1. The Brain and
Energy
-The interface between
computation and metabolism
-The basic structural and
functional unit of the brain and
its role in psychiatric disorders
ADONIS SFERA, MD

2. Brain’s Energy Bill
 Most of what the brain does is accomplished by synaptic transmission
between neurons, and by calling upon the information encoded by
past transmissions across synapses.
 The brain accomplishes this task with the help of a collection of
parallel processing systems or neural networks.
 The neural networks allow humans to accomplish three things:
-Think (cognition)
-Attach value to things (emotions)
-Set and achieve goals (motivation)
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TOTAL ENERGY COST: The brain uses 20% of the energy generated in the
body.
Charles F. Zorumski, Eugene H. Rubin;Psychiatry and clinical neuroscience;Oxford University Press 2011;page 3

3. The Brain Does Not Store Energy
 The brain cells have no back up energy sources (except a small
amount of glycogen in astrocytes) such as creatine phosphate (CP)
that muscle cells have.
 Thus, the brain depends on a second by second supply of oxygen
and glucose by the blood.

4. The Brain Does Not Transport Energy
 Human made systems usually use a central energy source
connected with the energy consumers by conductors (like
the electric grid).
 In contrast, the brain uses a decentralized model wherein the
energy is produced at the site of utilization (in house power
plant model).

5. Computation and Metabolism:
The Two Faces of Janus
 Because the brain does not store or transport energy, the
energy source (metabolism) and work (information
processing) are one and the same and occur in the same
cellular system.

6. The brain uses a local energy supply model
(The Neuro-Vascular Unit or NVU)
 The transmission and metabolism of the synapse occur in a
local cellular system, a genuine house with an inbuilt power
plant.
 If you’d like a one word name for the NVU, you may prefer
the term cerebrom.

7. Advantages of Local Energy Supply
 No wiring is necessary for energy transport, which
means that the brain can utilize wiring exclusively
for information processing.
 Ifa region of the brain is lost due to trauma or
disease there will be no energy black out in the rest
of the organ(the brain can function even if large
areas are turned off).

8. Confocal images of the Neuro-Vascular
Unit (NVU)
The neuro-vascular unit (NVU) is the basic structural and functional
unit of the brain Involved in information processing.
A, astrocytes (red) and neurons (green) are shown in close proximity to a blood vessel.
The outlined area in A is enlarged in B to highlight the NVU.
Maira L. Forestia, b, Gabriel M. Arisia, b, Lee A. Shapiroa; Role of glia in epilepsy-associated neuropathology, neuroinflammation
and neurogenesis; Brain Research Reviews Volume 66, Issues 1–2, 7 January 2011, Pages 115–122

9. The Structure of the NVU
-A brain capillary with endothelial cells and pericytes
-Astrocytes and microglia
-Neurons and interneurons
-The surrounding extracellular matrix

10. Basic Structural And Functional Units of
Other Organs Are Cell Systems as Well
Liver Acinus
Alveolus
The Nephron
The NVU

11. NVU Is The Electro-Metabolic System Of
The Brain
The function of the NVU is local generation of energy in the form of ATP
used by the synapse for information processing.
Fahmeed Hyder, , Douglas L. Rothman; Quantitative fMRI and oxidative neuroenergetics; NeuroImage Volume 62, Issue 2, 15
August 2012, Pages 985–994

12. Intermittent Local Hyperemia
Energy On Demand
The NVU has an auto-regulatory mechanism of functional hyperemia.
Microvasculature dilates temporarily in response to local neural activity
in order to meet the increased demand for blood flow and oxygen
(energy on demand).
Costantino Iadecolaand Robin L. Davisson; Hypertension and Cerebrovascular Dysfunction; Cell Metabolism, Volume 7, Issue 6,
476-484, 4 June 2008 doi:10.1016/j.cmet.2008.03.010

13. Cognitive Tasks or Sensory Stimuli Result
in Immediate Local Functional Hyperemia
Within seconds after the onset of brain activity there is increase in local
blood flow and metabolism.
Sepideh Sadaghiani , Guido Hesselmann , Karl J. Friston and Andreas Kleinschmidt; The relation of ongoing brain activity,
evoked neural responses, and cognition; Front. Syst. Neurosci., 23 June 2010 | doi: 10.3389/fnsys.2010.00020

14. FMRI BOLD
The Metabolic Signature of Information Processing

15. What Does FMRI Reveal?

16. Local Hyperemia and Volume Transmission
 Local neural activity (during a cognitive task) triggers release
of vasoactive mediators in the extracellular fluid (matrix)
whose end result is local hyperemia.

