Brain networks and the matrix and the mind

Brain Networks, the Matrix and the Mind
Nature does not seem to waste ideas. From the macrocosmos of the universe to the
microcosmos of the atom, everything appears to be comprised of matter and void as if this was
nature’s binary system. But the void is far from being empty or useless, in fact it is the theater
where atomic, electric or gravity forces interact, cementing the matter together.
The same principle is at work in biology: tissues are made of cells and the extracellular space.
Again, the extracellular space is far from being empty or useless; it holds the tissue together,
supports cellular communication and enables the function of organs. Likewise, the brain is
comprised of cells and the extracellular matrix (ECM). The ECM cements the organ together,
supports signaling among cells and participates in engendering the mind.

The brain is made of cells and the extracellular matrix (ECM)

As we are getting well into the 21st century, it has become clearer that the mind is the product
of the brain, just as the body movement is the product of the musculoskeletal system. With the
same token, it is clearer and clearer that psychiatric disorders are disruptions of cellular or
molecular communication in brain networks. In this context, studying the cellular cross-talk
and connectivity in these networks offers the best modality of a brain-based understanding of
psychiatric disorders.
Like any other organ, the brain can be currently studied at two levels of organization: cellular
and molecular. These two realms follow different sets of rules, but complement each other in
generating the mind.

Cellular Networks and the Neurovascular Unit (NVU)
In order to illustrate brain cellular networks, let’s take a stroll in a fascinating tropical forest. As
we walk, we note the long, delicate and entangled branches stretching in every direction as far
as we can see. The tree trunks are buzzing with activity as juices travel from the fertile ground
to crowns far away. There is life and exuberance everywhere, the canopy is majestic, thick,
knitted with intertwined branches that seem to be whispering to one another. The ground is
wet because few sunbeams penetrate the narrow spaces between the entangled crowns. This
forest is comprised of more than 100 billion neurons in addition to about as many glial cells,
and you’d be surprised to learn that it fits in about 1200 cm3 of gelatinous matter, the brain(1).
The cellular level of tissue organization, is characterized by the “sovereignty” of the cell
membranes which establish cellular boundaries, connect cells into networks and prevent
spilling of intracellular content into the extracellular space.
In order to perform their job of producing the mind, the brain cells are organized in networks.
Hebb named this architecture cell assemblies, and argued that repeated behavioral patterns
strengthen connections among cells in their corresponding assemblies, just like a frequently
used hiking trail would eventually broaden. Hebb presumed that repetitive presynaptic
stimulation strengthens synapses (i.e. neurons that fire together wire together) (2).
At this point the analogy with the tropical forest needs to be broadened because the picture
needs to accommodate about 600 km of brain microvessels composed of arterial and venous
capillaries accompanying each neuron at an average distance of 20 μm (3 ). Also large stellar
cells, the astrocytes, need to be pictured with extensions that wrap the synapse and the
capillaries (4).

NVU, the building block of a complex cellular network comprised of neurons, glia and brain microvessels

Brain networks may be didactically divided into neuronal, glial or neuronal-glial networks,
however practically such networks cannot exist without microvessels. Indeed, each brain cell is
in immediate vicinity of an arterial and a venous capillary without which the networks could not
be functional. Therefore, all brain networks have three compartments: neuronal, glial and
capillary which render them complex cellular networks (CCN). In addition to their proximity to
each other, neurons, glia, endothelial cells of capillaries and pericytes engage in extensive
cross-talk and together comprise the basic structure of information processing, the
neurovascular unit (NVU).

Endothelial cells’ and pericytes’ cross-talk

The NVU is the basic building block of CCNs as well as the basic cellular assembly of
computation akin to a transistor. To illustrate the relationship of the NVU with CCNs let’s
picture the CCN as a population of brain cells in which the NVU is a family. Likewise, to illustrate
the same relationship in regards to computation, if the CCN is depicted as a microchip, the NVU
would represent a component transistor.
Hypothesis: the NVU, not the neuron, is the minimal cell assembly for information processing
in the brain. It is hypothesized further that, within the NVU, all cells are involved in
information processing.
Anatomically, the NVU can be described in terms of its component cells, however
physiologically, the NVU can be better comprehended as a whole. Likewise, a nephron, for
example can be anatomically discerned through its parts (i.e. glomerulus, Bowman’s capsule
and ducts), but its physiological function can be better grasped as a whole.

