SlideShare ist ein Scribd-Unternehmen logo
1 von 16
Downloaden Sie, um offline zu lesen
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.
References:
1. Sung S. Connectome How the Brain Wiring Makes Us Who We Are. Houghton Mifflin
Harcourt, New York (2012)pp. IX
2. Hebb DO, Organization of Behavior: A Neuropsychological Theory. New York: John Wiley and
sons.
3. Wong AD, Ye M, Levy AF, Rothstein JD, BerglesDE, Searson PC. The blood-brain barrier: an
engineering perspective. Front. Neuroeng., 30 August 2013. doi: 10.3389/fneng.2013.0000
4. Oberheim NA, Wang X, Goldman S, Nedergaard M. Astrocytic complexity distinguishes the
human brain.Trends Neurosci. 2006 Oct;29(10):547-53.
5. Gordon GR, Mulligan SJ, MacVicar BA(2007) Astrocyte control of the cerebrovasculature. Glia
55:1214–1221
6. Iadecola C, Nedergaard M(2007) Glial regulation of the cerebral microvasculature. Nat
Neurosci 10:1369–1376
7. Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, Newman EA(2010) Glial and
neuronal control of brain blood flow. Nature 468:232–243
8. Raichle ME, Mintun MA. Brain work and brain imaging. Annu Rev Neurosci. 2006;29:449-76.
9 Kida I, Hyder F.Physiology of functional magnetic resonance imaging: energetics and function.
Methods Mol Med. 2006;124:175-95.
10. P T Fox and M E Raichle. Focal physiological uncoupling of cerebral blood flow and oxidative
metabolism during somatosensory stimulation in human subjects. PNAS vol. 83 no. 4 > P T Fox,
1140–1144
11. Han, Ke-li; Zhang, Xin; Yang, Ming-jun (Eds.). Protein Conformational Dynamics Advances in
Experimental Medicine and Biology, Vol. 805 2014, XIII, 457 p. 123 illus.,ISBN 978-3-319-029696
12. Wolf N, Priel A, Tuszynski J. Nanoneuroscience, Springer Heidelberg (2009) pp.85-112
13. Ron I, Pecht I, Sheves M, Cahen D. Proteins as solid-state electronic conductors. Acc Chem
Res. 2010 Jul 20;43(7):945-53. doi: 10.1021/ar900161u.
14. Brian A. Kidd, David Baker, Wendy E. Thomas . Computation of Conformational Coupling in
Allosteric Proteins. PCBI, 2009. DOI: 10.1371/journal.pcbi.1000484
15. Muñoz V. Conformational dynamics and ensembles in protein folding. Annu Rev Biophys
Biomol Struct. 2007;36:395-412.
16. Ron I, Pecht I, Sheves M, Cahen D. Proteins as solid-state electronic conductors. Acc Chem
Res. 2010 Jul 20;43(7):945-53. doi: 10.1021/ar900161u.
17. Effirul Ikhwan Ramlan, Klaus-Peter Zauner. In-silico design of computational nucleic acids
for molecular information processing. Journal of Cheminformatics 2013, 5:22
doi:10.1186/1758-2946-5-22
18. Yu-Shiun Chen, Meng-Yen Hong & G. Steven Huang. A protein transistor made of an
antibody molecule and two gold nanoparticles. Nature Nanotechnology 7, 197–203 (2012)
doi:10.1038/nnano.2012.7
19. Honglan Qi, Xiaoying Qiu, Chen Wang, Qiang Gaoa and Chengxiao Zhanga . Digital
electrogenerated chemiluminescence biosensor for the determination of multiple proteins
based on Boolean logic gate. Anal. Methods, 2013,5, 612-615. DOI: 10.1039/C2AY26054A
20. Simon Ausländer, David Ausländer, Marius Müller, M December 2012, Volume 38, Issue 12,
pp 1965-1973
21. Markus Wieland, Martin Fussenegger. Programmable single-cell mammalian biocomputers.
Nature (2012) doi:10.1038/nature11149
22. K Fuxe, M Canals, M Torvinen, D Marcellino, A Terasmaa, S Genedani, G Leo, D Guidolin, Z
Diaz-Cabiale, A Rivera, L Lundstrom, U Langel, J Narvaez, S Tanganelli, C Lluis, S Ferré, A Woods,
R Franco, L F Agnati. Intramembrane receptor-receptor interactions: a novel principle in
molecular medicine. Journal of Neural Transmission (2007); 114(1):49-75. DOI:10.1007/s00702006-0589-0
23. Shaw RM, Fay AJ, Puthenveedu MA, von Zastrow M, Jan YN, Jan LY. Microtubule plus-endtracking proteins target gap junctions directly from the cell interior to adherens junctions. Cell.
2007 Feb 9;128(3):547-60.
24. Brian A. Kidd, David Baker, Wendy E. Thomas . Computation of Conformational Coupling in
Allosteric Proteins. PCBI, 2009. DOI: 10.1371/journal.pcbi.1000484
25. Lee HS, Anekal P, Lim CJ, Liu CC, Ginsberg MH. Two modes of integrin activation form a
binary molecular switch in adhesion maturation. Mol Biol Cell. 2013 May; 24(9):1354-62
26. Agnati LF, Zunarelli E, Genedani S, Fuxe K. On the existence of a global molecular network
enmeshing the whole central nervous system: physiological and pathological implications. Curr
Protein Pept Sci. 2006 Feb;7(1):3-15
27. Angelo Corti and Flavio Curnis. Isoaspartate-dependent molecular switches for integrin–
ligand recognition. Journal of Cell Science 124, 515-522 doi:10.1242/jcs.077172
28. Britta Engelhardt. β1-Integrin/matrix interactions support blood–brain barrier integrity.
Journal of Cerebral Blood Flow & Metabolism (2011) 31, 1969–1971;
doi:10.1038/jcbfm.2011.98; published online 20 July 2011
29. Wang, Haowei. A Single Molecule Study of Two Bacteriophage Epigenetic Switches, 2011.
Dissertation (233 pages). Committee Chair / Thesis Adviser: Finzi, Laura. Permanent url:
http://pid.emory.edu/ark:/25593/bm7z5
30. David S. Harburger and David A. Calderwood. Integrin signalling at a glance. Journal of Cell
Science 122, 1472 (2009) doi:10.1242/jcs.052910
31. Cantiello HF.Role of actin filament organization in CFTR activation. Pflugers Arch. 2001;443
Suppl 1:S75-80.
32. Meggs, W.J.: Electric fields determine the spatial organization of microtubules and actin
filaments. Med. Hypotheses 26(3), 165–170 (1988)
33. Honglan Qi, Xiaoying Qiu, Chen Wang, Qiang Gaoa and Chengxiao Zhanga . Digital
electrogenerated chemiluminescence biosensor for the determination of multiple proteins
based on Boolean logic gate. Anal. Methods, 2013,5, 612-615. DOI: 10.1039/C2AY26054A
34. Avner Priel, Jack A. Tuszynski, Nancy J. Woolf.Neural cytoskeleton capabilities for learning
and memory. J Biol Phys. 2010 January; 36(1): 3–21. doi: 10.1007/s10867-009-9153-0
35. Wiet de Ronde, Pieter Rein ten Wolde, Andrew Mugler. Protein logic: a statistical