17. What Is Volume Transmission?
 Although synaptic transmission is an important means of
communication between neurons, neurons also communicate
among themselves and with glia by extra-synaptic “volume
transmission”, which is mediated by diffusion in the extracellular
fluid (matrix),

18. Volume Transmission Within The NVU
 The elements of the NVU communicate with each other in
two ways:
-“Wired” (synaptic transmission - energy consuming)
-“Wireless” (volume transmission - energy saving)
Courtesy, Dr. Arthur W. Toga, Laboratory of Neuro Imaging at UCLA

19. Volume Transmission and Synchronization
with Local Neuronal Activity
 There is synchronization between local neuronal
activity and the density of capillary bed.
 neuronal activation over longer periods of time
triggers the release of vasoactive substances that
stimulate angiogenesis resulting in increased
capillary density .
 Conversely, a constant decrease in neuronal
activation reduces the area capillary density.

20. Systemic Coordination Among NVU Cellular System
Occurs By Volume Transmission
During Conversely,
development endothelial cells
neurons produce brain
express derived
vascular neurotrophic
endothelial factor (BDNF),
growth factors which binds
(VEGF) that with Trk on
induce nerve cells, and
proliferation of stimulate
endothelial neurite growth.
cells through
its receptors
(VEGFR
and/or NRP).
Jeong-Ae Parka, Kyu-Sil Choia, Soo-Young Kima, b, Kyu-Won Kim; Coordinated interaction of the vascular and nervous systems: from
molecule- to cell-based approaches; Biochemical and Biophysical Research Communications Volume 311, Issue 2, 14 November
2003, Pages 247–253

21. The Role of Astrocyte In the NVU
(Fuel Injection)
The astrocyte can be thought of as:
-“fuel injector” of lactate into the combustion chamber of the synapse
(lactate shuttle).
-“house keeper” of the combustion chamber – recycles left over
glutamate from the synapse.

22. Energy and Neuroprotection
(in a single amazing mechanism)
 Glycogenolysis in astrocytes and transport of the released lactate
into neurons play a vital role in memory formation via support of
synaptic plasticity processes as well as neuroprotection of neurons
under stress conditions (e.g., excitotoxicity).
Magistretti et al. (1999), copyright, 1999 American Association for Advancement of Science .

23. The Neuroprotective Role of The Pericyte
NVU as a self sustaining machine
Recent studies suggest that pericytes produce
neuroprotective mediators such as neuronal growth factor
(NGF) and neurotrophin-3 (NT-3).
Koji Ishitsuka, Tetsuro Agoa, Koichi Arimuraa, et al.; Neurotrophin production in brain pericytes during hypoxia: A role of pericytes
for Neuroprotection; Microvascular ResearchVolume 83, Issue 3, May 2012, Pages 352–359

24. Pericytes Are Contractile Cells
That React To Glutamate
Capillaries lack smooth muscle but in places are surrounded by
pericytes, which express actin and myosin and are able to contract.
Pericyte contraction and relaxation is the mechanism of local
hyperemia (in addition to arterioles).
Pericytes relax in response to glutamate (this action decreases
cerebral vascular resistance).
Claire M. Peppiatt, Clare Howarth, Peter Mobbs and David Attwell; Bidirectional control of CNS capillary diameter by pericytes;
Nature 443, 700-704 (12 October 2006) | doi:10.1038/nature05193; Received 15 May 2006; Accepted 24 August 2006;

25. The Molecular Mechanism of Hyperemia
1. Increased neural
activity leads to
increased glutamate in
the synapse.
2. Excess glutamate is
released into the
extracellular space.
3. Extracellular glutamate
is taken by the astrocyte
(to be recycled into
glutamine).
4. The intra-astrocytic
glutamate creates “a
calcium wave”.

26. Calcium Waves Triggers A Cascade
of Vasodilators
Glutamate induced calcium waves in the astrocyte trigger NO,
prostaglandins, arachidonic acid, adenosine, and potassium that
directly alter blood vessel tone, causing pericye relaxation (vasodilation).
Bachneff SA.; Regional cerebral blood flow in schizophrenia and the local circuit neurons hypothesis; Schizophr
Bull. 1996;22(1):163-82.

