding nECM, a process analogous to ink-jet
printing on paper. A pattern of metal-centered complexes is “written” within
the nECM around the neurons, effectively encoding cognitive unit(s) of
information (cuinfo).
To “read”, the neuron employs at least 3 types
of “sensors”, aggregates of proteins (i.e., mosaics embedded within its
membrane, examples being GPCR mosaics, K2P channels and acetylcholine receptors
(AcCholR)), all which number many thousands per neuron. They perform as dynamic
chemo-sensors (reported diffusion: 10-1 to 10-3 um2/sec),
which transform the cuinfo code, the “engrams” around individual
neurons, into chemo-electric synaptic signals.
The neural net transforms and consolidates the
chemical signals into coherent psychic states, also instigating reactions of
glands and muscles.
Keywords: Cognitive information, Emotions,
Neurotransmitter, Trace metal, Psycho-chemistry
BACKGROUND
“It was as if I discovered a whole new
universe of chemical elements and had begun to see certain relations between
them, but had no means to organize the whole series into a harmonious and
coherent union.”
-Thomas Wolfe: The Story of a Novel (1936)
“The past is beautiful because one never
realises an emotion at the time. It expands later and thus we do not have
complete emotions about the present, only about the past.”
-Virginia Woolf (1882-1904)
Man may control what he thinks (sometimes),
but not how. How does the brain in animals and man, composed entirely of
matter, experience the psychic talent of persistent recall, to guide behavior?
One could say:
“Mind and memory are inseparable aspects of
the mentating brain.” Leaving aside spirits, ghosts, quantum entanglements and
ethereal entities (literature too vast to cite here), one queries: What happens
between “sensation” and “action”, that we recall as “memory”?
“All mental processes are biological.
Therefore, any disorder must also have a biological basis”.
-Kandel [1]
To the above quote, one could easily
substitute the word “chemical” for “biological”. We modern neuroscientists desire
a unifying principle for memory, but do not want explanations based on ghosts, spirits,
black holes, strings or quantum uncertainty.
Just as today’s medical diagnoses and
clinical treatments are based on chemical considerations, we turn to the
discipline of chemistry for mechanistic clarification of a mental state, such
as memory. After all, who can deny that we are chemical creatures, imbued with
moods and psychic talents that emerge from the chemical reactions in our
brains? The mood-altering drug industry certainly ascribes to this, witness the
multi-billion $ prescription drug market for Ritalin, Prozac, sedatives and the
like, not to mention illegal mood-altering molecules. Curiosity about the
process that generates neural memory has instigated numerous philosophic and
scientific musings [2-11]. For example, Bergson attempted (~1912) to identify
“images” without representation, to measure the interval between matter and
conscious perception [5]. But he wrote his thesis before the age of codes and
coding instigated by Babbage, Turing, Shannon, et al.
And what about emotions? DNA can be
considered as a carrier of “genetic memory” but cannot encode emotions. Marr, a
more contemporary scientist considered “orthogonalizing a set of key vectors”
into higher dimensional space, with “codons” as basic cognitive units (6-8).
The use of the term “codon” was unfortunate in that it suggested that memory
was encoded as a DNA-type information sequence. Marr’s codons and mathematical
equations are equivalent to binary-type synaptic signals with no emotive
signifiers, totally “demotive”. Without dwelling on this overly, it is clear
that a codon cannot encode neural memory, as it does not covey an emotive trace
of past events, of parent to offspring.
Language presents barriers to understanding
the molecular underpinnings of emotions and memory. Explanations become
entangled with the conundrums, inferences and paradoxes of the spoken and
written word (4). Also, words do not apply to non-verbal animals, who also
exhibit “memory”. Rather, we would rather consider a “universal” neural memory
process that is applicable also to non-verbal neural creatures. But what kind
of code can one consider for the “universal” neural net?