mechanical study of signal integration at the single-molecule level. Institute AMOLF, Science
Park 104, 1098 XG, Amsterdam arXiv:1209.1912v1 [q-bio.MN] 10 Sep 2012.
36. Prehoda K.E., Lim W.A. How signaling proteins integrate multiple inputs: a comparison of NWASP and Cdk2. Curr. Opin. Cell Biol. 2002;14:149–154.
37. Wang B, Buck M. Customizing cell signaling using engineered genetic logic circuits. Trends
Microbiol. 2012 Aug;20(8):376-84. doi: 10.1016/j.tim.2012.05.001
38. Rafael Yuste. Dendritic Spines Hardcover (2010) Massachusetts Institute of Technology.
ISBN: 9780262013505. Pp. 218.
39. Zimmermann DR, Dours-Zimmermann MT. Extracellular matrix of the central nervous
system: from neglect to challenge. Histochem Cell Biol. 2008 Oct;130(4):635-53. doi:
10.1007/s00418-008-0485-9.
40. Lulu Xie, Hongyi Kang, Qiwu Xu, Michael J. Chen, Yonghong Liao, Meenakshisundaram
Thiyagarajan, John O'Donne, Daniel J. Christensen, Charles Nicholson, Jeffrey J. Iliff, Takahiro
Takano, Rashid Deane, Maiken Nedergaard (2013). "Sleep Drives Metabolite Clearance from the
Adult Brain". Science 342 (6156): 373–377. doi:10.1126/science.1241224. Retrieved 18 October
2013.
41. Vinita Rangroo Thrane, Alexander S. Thrane, Benjamin A. Plog, Meenakshisundaram
Thiyagarajan, Jeffrey J. Iliff, Rashid Deane, Erlend A. Nagelhus, Maiken Nedergaard (2013).
"Paravascular microcirculation facilitates rapid lipid transport and astrocyte signaling in the
brain". Scientific Reports 3 (2582)(2013). doi:10.1038/srep02582.
42. Y. Yamaguchi. Lecticans: organizers of the brain extracellular matrix. CMLS, Cell. Mol. Life
Sci. 57 (2000) 276–289
43. Flavie Waters,Neepa Naik, and Daniel Rock. Sleep, Fatigue, and Functional Health in
Psychotic Patients. Schizophrenia Research and Treatment. Volume 2013 (2013),
http://dx.doi.org/10.1155/2013/425826
44. Sarama Sathyaseelan Deepa, Daniela Carulli, Clare Galtrey, Kate Rhodes, Junko Fukuda,
Tadahisa Mikami, Kazuyuki Sugahara and James W. Fawcett.Composition of Perineuronal Net
Extracellular Matrix in Rat Brain:A DIFFERENT DISACCHARIDE COMPOSITION FOR THE NETASSOCIATED PROTEOGLYCANS. The Journal of Biological Chemistry (2006), 281, 17789-17800
doi: 10.1074/jbc.M600544200
45. Wang D, Fawcett J(2012) The perineuronal net and the control of CNS plasticity. Cell Tissue
Res 349(1):147–160
46. Kobayashi K, Ikeda Y, Sakai A, Yamasaki N, Haneda E, Miyakawa T, Suzuki H: Reversal of
hippocampal neuronal maturation by serotonergic antidepressants. Proc Natl Acad Sci U S A
2010, 107:8434-8439.
47. Koji Ohira, Rika Takeuchi, Tsuyoshi Iwanaga and Tsuyoshi Miyakawa. Chronic fluoxetine
treatment reduces parvalbumin expression and perineuronal nets in gamma-aminobutyric
acidergic interneurons of the frontal cortex in adult mice. Molecular Brain 2013, 6:43
doi:10.1186/1756-6606-6-4
48. Gunnar Dick, Chin Lik Tan, Joao Nuno Alves, Erich M. E. Ehlert, Gregory M. Miller‖, Linda C.
Hsieh-Wilson‖, Kazuyuki Sugahara, Arie Oosterhof, Toin H. van Kuppevelt, Joost Verhaagen,
James W. Fawcett and Jessica C. F. Kwok. Semaphorin 3A Binds to the Perineuronal Nets via
Chondroitin Sulfate Type E Motifs in Rodent Brains. The Journal of Biological Chemistry (2013),
288, 27384-273952013, doi: 10.1074/jbc.M111.310029
49. Dityatev, Melitta Schachner, Peter Sonderegge.The dual role of the extracellular matrix in
synaptic plasticity and homeostasis. Nature Reviews Neuroscience 11, 735-746 (November
2010) | doi:10.1038/nrn2898
50. A Shah and D J Lodge . A loss of hippocampal perineuronal nets produces deficits in
dopamine system function: relevance to the positive symptoms of schizophrenia. Translational
Psychiatry (2013) 3, e215; doi:10.1038/tp.2012.145
51. Berretta S. Extracellular matrix abnormalities in schizophrenia. Neuropharmacology 2012;
62: 1584–1597.
52. Pantazopoulos H, Woo TUW, Lim MP, Lange N, Berretta S. Extracellular matrix-glial
abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia.
Arch Gen Psychiatry 2010; 67: 155–166.
53. Johannes Prox, Christian Bernreuther, Hermann Altmeppen, Jasper Grendel, Markus Glatzel,
Rudi D'Hooge, Stijn Stroobants, Tariq Ahmed, Detlef Balschun, Michael Willem, Sven Lammich,
Dirk Isbrandt, Michaela Schweizer, Katrien Horré, Bart De Strooper, and Paul Saftig. Postnatal
Disruption of the Disintegrin/Metalloproteinase ADAM10 in Brain Causes Epileptic Seizures,
Learning Deficits, Altered Spine Morphology, and Defective Synaptic Functions. The Journal of
Neuroscience, 7 August 2013, 33(32): 12915-12928; doi: 10.1523/JNEUROSCI.5910-12.2013
54. Timothy D. Girard, Lorraine B. Ware, Gordon R. Bernard, Pratik P. Pandharipande, Jennifer L.
Thompson, Ayumi K. Shintani, James C. Jackson, Robert S. Dittus, E. Wesley Ely. Associations of
markers of inflammation and coagulation with delirium during critical illness. Intensive Care
Medicine. December 2012, Volume 38, Issue 12, pp 1965-1973
55. John C. Adair, MD; Julius Charlie, MD; John E. Dencoff, BS; Jeffrey A. Kaye, MD; Joseph F.
Quinn, MD; Richard M. Camicioli, MD; William G. Stetler-Stevenson, MD, PhD; Gary A.
Rosenberg, MD. Measurement of Gelatinase B (MMP-9) in the Cerebrospinal Fluid of Patients
With Vascular Dementia and Alzheimer Disease. Stroke. 2004; 35: e159-e162, doi:
10.1161/01.STR.0000127420.10990.76
56. P.M. Abdul-Muneera, Heather Schuetza, Fang Wangc, Maciej Skotakc, Joselyn Jonesb,
Santhi Gorantlaa, Matthew C. Zimmermanb, Namas Chandrac, James Haorah. Induction of
oxidative and nitrosative damage leads to cerebrovascular inflammation in an animal model of
mild traumatic brain injury induced by primary blast. Radical Biology and Medicine (2013).
Volume 60, Pages 282–291
57. Nadine Gogolla, Pico Caroni, Andreas Lüthi, Cyril Herry. Perineuronal Nets Protect Fear
Memories from Erasure. Science 4 September 2009: Vol. 325 no. 5945 pp. 1258-1261. DOI:
10.1126/science.1174146
58. Dujardin, Erik, and Stephen Mann. "Bio-inspired materials chemistry." Advanced Materials
14.11 (2002): 775.