It is currently assumed that neuroimaging such as fMRI and BOLD reveal activation of neuronal
networks. However, it is known that functional hyperemia (and oxygenated hemoglobin) do not
correlate well with activation of neuronal networks (5)(6) (7) (8) (9) (10). Thus considering
neuronal networks activation in isolation from ECM, glial and vascular compartments should be
avoided.

NVU- family as part of CCN population

On the other hand, if brain activation is fathomed as activation of CCNs comprised of numerous
NVUs, this correlation can be positively established. The holistic understanding of the NVU as a
compact assembly representing more than the sum of its cells can be discerned with more
precision if examined from the molecular perspective.

Molecular Networks and the NVU
So far we have been strolling in the tropical forest by carefully stepping on the jungle floor,
observing the trees, branches and crowns. It is time now to take an imaginary elevator one
floor down into the molecular realm and examine the nuts and bolts of life, the molecules. Our
descent into the soil is even more fascinating, lo and behold the soil is alive, it is comprised of
intertwining roots (molecular networks) and ground water bathing them (ISF).
If the properties of matter could be summarized in one word, it would probably be “motion.”
Indeed, matter and motion are always in tandem like the two faces of Janus. In biology, the
molecules of life, the proteins, are endowed with motion of their subunits and conformational
changes. One of the sine qua non aspects of life seems to be the indivisible marriage between

proteins conformational dynamics and their biological functions (11 ). Dynamic subunits of
macromolecules can build on each other in “lego-like” fashion, self-assemble and disassemble
in “Transformers’-like” manner, or fold and unfold like paper in the ancient Japanese art of
origami. In addition to their mechanical properties, or possibly because of them, proteins are
endowed with electrical conductance (12)(13) and access to logic
gates(14)(15)(16)(17)(18)(19)(20).
At the molecular level of brain organization we encounter a different world order in which
molecular networks do not respect the boundaries of cell membranes, which themselves are
comprised of horizontal molecular networks (22). The proteins comprising the cellular
cytoskeleton are known to assemble with membrane adhesion molecules such as integrins
(23)(24)(25) which in turn bind ECM proteins generating global molecular networks (GMN)
which crisscross the cells as well as the ECM, enmeshing the entire CNS (26).
The molecular networks should not be conceptualized as being static, since the ever-changing
environment induces continuous fluctuations in the states of these molecules (i.e. adhesion vs.
non-adhesion, assembly vs. disassembly, folding vs. unfolding). In the NVU those states are
reflected in molecular switches that can turn “on” or “off” information processing in GMNs. For
example when the integrin switch is “ON” adhesion is established between intra and
extracellular molecular networks and the GMN is brought on-line. Subsequently, when this
switch is “OFF”, there is loss of adhesion between intra and extracellular networks and the
GMN is off-line.

Integrins link the intracellular and extracellular molecular networks into global molecular networks

Integrins are trans-membrane receptors composed of three domains: an intracellular domain
which interacts with the cytoskeleton, a trans-membrane domain, and an extracellular domain
that interacts with the ECM macromolecules (27)(28). When a ligand binds to the cytoplasmic
domain, it causes elongation of the extracellular domain of the integrin molecule with
subsequent adhesion to ECM macromolecules (the switch is “ON”). Conversely, when a ligand
binds to the extracellular portion, the integrin shortens thus turning “OFF” the cytoskeletonECM adhesion (28)(29).
The molecular switching mechanisms endow the NVU with transistor-like access to Boolean
logic gates which are the building blocks of computation. Highly dynamic, shape-changing
proteins like integrins or G-proteins are utilized as molecular switches throughout the
molecular networks (30).
The switch aspect of proteins is not a new concept, indeed the epigenom consists of myriads of
switches changing transcription status from activation to repression and vice versa in different
sets of genes without inducing changes of the underlying DNA sequence (31) .