We suggest that the issues of neural memory
and emotions be addressed chemo dynamically, with the same terms used to
clarify other biological processes (such as metabolism, photosynthesis, blood
coagulation, reproduction, etc.), cognizant of the kinetics and energetics of
chemical bonds and mechanisms. Notwithstanding, we were inspired to undertake
such a chemical description of mental phenomena, by comments from two
philosophers and one linguist:
• “No shade of emotion is
without bodily reverberations.” - W. James, 1884 [2]
• “Feeling is the basis of
all mental experience.” - S. Langer, 1962 [3]
• “Since the subject is a
physical organism, the system attributed to this must have finite
representation.” – N. Chomsky, 1975 [4]
COMPUTER MODEL
The computer chip’s “memory material” [12-18]
and underlying “information theory” [19-31] establish the concept of a computer
memory code and provided models of physically encoding information as holes,
pits, magnetic orientation, electron spins, phase changes, distribution of
dopants within a matrix, etc. and the design of algorithms to perform (compute)
logical operations. For example, the chip can transform and store electronic
“input” information into physical correlates, encoded by the disposition of the
dopant metals within the chip’s matrix, for recall-on-demand, as electronic
memory. Electrochemical metallization memory chips have been fabricated from
matrices composed of SiO2, WO3, TiO2, etc. Doped with metals (such as Au, Co,
Cu, Ni, PT and W among other) to encode and store information, available for
retrieval. It has been suggested that “memresistive” devices and networks
compute like a brain, suggesting that “they promise to open new directions in
neuromorphic architectures and biological studies “. However, the wired
connections between electronic components that are proposed to store memory are
not analogous to neural synaptic gaps [discussed below in greater detail with
regard to the IBM brain chip and the Blue Brain Project, Marx & Gilon,
2017].
Some assume an
analogy between computer processing and neural mentation [29-31].
“The brain’s
analogue mechanism can be simulated through digital ones” [22].
“Computational
systems are useful … to describe brain processes mathematically” [29].
But something is
lacking in the mathematical treatment of information with its limited encoding
repertoire (0 1). We point out that even at the quantum level, binary formatted
information is monotonic, psychically dead, “flavorless”, “demotive”.
One queries: By
what alchemy could a biochemical process be transmuted into an emotive state?
To date, nobody has
written a mathematical formulation for pain, love, fear, etc., for feelings
that are recalled as emotions. By contrast, logical processes can be affected
through binary-coded algorithms. For example, pain is felt physically with
muscular contractions, pulse changes and an attendant psychic experience, that
are remembered (see conditioning training). But there are no digital codes or
algorithms to simulate an emotive state experienced by a neural creature
experiencing pain, from worm, to snail, to man [1,32]. Though forcefully
suggested by Marr [6-8], emotive states experienced by all neural creatures
appear to be beyond the ken of binary coding. One could say:
“There is no room
between 0 and 1 for emotions”.
ENCODING/DECODING COGNITIVE INFORMATION (COG-INFO): MOLECULAR RECOGNITION
Enter the chemist/physiologist with a palette of signalling molecules (i.e., metal atoms and neurotransmitters (NTs)) that can elicit emotive states. Modern biologists accept that signalling processes are based on molecular recognition, i.e., binding events [33-40]. Expanding on Darwin [41,42], we expect that the complex neural signals that result in emotive mentation and memory, evolved from the signalling processes expressed by more primitive cells. For example, colonies of bacteria employ a number of “modulators”, small molecules that function as signals to instigate group aggregation and tropic responses; for which they also express cognate receptors on their surfaces, effectively “sensors”. A bacterial colony can be considered as a chemo-dynamic aggregate of individual entities that exchange information to maintain contact and coordinate group responses to the environment, by means of chemical signals (Table 1) and cognate sensors.
BACTERIAL PRECURSOR
OF THE NEURAL NET
Continuing in this vein, the brain cab is
considered as an assembly of neurons, whose performance must be governed by the
laws of chemistry and described by the rules of biology. Its conscious state
(of awareness) operates under metabolic conditions and principles similar to
those of an aggregate of bacteria. In that the latter evolved from the former,
it is worth considering the signalling features of the bacterial aggregate and
see how they apply to the neural net.
A bacterial colony feels and responds to its
environment by signalling with molecules (bio modulators) that signal and
instigate group responses (i.e., feelings) to stimuli (Table 1). Here, the discipline of chemistry with its techniques
and theories helps establish biologic facts.