Weitere ähnliche Inhalte

Was ist angesagt?

Was ist angesagt? (13)

Microanatomy and neurons
Microanatomy and neuronsMicroanatomy and neurons
Microanatomy and neurons
 
Mitosis
MitosisMitosis
Mitosis
 
Histology of nervous system
Histology of nervous systemHistology of nervous system
Histology of nervous system
 
Cell junction & Junctional complexes
Cell junction & Junctional complexes Cell junction & Junctional complexes
Cell junction & Junctional complexes
 
Brain
BrainBrain
Brain
 
Neuronal cell tumors
Neuronal cell tumorsNeuronal cell tumors
Neuronal cell tumors
 
cell_junctions
 cell_junctions cell_junctions
cell_junctions
 
Exosome pathway
Exosome pathwayExosome pathway
Exosome pathway
 
Cell junction
Cell junctionCell junction
Cell junction
 
G017434861
G017434861G017434861
G017434861
 
01 cellular introduction ma
01 cellular introduction ma01 cellular introduction ma
01 cellular introduction ma
 
Microtubules
MicrotubulesMicrotubules
Microtubules
 
Estructura Celular
Estructura CelularEstructura Celular
Estructura Celular
 

Andere mochten auch

The Default Mode Network
The Default Mode NetworkThe Default Mode Network
The Default Mode NetworkEvelyn McKelvie
 
Neural networks...
Neural networks...Neural networks...
Neural networks...Molly Chugh
 
How the brain learns, formation of new neuronal networks, makiong your meory...
How the brain learns,  formation of new neuronal networks, makiong your meory...How the brain learns,  formation of new neuronal networks, makiong your meory...
How the brain learns, formation of new neuronal networks, makiong your meory...Babu Appat
 
Bradley Voytek - Cognitive Networks
Bradley Voytek - Cognitive NetworksBradley Voytek - Cognitive Networks
Bradley Voytek - Cognitive NetworksUC San Diego
 
Brain Networks
Brain NetworksBrain Networks
Brain NetworksJimmy Lu
 
Machine Learning for Digital Advertising
Machine Learning for Digital AdvertisingMachine Learning for Digital Advertising
Machine Learning for Digital AdvertisingMarc Garcia
 
Replicating the human brain: Deep learning in action
Replicating the human brain: Deep learning in actionReplicating the human brain: Deep learning in action
Replicating the human brain: Deep learning in actionMarc Garcia
 
Introduction to functional areas of management
Introduction to functional areas of managementIntroduction to functional areas of management
Introduction to functional areas of managementmajoydrew
 
Gross anatomy of human brain
Gross anatomy of human brainGross anatomy of human brain
Gross anatomy of human brainssjjhawar
 
Neural networks
Neural networksNeural networks
Neural networksSlideshare
 
Neural network
Neural networkNeural network
Neural networkSilicon
 
neural network
neural networkneural network
neural networkSTUDENT
 
Blue brain project ppt
Blue brain project pptBlue brain project ppt
Blue brain project pptLishita Shah
 
Brain ppt
Brain pptBrain ppt
Brain pptcnps
 
Brain powerpoint
Brain powerpointBrain powerpoint
Brain powerpointMrsMendoza
 
The human brain presentation
The human brain presentationThe human brain presentation
The human brain presentationSilvia Borba
 

Andere mochten auch (18)

The Default Mode Network
The Default Mode NetworkThe Default Mode Network
The Default Mode Network
 
Neural networks...
Neural networks...Neural networks...
Neural networks...
 
How the brain learns, formation of new neuronal networks, makiong your meory...
How the brain learns,  formation of new neuronal networks, makiong your meory...How the brain learns,  formation of new neuronal networks, makiong your meory...
How the brain learns, formation of new neuronal networks, makiong your meory...
 
Bradley Voytek - Cognitive Networks
Bradley Voytek - Cognitive NetworksBradley Voytek - Cognitive Networks
Bradley Voytek - Cognitive Networks
 
Brain Networks
Brain NetworksBrain Networks
Brain Networks
 
Functional Brain Networks - Javier M. Buldù
Functional Brain Networks - Javier M. BuldùFunctional Brain Networks - Javier M. Buldù
Functional Brain Networks - Javier M. Buldù
 
Machine Learning for Digital Advertising
Machine Learning for Digital AdvertisingMachine Learning for Digital Advertising
Machine Learning for Digital Advertising
 
Replicating the human brain: Deep learning in action
Replicating the human brain: Deep learning in actionReplicating the human brain: Deep learning in action
Replicating the human brain: Deep learning in action
 
Introduction to functional areas of management
Introduction to functional areas of managementIntroduction to functional areas of management
Introduction to functional areas of management
 
Lecture11 - neural networks
Lecture11 - neural networksLecture11 - neural networks
Lecture11 - neural networks
 
