Brain networks and the matrix and the mind

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Brain networks and the matrix and the mind

  1. 1. 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.
  2. 2. 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
  3. 3. 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.
  4. 4. 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
  5. 5. 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.
  6. 6. 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) .
  7. 7. 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
  8. 8. 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).
  9. 9. 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
  10. 10. 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. References: 1. Sung S. Connectome How the Brain Wiring Makes Us Who We Are. Houghton Mifflin Harcourt, New York (2012)pp. IX
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