Without delving into the process of cellular
evolution but accepting it as an established Darwinian fact, one could consider
that neural nets, which evolved from bacteria, employ similar chemo-dynamic
signalling modalities. Indeed, analysis revealed that neurons signal one
another with the same biomodulators (now called neurotransmitters (NTs))
employed by bacteria (Table 1) along
with many additional signalling molecules (neuropeptides) (Table 2). Here too, the discipline of chemistry helps establish
the facts of neurobiology.
A clue to the mechanism of neural memory
might reveal an underlying principle applicable to other mental states. Our
“leap” of comprehension (of the psychic states achieved by neural nets), is
based on the neural morphology (extended, arborized shape), that permits many connections
not only with other neuron, but intimate contacts with the surrounding neural
extracellular matrix (nECM), which performs as an archival “memory material”.
An aggregate of bacteria is “conscious”, in
that it “feels” environment and responds by chemical signalling. But the
bacterial aggregate cannot be considered to be “thoughtful”; it has no memory
and cannot recall past stimuli. It responds only to current stimuli with
signalling molecules (Table 1),
sensorially attuned to its environment, conscious in the existential “now”. But
memory requires sets of neurons to recall details of past stimuli. An
increasingly complex memory talent could only emerge from ever more complex
neural structures and signalling (coding) processes. It is not farfetched to
suggest that the evolved neural creatures conserved the core mechanisms of
bacterial signalling [42-49] and developed new ones (Table 2), to perform feats of psychometric signalling, mentation
and memory. For example, C. Elegans,
a primitive organism with 302 neurons has been shown to exhibit memory, the
recall of past conditioning experiences (i.e. tapping, electric shock, [32]).
Presumably, elegans neurons are encased in their own unique nECM, though
characterization has not been reported. It has been established that slime
molds are surrounded by a slime of polanionic polysaccharides, through which
group signalling occurs [50].
Aplysia, a snail with ~20,000 neurons have a
memory, can remember past stimuli and act accordingly [1]. The evolving neural
systems of more complex animals, with ever more neurons organized into sparse
units and specialized anatomic compartments, developed neuropeptides as
additional molecular signals pertaining to the evocation of emotions (complex
psychic states) (Table 2).
Concomitantly, cognate receptors developed on the surfaces to detect the
nECM-tethered NTs, to be discussed further along our narrative. Characterization
of the nECM unique to Aplysia also has not been reported.
The fact that bacterial modulators also serve
as modulators of neural signals, emphasizes that neural mentation processes are
phyto-chemically related to those of bacterial signalling [44-49]. The
modulators (now called NTs) can elicit simultaneous responses from different
cells throughout the body or even under cell culture conditions (see [42] for
the history of the discovery of NTs).Thus, the multi-tasking NT “signal” to
which a neuron responds is entangled with varied responses of other body cells
to the same signal. For example, a list of cell types that respond to ACh would
include neurons, as well as heart, liver, kidney, pulmonary and endothelial
cells. In a neural creature, they all respond to an administered dose of NT not
to be overlooked are the psychic states elicited by the NTs.
NEURONS AND ASTROCYTES (GLIA CELLS)
Though many detailed studies have been
performed to characterize astrocytes, neurons and the nECM (cited here and in
our previous works), none has clarified the phenomenon of central interest: How
is the neural code, which implements mentation and memory, rendered psychically
operative by the interaction of neural cells with their surroundings.
The neurons connect to form a signalling
network employing both synaptic and non-synaptic (ephaptic or “volume
transmission”) signalling modalities [51-58]. The brain’s mental functions are
aided by the “housekeeping” performances of astrocytes/glia cells that
outnumber the neurons 10-fold [59-67]. The astrocytes have been described as
being involved in non-synaptic contacts between neurons. Neuron and glia
interactions regulate neuronal biosynthesis of the nECM and transmission
through it. Thus, glia cells impact short-term and long-term synaptic
connectivity, also correlated to learning and memory.
All these neural cells retain the core chemo
dynamic signalling molecules and cognate receptors of bacteria and help the
neuron to form contiguous networks coupled to sensors or muscles, as
illustrated in Figure 1.
DEFINITIONS
The nECM can be likened to a 3-D lace of organic polymers composed of sulphated glucoseaminoglycans
(GAGs) with foci at the metal-binding centres, who’s dielectric and epitopic aspects is set by the
biosynthesis of those sites. It is noteworthy that the process of metal
complexation occurs in a nanosecond (10-9 s) timeframe.