Gross anatomy of human brain
Gross anatomy of human brainGross anatomy of human brain
Gross anatomy of human brain
 
Neural networks
Neural networksNeural networks
Neural networks
 
Neural network
Neural networkNeural network
Neural network
 
neural network
neural networkneural network
neural network
 
Blue brain project ppt
Blue brain project pptBlue brain project ppt
Blue brain project ppt
 
Brain ppt
Brain pptBrain ppt
Brain ppt
 
Brain powerpoint
Brain powerpointBrain powerpoint
Brain powerpoint
 
The human brain presentation
The human brain presentationThe human brain presentation
The human brain presentation
 

Ähnlich wie Brain networks and the matrix and the mind

Excitable tissues nerve
Excitable tissues nerveExcitable tissues nerve
Excitable tissues nerveDanielZulu8
 
Consciousness, microtubules and the quantum world
Consciousness, microtubules and the quantum worldConsciousness, microtubules and the quantum world
Consciousness, microtubules and the quantum worldJulio Banks
 
Nerve tissue . The Nervous System
Nerve tissue . The Nervous SystemNerve tissue . The Nervous System
Nerve tissue . The Nervous SystemEneutron
 
Understanding The Structure And Function Of A Neuron
Understanding The Structure And Function Of A NeuronUnderstanding The Structure And Function Of A Neuron
Understanding The Structure And Function Of A NeuronKelly Doepke
 
histologic structure of nervous system
histologic structure of nervous systemhistologic structure of nervous system
histologic structure of nervous systemwayan sugiritama
 
What is different about activities on the two sides of the synapse?
What is different about activities on the two sides of the synapse?What is different about activities on the two sides of the synapse?
What is different about activities on the two sides of the synapse?Salman Ul Islam
 
Epilepsy Is A Central Nervous System Disorder ( Cns )
Epilepsy Is A Central Nervous System Disorder ( Cns )Epilepsy Is A Central Nervous System Disorder ( Cns )
Epilepsy Is A Central Nervous System Disorder ( Cns )Christy Hunt
 
Molecular Neurobiology Overview Presentation
Molecular Neurobiology Overview PresentationMolecular Neurobiology Overview Presentation
Molecular Neurobiology Overview PresentationRita Barakat
 
Synapse miltan chowdhury
Synapse miltan chowdhurySynapse miltan chowdhury
Synapse miltan chowdhurymiltanc
 
Please help, these quesitons are all wrapped into one large point va.pdf
Please help, these quesitons are all wrapped into one large point va.pdfPlease help, these quesitons are all wrapped into one large point va.pdf
Please help, these quesitons are all wrapped into one large point va.pdfarjunstores123
 

Ähnlich wie Brain networks and the matrix and the mind (20)

Excitable tissues nerve
Excitable tissues nerveExcitable tissues nerve
Excitable tissues nerve
 
Consciousness, microtubules and the quantum world
Consciousness, microtubules and the quantum worldConsciousness, microtubules and the quantum world
Consciousness, microtubules and the quantum world
 
Brain
BrainBrain
Brain
 
The cell
The cellThe cell
The cell
 
Nervous system summary
Nervous system summaryNervous system summary
Nervous system summary
 
Nerve tissue . The Nervous System
Nerve tissue . The Nervous SystemNerve tissue . The Nervous System
Nerve tissue . The Nervous System
 
Neurons and Synapse pdf.pdf
Neurons and Synapse pdf.pdfNeurons and Synapse pdf.pdf
Neurons and Synapse pdf.pdf
 
Model Neurons
Model NeuronsModel Neurons
Model Neurons
 
Understanding The Structure And Function Of A Neuron
Understanding The Structure And Function Of A NeuronUnderstanding The Structure And Function Of A Neuron
Understanding The Structure And Function Of A Neuron
 
histologic structure of nervous system
histologic structure of nervous systemhistologic structure of nervous system
histologic structure of nervous system
 
What is different about activities on the two sides of the synapse?
What is different about activities on the two sides of the synapse?What is different about activities on the two sides of the synapse?
What is different about activities on the two sides of the synapse?
 
Lectura 01.pdf
Lectura 01.pdfLectura 01.pdf
Lectura 01.pdf
 
Epilepsy Is A Central Nervous System Disorder ( Cns )
Epilepsy Is A Central Nervous System Disorder ( Cns )Epilepsy Is A Central Nervous System Disorder ( Cns )
Epilepsy Is A Central Nervous System Disorder ( Cns )
 
Jap 1 anat pathol
Jap 1 anat pathol Jap 1 anat pathol
Jap 1 anat pathol
 
Molecular Neurobiology Overview Presentation
Molecular Neurobiology Overview PresentationMolecular Neurobiology Overview Presentation
Molecular Neurobiology Overview Presentation
 
Synapse miltan chowdhury
Synapse miltan chowdhurySynapse miltan chowdhury
Synapse miltan chowdhury
 
Please help, these quesitons are all wrapped into one large point va.pdf
Please help, these quesitons are all wrapped into one large point va.pdfPlease help, these quesitons are all wrapped into one large point va.pdf
Please help, these quesitons are all wrapped into one large point va.pdf
 
49 nervous systems
49   nervous systems49   nervous systems
49 nervous systems
 
Nucleus.pptx
Nucleus.pptxNucleus.pptx
Nucleus.pptx
 
Plant cell
Plant cellPlant cell
Plant cell
 

Mehr von Adonis Sfera, MD

Preventing delirium in geroforensic population
Preventing delirium in geroforensic populationPreventing delirium in geroforensic population
Preventing delirium in geroforensic populationAdonis Sfera, MD
 
Jung frankel and the 20th century psychiatry
Jung frankel and the 20th century psychiatryJung frankel and the 20th century psychiatry
Jung frankel and the 20th century psychiatryAdonis Sfera, MD
 
Frontotemporal dementia and criminal behavior
Frontotemporal dementia and criminal behaviorFrontotemporal dementia and criminal behavior
Frontotemporal dementia and criminal behaviorAdonis Sfera, MD
 
Genomic and proyeomic markers in forensic psychiatry
Genomic and proyeomic markers in forensic psychiatryGenomic and proyeomic markers in forensic psychiatry
Genomic and proyeomic markers in forensic psychiatryAdonis Sfera, MD
 
What is going on in psychiatry when nothing seems to happen
What is going on in psychiatry when nothing seems to happenWhat is going on in psychiatry when nothing seems to happen
What is going on in psychiatry when nothing seems to happenAdonis Sfera, MD
 