27. Endothelial Cells Cross Talk To NVU Cells
receptors and transporters
TRANSPORTERS:
EAAT1–3, excitatory amino acid
transporters 1–3;
GLUT1, glucose transporter 1;
LAT1, L-system for large neutral
amino acids;
RECEPTORS:
Serotonin (5-HT1B, 5-HT1D, 5-
HT1F, 5-HT2A).
ANG1, angiopoetin 1;
bFGF, basic fibroblast growth factor;
ET1, endothelin 1;
GDNF, glial derived neurotrophic
factor;
P2Y2, purinergic receptor;
TGF, transforming growth factor
TIE2, endothelium-specific receptor
tyrosine kinase 2
N. Joan Abbott, Lars Rönnbäck & Elisabeth Hansson; Astrocyte–endothelial interactions at the blood–brain barrier; Nature
Reviews Neuroscience 7, 41-53 (January 2006) doi:10.1038/nrn1824

28. Pericyte/Endothelial Cells Communication
Pericytes communicate
with endothelial cells of
the brain capillaries by
means of both direct
physical contact and
paracrine signaling
(volume transmission) by:
1. HIF 1 = hypoxia
induced factor
2. PDGF beta = platelet
derived growth factor
beta
3. Ang 1,2 = angiopoietin
1 and 2

29. Drugs and The Brain: Analyze This!
 Thecurrent tenet of psychopharmacology is that
psychiatric conditions are caused by synaptic
dysfunction.
 Drugswork by restoring the adequate synaptic
function, thus eliminating or ameliorating the
symptoms.

30. Findings That Do Not Fit The Synaptic Model
1. The existence of extra-synaptic receptors on neurons as
well as astrocytes, pericytes and endothelial cells.
2. Communication among brain cells by chemical signals
in the absence of synaptic connections.
3. Receptor/Neurotransmitter mismatch throughout the
CNS.
4. Not only neurons, but also astrocytes, endothelial cells,
and pricytes can release and uptake neuro-transmitters.

31. Extra-Synaptic Receptors And Volume Transmission
“Wireless” Communication
Presence of extra-synaptic receptors opens intriguing possibility that
brain cells can communicate to each other by chemical signals even if
they do not have synaptic connections between them.

32. Receptor/Neuro-Transmitter Mismatch
The Inconvenient Truth
Autoradiography mapping shows
that the correspondence
between receptors and
neurotransmitters release sites is
the exception rather than the rule
throughout the brain.
C.Thomas Gualtieri; Brain Injury and Mental Retardation Psychopharmacology and Neuropsychiatry;2002 Lippincott Williams and
Wilkins; page 452-457

33. Examples of neurotransmitter/receptor
Mismatch
 Nicotinic receptors in the brain are only occasionally
associated with cholinergic terminals.
 Dopamine D1 receptors without dopamine innervation are
found in the hippocampus, thalamus, superior colliculus and
cerebellum.
 Neuroactive peptides (such as opiates, neurotensin,
somatostatin, thyrotropin-releasing hormone) and their
receptors are not anatomically related and, instead, seem
to be independently distributed in the brain.
 C.Thomas Gualtieri;Brain Injury and Mental Retardation Psychopharmacology and
Neuropsychiatry;2002 Lippincott Williams and Wilkins; page 452-457

34. Neurons Are Not The Only Cells That
Uptake Neurotransmitters
Brain arterioles and capillaries are known to express serotonin receptors
5-HT1B, 5-HT1D, 5-HT1F, 5-HT2A.
Serotonin receptors were detected in human brain astrocytes with a
predominance of the 5-HT2A and 5-HT7 subtypes
Zvi Cohen, Isabelle Bouchelet, André Olivier, Jean-Guy Villemure, Rita Ball*, Danica B Stanimirovic* and Edith Hamel; Multiple
Microvascular and Astroglial 5-Hydroxytryptamine Receptor Subtypes in Human Brain: Molecular and Pharmacologic
Characterization; Journal of Cerebral Blood Flow & Metabolism (1999) 19, 908–917; doi:10.1097/00004647-199908000-00010

35. NVU and Psychopathology
 Totalk about psychiatric disorders without
considering the NVU is like talking about renal
disease without mentioning the nephron.

36. Serotonergic Neurons and Depression
Only Half Of The Story
 Astrocytes regulate synaptic serotonin concentration through the
uptake of serotonin via SERT, and subsequent degradation by MAO.
 S100B is a calcium-binding protein,
produced and secreted by astrocytes.
 Peripheral elevation of S100B is positively
correlated with a therapeutic
antidepressant response, particularly to
selective serotonin reuptake inhibitors
(SSRIs), suggesting that other molecular
targets may be relevant for antidepressant activity.
Cheryl Watson, Jonatha Bates and Rod Franczak; Serotonin Regulation by Astrocytes; FASEB J. April 2009 23 (Meeting Abstract
Supplement) 790.2
Masato Inazu, Hiroshi Takeda, , Hideaki Ikoshi, Masaya Sugisawa, Yoshihiro Uchida, Teruhiko Matsumiya; Pharmacological
characterization and visualization of the glial serotonin transporter; Neurochemistry International
Volume 39, Issue 1, July 2001, Pages 39–49