The term “extracellular space” is misleading,
as it implies an empty vacuum around the neurons. Not only are the neurons
continuously bathed in a watery (serum, lymph) fluid, they are constrained in a
hydrogel lattice comprising a web of glycosaminoglycans (GAGs) in the nECM [68-85]
that permits the binding of cationic metals to encode cog-info, as discussed
below. Thus, the nECM can be likened to a substrate that has been
biosynthesized and treated (i.e., sulphated) so as to prepare metal-binding
sites, which serve as nucleating centres for encoding cognitive information
involving the binding of NTs [85].
By the term “neuron”, we include combinations
of neurons and glia cells that operate in concert to biosynthesize nECM and maintain
the neural synaptic and non-synaptic signalling contacts through the nECM,
whose performance as a chemo-dynamic “memory material” is manifest as
“plasticity”. But the term “synaptic plasticity” (SP) [52, 63, 70] does not
serve as a mechanistic explanation of atomic-scale events. Rather, the
morphologic changes that are observed in neural dendrites serve to augment the
ability of the neuron to interact with the nECM, to recall the code embodied
therein. In rats, SP has been observed in a period 5-10 h after the learning
experience [11]. But perception occurs in a much shorter time frame (i.e., <1
s). Thus, one must look for faster processes for coding/decoding memory, as
discussed below.
The term “imprinting” has been used to
describe the recall of young animals to specific stimuli [11]. But unlike the
classical meaning of the word “printing” (the transfer of ink to paper), the
“imprinting of behavior” is not meant literally but metaphorically i.e., as a
learning process presumed to operate on the basis of repeated synaptic
connectivity (i.e. SP). But this does not provide a mechanistic understanding
of the process of neural recall.
TRIPARTITE MECHANISM
OF MEMORY
Consider a tripartite mechanism [86-93],
whereby the “neuron” marshals the components available to it. These include the
extracellular matrix (nECM in whose lattice it is wrapped) (see above) and the
dopants (such as metals and NTs), which the neuron accumulates within vesicles,
which it ejects. With these, the neuron encodes molecular (rather than
cellular) building blocks memory.
A chemographic notation, which describes the
chemical basis of the neural memory code as cuinfo, is presented (Figure 2).
The nECM can be likened to a 3-D lace of
organic polymers composed of sulfated glucoseaminoglycans (GAGs) that serve as
metal-binding centers. In emotive memory, NTs that complex with the metals
within the cuinfo, are released from vesicles and are
available to form cuinfo:NT complexes. It is noteworthy that the
chemical processes of metal complexation occur in a nanosecond (10-7)
timeframe. Thus, it is much faster than neural signalling and would not impede
neural communications.
“WRITING” NEURAL
MEMORY
We propose that the “writing” of cuinfo occurs
by neural ejection of vesicles.
The presynaptic neuron (the one that gets an
action potential signal) “writes” cuinfo by ejecting the content of
vesicles [94-118] which contain metals and NTs, to specific addresses within
the nECM (Figure 3A and B). The only
known function of synaptic vesicles is to release neurotransmitters and metals
into the nECM [101,102]. The metals are released into the nECM GAGs that have
specific pattern of varied planar orientations or densities corresponding to
the location of the sulphate groups. Like “inkjet printing” which is based on
the piezoelectric dispersion of colored inks as droplets deposited onto paper (Figure 3C).
Other workers have suggested that chemical
modulators are involved in imprinting memory [113-120], but details of this
process need to be clarified. We use the term “neuron” to include the
astrocytes (glial cells) that have been shown to release “gliatransmitters”,
glutamate and ATP [117].
“READING” NEURAL
MEMORY
It has been pointed out that cell membranes
act as signalling platforms. In that vein, we propose that “reading” of cuinfo
occurs by virtue of the many sensors embedded within the neural membrane. They
detect and decode the various metal-centered complexes contained within the
nECM. Based on the literature, we have identified 3 classes of chemo dynamic
sensors embedded within the neural membrane, as discussed below:
1. GPCR receptors [121-150]: These are
multimeric proteins (dimers, tetramers, mosaics, aggregates) whose canonical
motifs are based on 3 domains: An extracellular domain, extending more than 50Å
into the nECM; a transmembrane domain (i.e. 7-helical barrels penetrating the
membrane; an intracellular domain, coupled to ATP/GTP metabolism, capable of
signalling to its own nucleus as well as to other neurons.