A growing number of biophysical studies demonstrate how cytoskeletal macromolecules such
as actin filaments are able to act as genuine “electric cables” (32)(33). Both microtubules and
actin filaments have highly charged surfaces that enable them to process both electric currents
and information (27) (28). In addition to conducting electronic signals, cytoskeletal
macromolecules respond to electromagnetic fields which may be able to induce structural
organization of both actin filaments and microtubules (34)(35).
Information processing and decision making have been well documented in transcription-linked
molecular networks, but recently it was demonstrated that individual proteins can perform
logic operations as well (35). For example, performance of the logic gate AND by the actin
regulatory protein N-WASP was described (36). Moreover, synthetic proteins based upon
naturally existing proteins have been constructed and shown to perform a number of different
logic operations (37). Dendritic spines proteins were hypothesized to endow neuronal networks
with Boolean logic (38).
Like the skin, the brain derives from the ectoderm, and represents the interface between the
body and the unpredictable, ever-changing environment. Decreasing risk of injury and death
was probably the driving force that led to the development of the mind. Making adequate
plans, contingency plans and decisions in unpredictable situations was essential for survival.
This is probably how the brain evolved the ability of “virtual reality”, that is creating a replica of
the environment in its inner mental space where it could be studied, analyzed and a multitude
of risks, or reactions simultaneously assessed. Creating or disposing of the external world
mental image renders the mind is more a verb than a noun. The “virtual reality” aspect of the
mind allows enactment and evaluation of possible real-life situations, while eliminating the
need to live through each one of them. The mind enables other human attributes such as
planning, goal setting, assigning value to objects, individuals or ideas, and also finding
fulfillment and meaning.
Some patterns of information processing may be transpersonal or species specific. It has been
known that instead of being born “tabula rasa”, infants come prepared with built-in patterns of
information processing or archetypes, specific to human race (C.G. Jung ). Protein properties of
allostery, folding and conformational dynamics may offer a plausible explanation for these
patterns of information processing. In the world of proteins, folding, for example, could occur
along innumerable lines, but like in origami, only one axis is chosen because it represent the
lowest energy level (LEL) for that particular molecular network. Out of a multitude of possible
conformations that a receptor could take in the presence of ligands, it chooses the LEL, which is
also the biologically adaptive one. In order to illustrate this important aspect of proteins, let’s
imagine a blindfolded golfer, on a flat field; his chances to score are minimal, however if the

field is curved or funnel-shaped, his chances to score may approach 100%, regardless in which
direction he aims.
Hypothesis: transpersonal patterns of information processing (i.e. archetypes) may represent
LEL of a particular molecular network.
Extracellular Matrix (ECM) within the NVU
In the NVU the ECM surrounds the cells, comprising the fourth brain compartment in which the
other three: neuronal, glial and microvessels are embedded. This positions the ECM at the
center of integration and synchronization of both cellular and molecular networks. In addition
the ECM also couples intra and extracellular molecular networks into GMNs, contributing to the
“binding phenomenon”(22).
The ECM is comprised of a solid and a fluid phase (4). The solid phase contains hyaluronic acid,
lecticans, hyaluronan, link proteins, and tenascins (39). The fluid phase of ECM is comprised of
interstitial fluid (ISF) which represents the internal sea that bathes the cellular networks
enabling both the glymphatic system clearance and volume transmission.
The volume of the ECM fluctuates during a 24 hours interval, being about 60% higher during
sleep (40). Volume fluctuations during sleep are believed to occur because of the glymphatic
system exchange between CSF and ISF (41). However, this exchange may be enabled by the
“OFF” position of integrin switches, characterized by shortening of integrines’ molecules (i.e.
“loose” matrix)(42).
Hypothesis: the dynamic switching of integrins to non-adhesive state (“OFF”) occurs during
sleep and adhesive states (“ON”) during wakefulness. This may explain the increase in ECM
volume during sleep which empowers the glymphatic system to thoroughly remove
molecular waste.
The perimeter of the NVU is demarcated by the arterial and venous capillary (a distance of
about 40 μm. This space is filled with ECM in which the neuron, glia and both capillaries are
embedded. This is the arena where the glymphatic system operates during sleep as the ECM is
“loose”. This is also where the molecular switches operate, bringing on-line and off-line GMNs.
For example, during sleep intra and extracellular molecular networks are “off line”, temporarily
disabling the GMN. It can be further hypothesized that the primary mental processes
experienced during dreaming reflect the “off line” status of intra and extracellular molecular
networks. Conversely, rational, secondary mental processes require intracellular and
extracellular molecular networks to be on-line (i.e synchronized). Interestingly, psychotic states,
also characterized by primary mental processes are frequently triggered and/or accompanied
by sleep disturbances (43).