A century of schizophrenia
A century of schizophreniaA century of schizophrenia
A century of schizophreniaAdonis Sfera, MD
 
Aquaporins in schizophrenia
Aquaporins in schizophreniaAquaporins in schizophrenia
Aquaporins in schizophreniaAdonis Sfera, MD
 
When proteins misbehave, part 2
When proteins misbehave, part 2When proteins misbehave, part 2
When proteins misbehave, part 2Adonis Sfera, MD
 
When proteins misbehave (part 3)
When proteins misbehave (part 3)When proteins misbehave (part 3)
When proteins misbehave (part 3)Adonis Sfera, MD
 
When proteins misbehave (part 1)
When proteins misbehave (part 1)When proteins misbehave (part 1)
When proteins misbehave (part 1)Adonis Sfera, MD
 
Are elderly with schizophrenia more or less likely to (docx) (1)
Are elderly with schizophrenia more or less likely to (docx) (1)Are elderly with schizophrenia more or less likely to (docx) (1)
Are elderly with schizophrenia more or less likely to (docx) (1)Adonis Sfera, MD
 
Schizophrenia Past, Present and Future
Schizophrenia Past, Present and FutureSchizophrenia Past, Present and Future
Schizophrenia Past, Present and FutureAdonis Sfera, MD
 

Mehr von Adonis Sfera, MD (20)

Preventing delirium in geroforensic population
Preventing delirium in geroforensic populationPreventing delirium in geroforensic population
Preventing delirium in geroforensic population
 
Jung frankel and the 20th century psychiatry
Jung frankel and the 20th century psychiatryJung frankel and the 20th century psychiatry
Jung frankel and the 20th century psychiatry
 
Frontotemporal dementia and criminal behavior
Frontotemporal dementia and criminal behaviorFrontotemporal dementia and criminal behavior
Frontotemporal dementia and criminal behavior
 
Aging with meaning
Aging with meaningAging with meaning
Aging with meaning
 
Genomic and proyeomic markers in forensic psychiatry
Genomic and proyeomic markers in forensic psychiatryGenomic and proyeomic markers in forensic psychiatry
Genomic and proyeomic markers in forensic psychiatry
 
Protein misfolding
Protein misfoldingProtein misfolding
Protein misfolding
 
Principal investigator
Principal investigatorPrincipal investigator
Principal investigator
 
What is going on in psychiatry when nothing seems to happen
What is going on in psychiatry when nothing seems to happenWhat is going on in psychiatry when nothing seems to happen
What is going on in psychiatry when nothing seems to happen
 
A century of schizophrenia
A century of schizophreniaA century of schizophrenia
A century of schizophrenia
 
Aquaporins in schizophrenia
Aquaporins in schizophreniaAquaporins in schizophrenia
Aquaporins in schizophrenia
 
When proteins misbehave, part 2
When proteins misbehave, part 2When proteins misbehave, part 2
When proteins misbehave, part 2
 
When proteins misbehave (part 3)
When proteins misbehave (part 3)When proteins misbehave (part 3)
When proteins misbehave (part 3)
 
When proteins misbehave (part 1)
When proteins misbehave (part 1)When proteins misbehave (part 1)
When proteins misbehave (part 1)
 
Are elderly with schizophrenia more or less likely to (docx) (1)
Are elderly with schizophrenia more or less likely to (docx) (1)Are elderly with schizophrenia more or less likely to (docx) (1)
Are elderly with schizophrenia more or less likely to (docx) (1)
 
The brain and energy
The brain and energyThe brain and energy
The brain and energy
 
Tryptophan and madness
Tryptophan and madnessTryptophan and madness
Tryptophan and madness
 
Drugs and the brain
Drugs and the brainDrugs and the brain
Drugs and the brain
 
Factitious disorders
Factitious disordersFactitious disorders
Factitious disorders
 
Normal aging
Normal agingNormal aging
Normal aging
 
Schizophrenia Past, Present and Future
Schizophrenia Past, Present and FutureSchizophrenia Past, Present and Future
Schizophrenia Past, Present and Future
 

Kürzlich hochgeladen

Pharmacokinetic Models by Dr. Ram D. Bawankar.ppt
Pharmacokinetic Models by Dr. Ram D.  Bawankar.pptPharmacokinetic Models by Dr. Ram D.  Bawankar.ppt
Pharmacokinetic Models by Dr. Ram D. Bawankar.pptRamDBawankar1
 
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdfSGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdfHongBiThi1
 
Physiology of Smooth Muscles -Mechanics of contraction and relaxation
Physiology of Smooth Muscles -Mechanics of contraction and relaxationPhysiology of Smooth Muscles -Mechanics of contraction and relaxation
Physiology of Smooth Muscles -Mechanics of contraction and relaxationMedicoseAcademics
 
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdf
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdfSGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdf
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdfHongBiThi1
 
Male Infertility Panel Discussion by Dr Sujoy Dasgupta
Male Infertility Panel Discussion by Dr Sujoy DasguptaMale Infertility Panel Discussion by Dr Sujoy Dasgupta
Male Infertility Panel Discussion by Dr Sujoy DasguptaSujoy Dasgupta
 
Different drug regularity bodies in different countries.
Different drug regularity bodies in different countries.Different drug regularity bodies in different countries.
Different drug regularity bodies in different countries.kishan singh tomar
 
"Radical excision of DIE in subferile women with deep infiltrating endometrio...
"Radical excision of DIE in subferile women with deep infiltrating endometrio..."Radical excision of DIE in subferile women with deep infiltrating endometrio...
"Radical excision of DIE in subferile women with deep infiltrating endometrio...Sujoy Dasgupta
 
Role of Soap based and synthetic or syndets bar
Role of  Soap based and synthetic or syndets barRole of  Soap based and synthetic or syndets bar
Role of Soap based and synthetic or syndets barmohitRahangdale
 
Red Blood Cells_anemia & polycythemia.pdf
Red Blood Cells_anemia & polycythemia.pdfRed Blood Cells_anemia & polycythemia.pdf
Red Blood Cells_anemia & polycythemia.pdfMedicoseAcademics
 
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...Shubhanshu Gaurav
 
Unit I herbs as raw materials, biodynamic agriculture.ppt
Unit I herbs as raw materials, biodynamic agriculture.pptUnit I herbs as raw materials, biodynamic agriculture.ppt
Unit I herbs as raw materials, biodynamic agriculture.pptPradnya Wadekar
 
ayurvedic formulations herbal drug technologyppt
ayurvedic formulations herbal drug technologypptayurvedic formulations herbal drug technologyppt
ayurvedic formulations herbal drug technologypptPradnya Wadekar
 