2. The NTs are the molecular equivalents of
emotive states, which the GPCRs can detect. The external facet of the moving
GPCR sensor (Figure 4) is sensitive
to pattern of NTs tethered to the cuinfo in the nECM. More than 800
distinct types of GPCRs have been identified; neurons express millions of these
on their surface (Table 3). The
seven-transmembrane helix structure of the primitive bacterio-rhodopsin sensor
motif is conserved and adapted in all GPCR types (Figure 5A).
Assuming a 10x10Å size of a cuinfo,
this would translate into a “reading” of 105 to 107 cuinfo/sec
by a single mosaic. Considering that the neuron expresses many thousands of
mosaics on its surface, the numbers suggest that the neuron can effectively
refresh its recall of many stored memory units.
As the GPCR aggregates are associated with
ion channels, they can transduce chemical affinities for tethered ligands (like
affinity chromatography [121], into mini-gating responses related to
mini-electric action potentials relating to short-term memory. Some are
functionally connected to the cell nucleus, to instigate the biosynthesis of
new nECM and proteins, the basis of persistent, long term memory. The GPCRs can
perform like dynamic switches, combining and recombining into circuits,
diffusing within and through the lipid bilayer surface of the neuron, in continuous
contact with the surrounding nECM, “perusing” the exposed cuinfo as they
traverse along the exposed nECM.
K+
Channels [151-158]:
Consider a phonograph needle capable of
sensing engraved tracings in a vinyl record with a sharp needle, to transduce
tracings into sound (Figure 6A and B).
The 2-pore K-channels (K2P) exhibit a
structure expected of a sensor. They are organized as 3-domains; an
extracellular domain (a sensor cap with an S-S “needle”), a transmembrane
region and an intracellular domain. The cap structure extends 35 Å into the extracellular domain and
exposes the S-S moiety at its tip to the metals tethered to the cuinfo within
the nECM.
structure extends 35 Å into the extracellular domain and exposes the S-S moiety at
its tip to the metals tethered to the cuinfo within the nECM.
The reactivity of the S-S moiety to metals is
well known to chemists. Allosteric flexing induced by the “S-S tip” as it
adsorbs/desorbs to a tethered metal cation (of a cuinfo) during its
traverse of the membrane, could transduce into a mini-gating event, affecting
electrical signalling to the neural net, as for example, the tiny spikes around
the major action potential spikes. The S-S bond is relatively weak compared to
a C-C bond and could be sensitive to different metals entrapped by the cuinfo,
as exemplified by the reactions of S-S moieties with soluble metals or metal
surfaces (Figure 4).
Recent x-ray crystallography findings
confirmed this model. The K2P channel was shown to be modulated by a drug
(Prozac) which binds to the junction of the channel, where it merges with the
membrane of the neuron [156,157]. Interestingly, the side effects of Prozac are
loss of memory and changes in psychic states. The binding of Prozac to K2P
appears to interfere with the motility of the extracellular region, specifically
with the cuinfo-reading S-S moiety at the tip of the K2P. Loss of this
reading ability is mirrored by forgetting.
Acetylcholine
receptors (AChR) [159-167]
The nAChR neuro-receptor is a well-studied
ligand-gated ion channel that opens upon acetylcholine binding, and is
responsive to the cationic acetylcholine (Figures
7A and B).
The exterior facet of the receptor AChR is
anionic, presents a 10Å wide, negatively charged face to the outside. This
serves to attract the cationic AChol into the channel to become attached to the
ligand-binding site. But the negative facet of the AChR could also respond and
sense positively charged side chains from NTs tethered to a cuinfo through
a metal, as illustrated in Figure 7.