Other important molecular switches in the ECM of some NVUs are perineuronal nets (PNNs).
They are well-organized, lattice-like structures that surround cell bodies, dendrites, and axons
(44). It is believed that PNNs contribute to synaptic plasticity during the development, but
switch off plasticity during adulthood (45). This renders PNNs extremely interesting for both
physical and memory rehabilitation, rendering ECM macromolecules possible
psychopharmacological targets. For example It was reported that chronic treatment with
fluoxetine causes restoration of synaptic plasticity especially in the dentate gyrus of
hippocampus (46)(47). In addition, it was demonstrated that enzymatic degradation of PNNs or
their genetic deletion in mice leads to prolongation or restoration of synaptic plasticity (45).
PNNs seem to contribute to synaptic stabilization of parvalbumine inhibitory interneurons in
the hippocampus and cortex (49). Interestingly, these same neurons were involved in
schizophrenia (50). A loss of PNNs throughout the medial temporal lobe has been reported in
schizophrenic patients (51)(52). In addition, there is a growing body of evidence pointing to the
involvement of ECM components such as reelin and chondroitin sulfate proteoglycans in
schizophrenia (51)(52).
The ECM metalloproteinase (MMPs) have been heavily implicated in both cortical development
and its psychopathology, for example a newly identified ADAM-10 metalloproteinase is
involved in autism(53)(54), MMP-9 were involved in delirium ( 55), dementia (56 ) and PTSD
(57) .
Looking at the Future
We started this road trip with a stroll in the tropical forest at the cellular level of brain
organization, than we took an imaginary elevator and descended one floor down to the
molecular level. On January 6, 2014 the United States' Brookhaven National Laboratory
announced the unprecedented ability to visualize chemical reactions at atomic level in realtime.
This sets the stage for studying the brain at yet another level, the nano level. A nanometer is
one billionth of a meter; for visual perspective, a human hair has 100,000 times the diameter of
a carbon nanotube, which approximates the size of many biomolecules at work throughout the
CNS. To be defined as "nano," the technology must have one dimension (length, width or
height) that is between 0.1 and 100 nanometers.
Nanoneuroscience is a new discipline which bridges neuroscience and nanotechnology, it uses
potential nanomaterials (such as nanodiamonds or nanoparticles made from semiconducting
materials) to diagnose neuropsychiatric disorders, to measure neurotransmitter levels or
electrical activity, or to stimulate in individual cells, and finally to build nanoscale molecular
prosthetic devices that may restore activity patterns and cognitive function to brain cellular and

molecular networks. Assessment methods such as labeling macromolecules with luminescent
nanorods have already been used to study self-assembly of microtubules (58), but in the future,
they will be used as interventions, such as replacing protein subunits in enzymes, ECM
macromolecules or cellular cytoskeleton. Cytoskeletal orthopedics and prostetics will correct
information processing in various networks, contributing to future treatments of
neurosychiatric disorders.
Conclusion
The intracellular and extracellular brain compartments are unified at the molecular level, where
the main function of the brain, generation of the mind originates. By virtue of uniting the four
CNS compartments, the NVU is the smallest metabolic and computation unit of brain, thus the
building block of mind.
The brain could not function without the amazing properties of the building blocks of life, the
proteins. They intimately connect the organic and inorganic realms of nature by coupling the
mechanical forces of motion with the biological actions in tissues. But proteins do more than
create bridges between inorganic and organic chemistry, they are endowed with computation
power by virtue of their abilities: storage, transmission and processing of information. It can
thus be emphatically stated that proteins represent the brain within the brain.
The CNS is situated at the interface between the environment and the body. The mind is the
brain’s adaptive response to nature’s unpredictability. Since the future events, such as life,
injury or death cannot be predicted, the mind evolved to accomplish the next best: increasing
the odds of survival by an actuarial strive for lowering risk. The mind accomplishes this by
planning, analyzing possible scenarios, and managing the odds. This process is possible only by
bringing the outside reality into the, inner, virtual space where it could be dissected, disposed
of and recreated at will.
Nanoneuroscience is opening new technological possibilities not only for evaluation, but also
for intervention in cellular and molecular networks with the purpose of correcting information
processing via novel proteomic methods such as replacing or activating enzymes, cytoskeletal
proteins, or designing and applying individualized molecular prosthetic devices that may correct
cellular signaling or recruit alternate networks to compensate for the dysfunctional ones.
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