37. Serotonin and The NVU
 A large body of physiologic evidence suggests that
brainstem serotonin (5-hydroxytryptamine, 5-HT) neurons can
regulate local cerebral blood flow (CBF) (Cohen et al., 1996).
 The predominant vascular response to 5-HT is a reduction in
local CBF (i.e., cerebral vasoconstriction), although increases
in flow (i.e., vasodilatation) have also been observed
(Bonvento and Lacombe, 1993; Cohen et al., 1996).
 The dual response to serotonin has been related to the initial
tone of the blood vessels (Rosenblum and Nelson, 1990) as
well as to the ability of different regions within the dorsal
raphe nucleus to trigger opposite vasomotor responses
(Underwood et al., 1992).

38. Serotonin and Cerebral Blood Flow (CBF)
Correlation between CBF and Cerebral
glucose utilization (CGU) in control
condition (control) and following
experimentally induced increase (↑) or
decrease (↓) in 5-HT neurotransmission.
An increased 5-HT release is accompanied
by a decrease of the CBF/CGU
slope, whereas the opposite is observed
when the 5-HT transmission is diminished.
These changes favor a vasoconstrictor role
for endogenously released 5-HT.
ZVI COHEN, GILLES BONVENTO, PIERRE LACOMBE, EDITH HAMEL;SEROTONIN IN THE REGULATION OF BRAIN MICROCIRCULATION;
Progress in Neurobiology Volume 50, Issue 4, November 1996, Pages 335–362

39. Capillary Blood Flow In Major Depression
Compromised regional cerebral
blood flow (rCBF) in major
depressive disorder may be partly
reversed by successful
antidepressant treatment.
Cerebral blood flow in depressed
individuals is lower than in healthy
control subjects, especially in the
frontal, limbic and subcortical
regions.
Caren B. Les; SPECT reveals aspects of clinical depression and its treatment; The Journal of Nuclear Medicine, August 2007, pp.
1273-1278.

40. Schizophrenia – Impaired Energy Supply
 Several studies of brain and peripheral tissues in schizophrenia
patients have indicated impaired energy supply to the brain.
 A number of studies have also demonstrated dysfunction of the
microvasculature in schizophrenia patients.
 Ultrastructural abnormalities of capillaries were found in
schizophrenia, suggesting that NVU dysfunction might contribute to
the pathogenesis of cortical lesions in schizophrenia
Harris LW, Wayland M, Lan M, Ryan M, Giger T, Lockstone H, Wuethrich I, Mimmack M, Wang L, Kotter M, Craddock R, Bahn S; The cerebral
microvasculature in schizophrenia: a laser capture microdissection study; PLoS One. 2008;3(12):e3964. doi: 10.1371/journal.pone.0003964. Epub
2008 Dec 17.

41. Vascular Dopamine Receptors in NVU
D1 and D5 receptors are expressed in arterioles and capillaries of many
brain areas.
D3 receptors are associated with astrocytes.

42. Inflammation and Impairment of
Energy Supply Within the NVU
Inflammatory
vascular disease
of CNS can lead
to psychosis,
exhibiting a
fluctuating course,
as the one seen in
schizophrenia
Daniel R Hanson and Irving I Gottesman
Theories of schizophrenia: a genetic-inflammatory-vascular synthesis; BMC Med Genet. 2005; 6: 7. Published online 2005 February
11. doi: 10.1186/1471-2350-6-7PMCID: PMC554096

43. Micro-vascular Disease
and Psychosis
 Genetically modulated inflammatory reactions can
damage the NVU, impairing energy supply to the synapse.
 Psychoses resulting from diffuse brain micro-vascular disease
are found in lupus and Sjogren syndrome (Hess D.1997).
 Psychoses due to substance abuse are associated with CNS
vasculitis (Fredericks R. 1991).
 Brain capillary abnormalities were described in depressed
elderly (Thomas A. 2002).
 Daniel R Hanson and Irving I Gottesman
Theories of schizophrenia: a genetic-inflammatory-vascular synthesis; BMC Med Genet. 2005; 6: 7. Published online 2005 February 11.
doi: 10.1186/1471-2350-6-7PMCID: PMC554096

44. Genes and Inflammatory Response
Genetic polymorphisms of inflammatory regulators in microglia and
astrocyte were described wherein activation of micro glia and
astrocytes occurs in an exaggerated way.
The immune system responds by mobilizing an exaggerated
inflammatory response directed against neurons and endothelial cells of
the NVU.