Its affinity for Ca+2 and other
cationic metals, due to its anionic surface and internal channels, make it
capable of sensing and allosterically decoding a cuinfo that expresses a
cationic ammonium group (R3NH+) (i.e. (e.g. secondary
amine in Epi or Arg and Lys neuropeptides) (Figure
8). One might also expect that its affinity for the cationic ACh is
mirrored by a (milder) response to Arg groups presented by NTs tethered to the
nECM. The detected moiety instigates a gated mini-signal to the neural net. The
opening and closing of ligand and voltage gated ion channel proteins causes
small electrical potential (resistivity) changes on a membrane resulting in
mini-electrical signals.
The exterior facet of the receptor AChR is
anionic, presents a 10Å wide, negatively charged face to the outside. This
serves to attract the cationic AChol into the channel to become attached to the
ligand-binding site. But the negative facet of the AChR could also respond to
select side chains from NTs tethered to a cuinfo through a metal.
SUMMARY OF
RECEPTORS/SENSORS
We describe 3 types of membrane-embedded
organelles that are involved in chemo dynamic neural “perusing” of the
cog-info encoded within the nECM around the
neuron. There may be other types “perusing” modes.
As regards the history of these receptors, the bacterial system has a number of receptors located within their surface membranes, as well as ion channels, all which evolved along with the neuron to form the signal sensing organelles (Table 3). Thus, feelings are experienced by neurons via the signalling properties of bio modulators (i.e. NTs) interacting with cognate receptors (Table 3), a system that evolved from bacteria (35-42), but adapted and added to, by the neurons to encode, evoke and remember emotive memory.
DISCUSSION
Memory can be classified as a psychic
experience instigated by the senses, which is recalled. Some presume that
memory is stored in the neuron; others opine that memory is stored as an
activity of a neural circuit, though such a “memory circuit” has not been
realized for electronic circuits. Of course, synaptic plasticity (SP) must be
involved in the various stages of the processing of cognitive information by
the neuron. However, the terms SP and its variant “long term potentiation (LTP)
do not describe the molecular features by which cog-info is encoded. Rather, it
describes the increased ability of the neuron to interact with its
surroundings, to decode the cog-info embodied in the nECM and to signal
neighboring neurons (see: synaptic contact).
Dogmas of
Neurobiology
In keeping with the modern approach to
medicine and clinical practice, one cannot simply overlook the explanatory role
of biochemistry in elucidating mental processes.
Q: What are the doctrinal guidelines that
a chemist refers to when advocating a possible mechanism regarding psychic
neural processes?
In particular, the dogmas of neurobiology
must be questioned, particularly:
• Cajal’s model of neural
signaling exclusively through synaptic contacts.
• Synaptic plasticity-a la
Hebb and Kandel
Q: How can one describe the molecular
features of brain that function to generate memory?
A: Establish facts – identify critical
components/parameters. Then weave the facts into a concept of operation that
conforms to the possible chemical interactions available to the neuron. Much
has been said about the electrodynamic signalling between synaptically
connected neurons. But this is incomplete description. Chemodynamic
interactions of the neurons with the nECM, as described by a chemical
recognition theory [33-40].
Q: How does one account for emotions,
which have no coding option in the binary world; how are emotions embodied and
encoded in the neural system?
A: Neurotransmitters (NTs) (also called
“biomodulators)”, are the only molecules in the neuron’s repertoire which can
affect physiologic reactions and elicit psychic states/emotional responses.
With the exception of acetylcholine which is cationic, most bio modulators
contain electron-rich ligands, avid for cationic metals, either free or
tethered to a matrix (as in affinity chromatography).
Four criteria for characterizing NTs
1. Biosynthesized
in or accumulated by the neuron, stored in vesicles.
2. Released from
the vesicles in sufficient quantities to produce a significant (measurable)
effect on the postsynaptic cell.
3. Artificial
administration of NTs mimics natural release (elicit physiologic and emotive
responses).
4. A mechanism
exists for NT removal from the synaptic cleft.
Q: What are we,
that we can recapitulate our life experiences through memory?
A: We are a
collection of cells composed of molecules and atoms interacting in a particular
way to generate, store and recall psychic experiences, remembered to achieve
survival.
The activated
neurons “write” by releasing dopant-loaded vesicles into the nECM. The vesicles,
which traverse the membrane, are loaded with trace metals and NTs; the neuron
controls the location and level of encoders released into the nECM, reminiscent
of ink-jet printing of different colors by focused piezo-electric impulses.