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdf
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdfSGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdf
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdfHongBiThi1
 
DNA nucleotides Blast in NCBI and Phylogeny using MEGA Xi.pptx
DNA nucleotides Blast in NCBI and Phylogeny using MEGA Xi.pptxDNA nucleotides Blast in NCBI and Phylogeny using MEGA Xi.pptx
DNA nucleotides Blast in NCBI and Phylogeny using MEGA Xi.pptxMAsifAhmad
 
How to cure cirrhosis and chronic hepatitis naturally
How to cure cirrhosis and chronic hepatitis naturallyHow to cure cirrhosis and chronic hepatitis naturally
How to cure cirrhosis and chronic hepatitis naturallyZurück zum Ursprung
 
Male Infertility, Antioxidants and Beyond
Male Infertility, Antioxidants and BeyondMale Infertility, Antioxidants and Beyond
Male Infertility, Antioxidants and BeyondSujoy Dasgupta
 
BENIGN BREAST DISEASE
BENIGN BREAST DISEASE BENIGN BREAST DISEASE
BENIGN BREAST DISEASE Mamatha Lakka
 

Kürzlich hochgeladen (20)

Pharmacokinetic Models by Dr. Ram D. Bawankar.ppt
Pharmacokinetic Models by Dr. Ram D.  Bawankar.pptPharmacokinetic Models by Dr. Ram D.  Bawankar.ppt
Pharmacokinetic Models by Dr. Ram D. Bawankar.ppt
 
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdfSGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
 
Rheumatoid arthritis Part 1, case based approach with application of the late...
Rheumatoid arthritis Part 1, case based approach with application of the late...Rheumatoid arthritis Part 1, case based approach with application of the late...
Rheumatoid arthritis Part 1, case based approach with application of the late...
 
Physiology of Smooth Muscles -Mechanics of contraction and relaxation
Physiology of Smooth Muscles -Mechanics of contraction and relaxationPhysiology of Smooth Muscles -Mechanics of contraction and relaxation
Physiology of Smooth Muscles -Mechanics of contraction and relaxation
 
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdf
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdfSGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdf
SGK LEUKEMIA KINH DÒNG BẠCH CÂU HẠT HAY.pdf
 
Male Infertility Panel Discussion by Dr Sujoy Dasgupta
Male Infertility Panel Discussion by Dr Sujoy DasguptaMale Infertility Panel Discussion by Dr Sujoy Dasgupta
Male Infertility Panel Discussion by Dr Sujoy Dasgupta
 
Different drug regularity bodies in different countries.
Different drug regularity bodies in different countries.Different drug regularity bodies in different countries.
Different drug regularity bodies in different countries.
 
"Radical excision of DIE in subferile women with deep infiltrating endometrio...
"Radical excision of DIE in subferile women with deep infiltrating endometrio..."Radical excision of DIE in subferile women with deep infiltrating endometrio...
"Radical excision of DIE in subferile women with deep infiltrating endometrio...
 
Biologic therapy ice breaking in rheumatology, Case based approach with appli...
Biologic therapy ice breaking in rheumatology, Case based approach with appli...Biologic therapy ice breaking in rheumatology, Case based approach with appli...
Biologic therapy ice breaking in rheumatology, Case based approach with appli...
 
Role of Soap based and synthetic or syndets bar
Role of  Soap based and synthetic or syndets barRole of  Soap based and synthetic or syndets bar
Role of Soap based and synthetic or syndets bar
 
Red Blood Cells_anemia & polycythemia.pdf
Red Blood Cells_anemia & polycythemia.pdfRed Blood Cells_anemia & polycythemia.pdf
Red Blood Cells_anemia & polycythemia.pdf
 
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
 
Unit I herbs as raw materials, biodynamic agriculture.ppt
Unit I herbs as raw materials, biodynamic agriculture.pptUnit I herbs as raw materials, biodynamic agriculture.ppt
Unit I herbs as raw materials, biodynamic agriculture.ppt
 
ayurvedic formulations herbal drug technologyppt
ayurvedic formulations herbal drug technologypptayurvedic formulations herbal drug technologyppt
ayurvedic formulations herbal drug technologyppt
 
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdf
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdfSGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdf
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdf
 
DNA nucleotides Blast in NCBI and Phylogeny using MEGA Xi.pptx
DNA nucleotides Blast in NCBI and Phylogeny using MEGA Xi.pptxDNA nucleotides Blast in NCBI and Phylogeny using MEGA Xi.pptx
DNA nucleotides Blast in NCBI and Phylogeny using MEGA Xi.pptx
 
How to cure cirrhosis and chronic hepatitis naturally
How to cure cirrhosis and chronic hepatitis naturallyHow to cure cirrhosis and chronic hepatitis naturally
How to cure cirrhosis and chronic hepatitis naturally
 
American College of physicians ACP high value care recommendations in rheumat...
American College of physicians ACP high value care recommendations in rheumat...American College of physicians ACP high value care recommendations in rheumat...
American College of physicians ACP high value care recommendations in rheumat...
 
Male Infertility, Antioxidants and Beyond
Male Infertility, Antioxidants and BeyondMale Infertility, Antioxidants and Beyond
Male Infertility, Antioxidants and Beyond
 
