The Brain andEnergy-The interface betweencomputation and metabolism-The basic structural andfunctional unit of the brain andits role in psychiatric disorders ADONIS SFERA, MD
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)--------------------------------------------------------------------------------------------------------TOTAL ENERGY COST: The brain uses 20% of the energy generated in thebody.Charles F. Zorumski, Eugene H. Rubin;Psychiatry and clinical neuroscience;Oxford University Press 2011;page 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.
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).
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.
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.
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).
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, neuroinflammationand neurogenesis; Brain Research Reviews Volume 66, Issues 1–2, 7 January 2011, Pages 115–122
The Structure of the NVU-A brain capillary with endothelial cells and pericytes-Astrocytes and microglia-Neurons and interneurons-The surrounding extracellular matrix
Basic Structural And Functional Units ofOther Organs Are Cell Systems as Well Liver AcinusAlveolus The Nephron The NVU
NVU Is The Electro-Metabolic System Of The BrainThe function of the NVU is local generation of energy in the form of ATPused by the synapse for information processing.Fahmeed Hyder, , Douglas L. Rothman; Quantitative fMRI and oxidative neuroenergetics; NeuroImage Volume 62, Issue 2, 15August 2012, Pages 985–994
Intermittent Local Hyperemia Energy On DemandThe NVU has an auto-regulatory mechanism of functional hyperemia.Microvasculature dilates temporarily in response to local neural activityin 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
Cognitive Tasks or Sensory Stimuli Result in Immediate Local Functional HyperemiaWithin seconds after the onset of brain activity there is increase in localblood 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
FMRI BOLDThe Metabolic Signature of Information Processing
What Does FMRI Reveal?
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.
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),
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
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.
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: frommolecule- to cell-based approaches; Biochemical and Biophysical Research Communications Volume 311, Issue 2, 14 November2003, Pages 247–253
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 overglutamate from the synapse.
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 .
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 pericytesfor Neuroprotection; Microvascular ResearchVolume 83, Issue 3, May 2012, Pages 352–359
Pericytes Are Contractile Cells That React To GlutamateCapillaries lack smooth muscle but in places are surrounded bypericytes, which express actin and myosin and are able to contract.Pericyte contraction and relaxation is the mechanism of localhyperemia (in addition to arterioles).Pericytes relax in response to glutamate (this action decreasescerebral 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;
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”.
Calcium Waves Triggers A Cascade of VasodilatorsGlutamate induced calcium waves in the astrocyte trigger NO,prostaglandins, arachidonic acid, adenosine, and potassium thatdirectly 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.
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 2N. Joan Abbott, Lars Rönnbäck & Elisabeth Hansson; Astrocyte–endothelial interactions at the blood–brain barrier; NatureReviews Neuroscience 7, 41-53 (January 2006) doi:10.1038/nrn1824
Pericyte/Endothelial Cells CommunicationPericytes communicatewith endothelial cells ofthe brain capillaries bymeans of both directphysical contact andparacrine signaling(volume transmission) by:1. HIF 1 = hypoxiainduced factor2. PDGF beta = plateletderived growth factorbeta3. Ang 1,2 = angiopoietin1 and 2
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.
Findings That Do Not Fit The Synaptic Model1. The existence of extra-synaptic receptors on neurons aswell as astrocytes, pericytes and endothelial cells.2. Communication among brain cells by chemical signalsin the absence of synaptic connections.3. Receptor/Neurotransmitter mismatch throughout theCNS.4. Not only neurons, but also astrocytes, endothelial cells,and pricytes can release and uptake neuro-transmitters.
Extra-Synaptic Receptors And Volume Transmission “Wireless” CommunicationPresence of extra-synaptic receptors opens intriguing possibility thatbrain cells can communicate to each other by chemical signals even ifthey do not have synaptic connections between them.
Receptor/Neuro-Transmitter Mismatch The Inconvenient TruthAutoradiography mapping showsthat the correspondencebetween receptors andneurotransmitters release sites isthe exception rather than the rulethroughout the brain.C.Thomas Gualtieri; Brain Injury and Mental Retardation Psychopharmacology and Neuropsychiatry;2002 Lippincott Williams andWilkins; page 452-457
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
Neurons Are Not The Only Cells That Uptake NeurotransmittersBrain 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 apredominance of the 5-HT2A and 5-HT7 subtypesZvi Cohen, Isabelle Bouchelet, André Olivier, Jean-Guy Villemure, Rita Ball*, Danica B Stanimirovic* and Edith Hamel; MultipleMicrovascular and Astroglial 5-Hydroxytryptamine Receptor Subtypes in Human Brain: Molecular and PharmacologicCharacterization; Journal of Cerebral Blood Flow & Metabolism (1999) 19, 908–917; doi:10.1097/00004647-199908000-00010
NVU and Psychopathology Totalk about psychiatric disorders without considering the NVU is like talking about renal disease without mentioning the nephron.
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 AbstractSupplement) 790.2Masato Inazu, Hiroshi Takeda, , Hideaki Ikoshi, Masaya Sugisawa, Yoshihiro Uchida, Teruhiko Matsumiya; Pharmacologicalcharacterization and visualization of the glial serotonin transporter; Neurochemistry InternationalVolume 39, Issue 1, July 2001, Pages 39–49
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).
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
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.
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 schizophreniaHarris LW, Wayland M, Lan M, Ryan M, Giger T, Lockstone H, Wuethrich I, Mimmack M, Wang L, Kotter M, Craddock R, Bahn S; The cerebralmicrovasculature in schizophrenia: a laser capture microdissection study; PLoS One. 2008;3(12):e3964. doi: 10.1371/journal.pone.0003964. Epub2008 Dec 17.
Vascular Dopamine Receptors in NVUD1 and D5 receptors are expressed in arterioles and capillaries of manybrain areas.D3 receptors are associated with astrocytes.
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 schizophreniaDaniel R Hanson and Irving I GottesmanTheories of schizophrenia: a genetic-inflammatory-vascular synthesis; BMC Med Genet. 2005; 6: 7. Published online 2005 February11. doi: 10.1186/1471-2350-6-7PMCID: PMC554096
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
Genes and Inflammatory ResponseGenetic polymorphisms of inflammatory regulators in microglia andastrocyte were described wherein activation of micro glia andastrocytes occurs in an exaggerated way.The immune system responds by mobilizing an exaggeratedinflammatory response directed against neurons and endothelial cells ofthe NVU.
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 andWilkins; page 452-457.
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.
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 GottesmanTheories of schizophrenia: a genetic-inflammatory-vascular synthesis; BMC Med Genet. 2005; 6: 7. Published online 2005 February11. doi: 10.1186/1471-2350-6-7PMCID: PMC554096
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.
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-synapticreceptors on neurons, glia, pericytes and endothelial cells.
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 andWilkins; page 452-457.
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 necrosisfactors, lipopolysaccharide, and changes in extracellular potassium(indicative of ruptured cells).
Microglia and Astrocyte:Activated and Inactivated Forms
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 againstAlzheimers disease; Cent Nerv Syst Agents Med Chem. 2009 Mar;9(1):12-9.
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 LinkBetween Immune System Dysregulation and Schizophrenia A Look at the Genetic Evidence; PsychiatricTimes. Vol. 28 No. 10