45. The Other Psychopharmacology
Thinking Outside The Synapse
 Psychopharmacology operates on a brain map that is
functional, diffuse and dynamic and better understood in
terms of processes rather than locations.
 The action of psychoactive drugs is non-specific, for example
fluoxetine can cause hypersomnia or insomnia, hyperphagia
or anorexia, akathisia or anergia, hypo or hyper-sexuality, etc.
 Also, aside from blocking synaptic serotonin
transporters, SSRIs and some antipsychotic drugs have anti-
inflammatory, vasoactive and neuroprotective properties.
C.Thomas Gualtieri; Brain Injury and Mental Retardation Psychopharmacology and Neuropsychiatry;2002 Lippincott Williams and
Wilkins; page 452-457.

46. Drugs and The NVU
 The synaptic model of psychopathology is incomplete without taking
into consideration the action of psychoactive drugs at the level of
the NVU because it does not take into consideration the drugs’
binding to extra-synaptic receptors or the drugs’ interaction with
neurotransmitters and cytokines in the extracellular fluid.

47. Psychopathology and The NVU
 Rather than being caused by synaptic dysfunction in one
geographic area, psychiatric conditions are disorders of
complex functional systems that are dispersed throughout the
neuraxis.
 The NVU is positioned at the very core of the energy supply to
the neural networks involved in cognition, mood and
motivation.
Daniel R Hanson and Irving I Gottesman
Theories of schizophrenia: a genetic-inflammatory-vascular synthesis; BMC Med Genet. 2005; 6: 7. Published online 2005 February
11. doi: 10.1186/1471-2350-6-7PMCID: PMC554096

48. Let’s Follow The Drug Throughout
The NVU
As drugs pass from the
bloodstream to the
extracellular fluid of the
brain(matrix), they
interact with the synaptic
and non-synaptic
receptors on neurons,
glia, pericytes and
endothelial cells, slowly
correcting the
derangements in the
cellular networks,
and/or helping recruit
compensatory systems
into the impaired
network.

49. Drugs Affect The Volume Transmission
of The NVU
Recent studies confirm that about 20% of the brain consists of
extracellular space.
In the extracellular space drugs interact with various extra-synaptic
receptors on neurons, glia, pericytes and endothelial cells.

50. Drugs and The Extra -Synaptic
Receptors
Drugs interact with the
extra-synaptic receptors
for serotonin,
acetylcholine and
dopamine that mediate
volume transmission
between astrocytes,
pericytes and endothelial
cells.
C.Thomas Gualtieri; Brain Injury and Mental Retardation Psychopharmacology and Neuropsychiatry;2002 Lippincott Williams and
Wilkins; page 452-457.

51. Drugs Interact With Cytokines in The
Extracellular Space of NVU
-Inactivated microglia produces Th 2 anti-inflammatory cytokines.
-Activated the microglia produces pro-inflammatory Th 1 cytokines.
-Microglia can be activated by a variety of factors including:
glutamate receptor agonists, pro-inflammatory cytokines, cell necrosis
factors, lipopolysaccharide, and changes in extracellular potassium
(indicative of ruptured cells).

52. Microglia and Astrocyte:
Activated and Inactivated Forms

53. Anti-inflammatory Effects of Antidepressants
Various types of antidepressants
were shown to suppress serum
and plasma levels of Th1 pro-
inflammatory cytokines in
patients with major depression.
Hashioka S, McGeer PL, Monji A, Kanba S.; Anti-inflammatory effects of antidepressants: possibilities for preventives against
Alzheimer's disease; Cent Nerv Syst Agents Med Chem. 2009 Mar;9(1):12-9.

54. Antipsychotic Drugs Have
Anti-inflammatory Properties
 Microglial cells are activated during psychosis (Bessis A. 2007).
 Activated microglia stimulate astrocyte production of S100B, a
marker of inflammation (Sen J. 2007).
 Serum levels of S 100B are elevated in schizophrenia .
 Antipsychotics such as haloperidol and clozapine decrease S
100B release from astrocytes (Zhang XY. 2010)
Dimitre H. Dimitrov, MD, Nicole Braida, MD, and Consuelo Walss-Bass, PhD | October 5, 2011; The Link
Between Immune System Dysregulation and Schizophrenia A Look at the Genetic Evidence; Psychiatric
Times. Vol. 28 No. 10

55. Thank You