BENIGN BREAST DISEASE
BENIGN BREAST DISEASE BENIGN BREAST DISEASE
BENIGN BREAST DISEASE
 

Brain networks and the matrix and the mind

  • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
  • 11. 2. Hebb DO, Organization of Behavior: A Neuropsychological Theory. New York: John Wiley and sons. 3. Wong AD, Ye M, Levy AF, Rothstein JD, BerglesDE, Searson PC. The blood-brain barrier: an engineering perspective. Front. Neuroeng., 30 August 2013. doi: 10.3389/fneng.2013.0000 4. Oberheim NA, Wang X, Goldman S, Nedergaard M. Astrocytic complexity distinguishes the human brain.Trends Neurosci. 2006 Oct;29(10):547-53. 5. Gordon GR, Mulligan SJ, MacVicar BA(2007) Astrocyte control of the cerebrovasculature. Glia 55:1214–1221 6. Iadecola C, Nedergaard M(2007) Glial regulation of the cerebral microvasculature. Nat Neurosci 10:1369–1376 7. Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, Newman EA(2010) Glial and neuronal control of brain blood flow. Nature 468:232–243 8. Raichle ME, Mintun MA. Brain work and brain imaging. Annu Rev Neurosci. 2006;29:449-76. 9 Kida I, Hyder F.Physiology of functional magnetic resonance imaging: energetics and function. Methods Mol Med. 2006;124:175-95. 10. P T Fox and M E Raichle. Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. PNAS vol. 83 no. 4 > P T Fox, 1140–1144 11. Han, Ke-li; Zhang, Xin; Yang, Ming-jun (Eds.). Protein Conformational Dynamics Advances in Experimental Medicine and Biology, Vol. 805 2014, XIII, 457 p. 123 illus.,ISBN 978-3-319-029696 12. Wolf N, Priel A, Tuszynski J. Nanoneuroscience, Springer Heidelberg (2009) pp.85-112 13. Ron I, Pecht I, Sheves M, Cahen D. Proteins as solid-state electronic conductors. Acc Chem Res. 2010 Jul 20;43(7):945-53. doi: 10.1021/ar900161u. 14. Brian A. Kidd, David Baker, Wendy E. Thomas . Computation of Conformational Coupling in Allosteric Proteins. PCBI, 2009. DOI: 10.1371/journal.pcbi.1000484 15. Muñoz V. Conformational dynamics and ensembles in protein folding. Annu Rev Biophys Biomol Struct. 2007;36:395-412. 16. Ron I, Pecht I, Sheves M, Cahen D. Proteins as solid-state electronic conductors. Acc Chem Res. 2010 Jul 20;43(7):945-53. doi: 10.1021/ar900161u.
  • 12. 17. Effirul Ikhwan Ramlan, Klaus-Peter Zauner. In-silico design of computational nucleic acids for molecular information processing. Journal of Cheminformatics 2013, 5:22 doi:10.1186/1758-2946-5-22 18. Yu-Shiun Chen, Meng-Yen Hong & G. Steven Huang. A protein transistor made of an antibody molecule and two gold nanoparticles. Nature Nanotechnology 7, 197–203 (2012) doi:10.1038/nnano.2012.7 19. Honglan Qi, Xiaoying Qiu, Chen Wang, Qiang Gaoa and Chengxiao Zhanga . Digital electrogenerated chemiluminescence biosensor for the determination of multiple proteins based on Boolean logic gate. Anal. Methods, 2013,5, 612-615. DOI: 10.1039/C2AY26054A 20. Simon Ausländer, David Ausländer, Marius Müller, M December 2012, Volume 38, Issue 12, pp 1965-1973 21. Markus Wieland, Martin Fussenegger. Programmable single-cell mammalian biocomputers. Nature (2012) doi:10.1038/nature11149 22. K Fuxe, M Canals, M Torvinen, D Marcellino, A Terasmaa, S Genedani, G Leo, D Guidolin, Z Diaz-Cabiale, A Rivera, L Lundstrom, U Langel, J Narvaez, S Tanganelli, C Lluis, S Ferré, A Woods, R Franco, L F Agnati. Intramembrane receptor-receptor interactions: a novel principle in molecular medicine. Journal of Neural Transmission (2007); 114(1):49-75. DOI:10.1007/s00702006-0589-0 23. Shaw RM, Fay AJ, Puthenveedu MA, von Zastrow M, Jan YN, Jan LY. Microtubule plus-endtracking proteins target gap junctions directly from the cell interior to adherens junctions. Cell. 2007 Feb 9;128(3):547-60. 24. Brian A. Kidd, David Baker, Wendy E. Thomas . Computation of Conformational Coupling in Allosteric Proteins. PCBI, 2009. DOI: 10.1371/journal.pcbi.1000484 25. Lee HS, Anekal P, Lim CJ, Liu CC, Ginsberg MH. Two modes of integrin activation form a binary molecular switch in adhesion maturation. Mol Biol Cell. 2013 May; 24(9):1354-62 26. Agnati LF, Zunarelli E, Genedani S, Fuxe K. On the existence of a global molecular network enmeshing the whole central nervous system: physiological and pathological implications. Curr Protein Pept Sci. 2006 Feb;7(1):3-15 27. Angelo Corti and Flavio Curnis. Isoaspartate-dependent molecular switches for integrin– ligand recognition. Journal of Cell Science 124, 515-522 doi:10.1242/jcs.077172
  • 13. 28. Britta Engelhardt. β1-Integrin/matrix interactions support blood–brain barrier integrity. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 1969–1971; doi:10.1038/jcbfm.2011.98; published online 20 July 2011 29. Wang, Haowei. A Single Molecule Study of Two Bacteriophage Epigenetic Switches, 2011. Dissertation (233 pages). Committee Chair / Thesis Adviser: Finzi, Laura. Permanent url: http://pid.emory.edu/ark:/25593/bm7z5 30. David S. Harburger and David A. Calderwood. Integrin signalling at a glance. Journal of Cell Science 122, 1472 (2009) doi:10.1242/jcs.052910 31. Cantiello HF.Role of actin filament organization in CFTR activation. Pflugers Arch. 2001;443 Suppl 1:S75-80. 32. Meggs, W.J.: Electric fields determine the spatial organization of microtubules and actin filaments. Med. Hypotheses 26(3), 165–170 (1988) 33. Honglan Qi, Xiaoying Qiu, Chen Wang, Qiang Gaoa and Chengxiao Zhanga . Digital electrogenerated chemiluminescence biosensor for the determination of multiple proteins based on Boolean logic gate. Anal. Methods, 2013,5, 612-615. DOI: 10.1039/C2AY26054A 34. Avner Priel, Jack A. Tuszynski, Nancy J. Woolf.Neural cytoskeleton capabilities for learning and memory. J Biol Phys. 2010 January; 36(1): 3–21. doi: 10.1007/s10867-009-9153-0 35. Wiet de Ronde, Pieter Rein ten Wolde, Andrew Mugler. Protein logic: a statistical mechanical study of signal integration at the single-molecule level. Institute AMOLF, Science Park 104, 1098 XG, Amsterdam arXiv:1209.1912v1 [q-bio.MN] 10 Sep 2012. 