Neurons chemo
dynamically “read” the nECM via sensor aggregates that move laterally within
the membrane lipid bilayer. The nECM structures may be viewed as molecular
scaffolds whereby varied planar orientations or densities of the sulphate
groups can achieve metal binding interactions which in turn affect affinities
for various ligands [85]. Significant inroads have been made in the sequencing
of GAGs and encoded sequences. The external facets of the sensors contact
facets of the nECM. As they diffuse over the membrane, they allosterically
“recognize” the cuinfo at each particular “address” in the nECM; the
chemically-induced resonance states of individual neurons are communicated to
neural network via electrodynamic signalling pathways.
One could consider the process in musical terms. The nECM is the “partitura”, the score which the neuron reads with its many dynamic sensors (Table 3), like a multi-stringed instrument (Figure 9), each string capable of generating a unique tone but resonating with others to generate harmonic overtones. And like music, the “note” must be considered in the context of a set, whose pattern is ‘read’ by the neuron to generate the experience of memory.
The sensors (receptors) perform as biologic
“switches which can combine into aggregates (“circuits”) to mentate the
individual neuron’s response to chemical signals decoded from the nECM. Some of
the sensors are capable of decoding the emotive quality of memory by virtue of
their affinity for tethered NTs; others may respond only to metals. Multiples
of such aggregates, which are associated with ion-channel gates, traverse the
neural surface to “read” the nECM. They effectively process the “chemical
algorithms” whereby the neural circuit mentates.
CONCLUSION
Is the search for a universal mechanism of
neural memory misguided? Are we forbidden by fear of Descarte’s Mind/Body
conundrum? Based on everything we know about the chemical basis of all
biological processes, the metaphor of an electronic artefact programmed in
binary code is inadequate to describe neural mental activities, as it lacks
emotive qualities (see current discussion of this in Science, April 2018 (174)).
We meld the observations of
neuro-morphologists (particularly Triller et al. [124-126] and Vizi [132,133])
with the concepts of the chemist, to present a coherent mechanism that
describes how cog-info can be encoded (written), stored and decoded (read). To
that end, we envision 4 tasks:
·
Define “emotions” with a molecular
vocabulary.
·
Identify a neural “memory material”
wherein persistent memory is stored.
·
Describe a neural encoding (writing)
process.
·
Describe a neural decoding (reading)
process.
The tripartite mechanism copes with these
points by positing that the neuron forms metal-centered complexes (cuinfo)
within the nECM around itself. Expectedly, each metal instigates a unique
binding structure with each of the many (>100) NTs and to the nECM. There is much evidence that NTs can elicit
physiologic responses as well as emotive states. Thus, it is not farfetched to
suggest that each cuinfo: NT presents a unique “ligand pattern” with
emotive context, which is sensed by the neural surface (sensors) to reconstruct
past experience as memory.
The psychic states achieved by neurons are stored as memory, signalled to the neural net, as schematically presented in Figure 10.
The heuristic implications of such a complex,
chemo-electric signalling process are manifold. For example, a demonstration of
an electrodynamic effect modulated by the interactions of metals with NTs or
polysaccharides (as models of the nECM) would augment the credibility of the
tripartite mechanism of neural memory. Such work is underway with our collaborators
as per the initial reports [168].
ACKNOWLEGEMENT
(By GM). A memorium to my wife and fan, the
artist Georgette Batlle (1940-2009), whose drawings helped me visualize
interactions of blood clotting factors modulated by metals, instigating an
epiphany regarding psycho-chemical processes. Thanks to friends, Lilly Rivlin
(New York, N.Y.) and the late Bill Needle (Eastchester, N.Y.) for their early
encouragement and financial support in the period 1980-1984. I appreciate
ongoing discussions with Karine Ahouva Leopold (Paris), regarding the
distinction between feelings, emotions and behaviour.
CONFLICT OF INTEREST
GM is a founder of MX Biotech Ltd., with the
commercial goal to develop new classes of “memory materials” and devices.
CG is emeritus professor of HU, but is active
in developing and patenting peptide-based tools for surgery and pharmacology.
Notwithstanding, the ideas forwarded here are
scientifically genuine and presented in good faith, without commercial clouding
of the concepts expressed herein.
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