36. Prehoda K.E., Lim W.A. How signaling proteins integrate multiple inputs: a comparison of NWASP and Cdk2. Curr. Opin. Cell Biol. 2002;14:149–154. 37. Wang B, Buck M. Customizing cell signaling using engineered genetic logic circuits. Trends Microbiol. 2012 Aug;20(8):376-84. doi: 10.1016/j.tim.2012.05.001 38. Rafael Yuste. Dendritic Spines Hardcover (2010) Massachusetts Institute of Technology. ISBN: 9780262013505. Pp. 218. 39. Zimmermann DR, Dours-Zimmermann MT. Extracellular matrix of the central nervous system: from neglect to challenge. Histochem Cell Biol. 2008 Oct;130(4):635-53. doi: 10.1007/s00418-008-0485-9. 40. Lulu Xie, Hongyi Kang, Qiwu Xu, Michael J. Chen, Yonghong Liao, Meenakshisundaram Thiyagarajan, John O'Donne, Daniel J. Christensen, Charles Nicholson, Jeffrey J. Iliff, Takahiro
  • 14. Takano, Rashid Deane, Maiken Nedergaard (2013). "Sleep Drives Metabolite Clearance from the Adult Brain". Science 342 (6156): 373–377. doi:10.1126/science.1241224. Retrieved 18 October 2013. 41. Vinita Rangroo Thrane, Alexander S. Thrane, Benjamin A. Plog, Meenakshisundaram Thiyagarajan, Jeffrey J. Iliff, Rashid Deane, Erlend A. Nagelhus, Maiken Nedergaard (2013). "Paravascular microcirculation facilitates rapid lipid transport and astrocyte signaling in the brain". Scientific Reports 3 (2582)(2013). doi:10.1038/srep02582. 42. Y. Yamaguchi. Lecticans: organizers of the brain extracellular matrix. CMLS, Cell. Mol. Life Sci. 57 (2000) 276–289 43. Flavie Waters,Neepa Naik, and Daniel Rock. Sleep, Fatigue, and Functional Health in Psychotic Patients. Schizophrenia Research and Treatment. Volume 2013 (2013), http://dx.doi.org/10.1155/2013/425826 44. Sarama Sathyaseelan Deepa, Daniela Carulli, Clare Galtrey, Kate Rhodes, Junko Fukuda, Tadahisa Mikami, Kazuyuki Sugahara and James W. Fawcett.Composition of Perineuronal Net Extracellular Matrix in Rat Brain:A DIFFERENT DISACCHARIDE COMPOSITION FOR THE NETASSOCIATED PROTEOGLYCANS. The Journal of Biological Chemistry (2006), 281, 17789-17800 doi: 10.1074/jbc.M600544200 45. Wang D, Fawcett J(2012) The perineuronal net and the control of CNS plasticity. Cell Tissue Res 349(1):147–160 46. Kobayashi K, Ikeda Y, Sakai A, Yamasaki N, Haneda E, Miyakawa T, Suzuki H: Reversal of hippocampal neuronal maturation by serotonergic antidepressants. Proc Natl Acad Sci U S A 2010, 107:8434-8439. 47. Koji Ohira, Rika Takeuchi, Tsuyoshi Iwanaga and Tsuyoshi Miyakawa. Chronic fluoxetine treatment reduces parvalbumin expression and perineuronal nets in gamma-aminobutyric acidergic interneurons of the frontal cortex in adult mice. Molecular Brain 2013, 6:43 doi:10.1186/1756-6606-6-4 48. Gunnar Dick, Chin Lik Tan, Joao Nuno Alves, Erich M. E. Ehlert, Gregory M. Miller‖, Linda C. Hsieh-Wilson‖, Kazuyuki Sugahara, Arie Oosterhof, Toin H. van Kuppevelt, Joost Verhaagen, James W. Fawcett and Jessica C. F. Kwok. Semaphorin 3A Binds to the Perineuronal Nets via Chondroitin Sulfate Type E Motifs in Rodent Brains. The Journal of Biological Chemistry (2013), 288, 27384-273952013, doi: 10.1074/jbc.M111.310029
  • 15. 49. Dityatev, Melitta Schachner, Peter Sonderegge.The dual role of the extracellular matrix in synaptic plasticity and homeostasis. Nature Reviews Neuroscience 11, 735-746 (November 2010) | doi:10.1038/nrn2898 50. A Shah and D J Lodge . A loss of hippocampal perineuronal nets produces deficits in dopamine system function: relevance to the positive symptoms of schizophrenia. Translational Psychiatry (2013) 3, e215; doi:10.1038/tp.2012.145 51. Berretta S. Extracellular matrix abnormalities in schizophrenia. Neuropharmacology 2012; 62: 1584–1597. 52. Pantazopoulos H, Woo TUW, Lim MP, Lange N, Berretta S. Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch Gen Psychiatry 2010; 67: 155–166. 53. Johannes Prox, Christian Bernreuther, Hermann Altmeppen, Jasper Grendel, Markus Glatzel, Rudi D'Hooge, Stijn Stroobants, Tariq Ahmed, Detlef Balschun, Michael Willem, Sven Lammich, Dirk Isbrandt, Michaela Schweizer, Katrien Horré, Bart De Strooper, and Paul Saftig. Postnatal Disruption of the Disintegrin/Metalloproteinase ADAM10 in Brain Causes Epileptic Seizures, Learning Deficits, Altered Spine Morphology, and Defective Synaptic Functions. The Journal of Neuroscience, 7 August 2013, 33(32): 12915-12928; doi: 10.1523/JNEUROSCI.5910-12.2013 54. Timothy D. Girard, Lorraine B. Ware, Gordon R. Bernard, Pratik P. Pandharipande, Jennifer L. Thompson, Ayumi K. Shintani, James C. Jackson, Robert S. Dittus, E. Wesley Ely. Associations of markers of inflammation and coagulation with delirium during critical illness. Intensive Care Medicine. December 2012, Volume 38, Issue 12, pp 1965-1973 55. John C. Adair, MD; Julius Charlie, MD; John E. Dencoff, BS; Jeffrey A. Kaye, MD; Joseph F. Quinn, MD; Richard M. Camicioli, MD; William G. Stetler-Stevenson, MD, PhD; Gary A. Rosenberg, MD. Measurement of Gelatinase B (MMP-9) in the Cerebrospinal Fluid of Patients With Vascular Dementia and Alzheimer Disease. Stroke. 2004; 35: e159-e162, doi: 10.1161/01.STR.0000127420.10990.76 56. P.M. Abdul-Muneera, Heather Schuetza, Fang Wangc, Maciej Skotakc, Joselyn Jonesb, Santhi Gorantlaa, Matthew C. Zimmermanb, Namas Chandrac, James Haorah. Induction of oxidative and nitrosative damage leads to cerebrovascular inflammation in an animal model of mild traumatic brain injury induced by primary blast. Radical Biology and Medicine (2013). Volume 60, Pages 282–291
  • 16. 57. Nadine Gogolla, Pico Caroni, Andreas Lüthi, Cyril Herry. Perineuronal Nets Protect Fear Memories from Erasure. Science 4 September 2009: Vol. 325 no. 5945 pp. 1258-1261. DOI: 10.1126/science.1174146 58. Dujardin, Erik, and Stephen Mann. "Bio-inspired materials chemistry." Advanced Materials 14.11 (2002): 775.