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What is the brain made of, how does it work and how can we maintain it? Nord Pool’s market forum 2007 Garmisch-Partenkirchen May 14 Jon Storm-Mathisen Linda Hildegard Bergersen Anatomy, Institute of Basic Medical Sciences & Centre for Molecular Biology and Neuroscience University of Oslo ISBN 978-82-995010-3-3 What’s the brain made of? • • • • 78% water, 10% lipid, 8% protein, 1% carbohydrate, 3% other All animals have a nervous system All mammalian brains are built in the same way The human brain is more complex than other brains (“the most complex structure in the universe”) "From the brain and the brain alone arise our pleasures, joys, laughter and jests, as well as our sorrows, pains and griefs" Hippocrates (‘Father of Medicine’, b ca 460 BC, island of Cos, Greece) The brain and spinal cord (central nervous system, CNS) form from the outer layer (“skin”) of the embryo The CNS forms as a tube at the end of the third week after conception The cavity of the tube becomes the ventricular system of the brain and spinal cord Langman’s Medical Embryology 6th edition The CNS floats in the cerebrospinal fluid, formed inside the ventricles The living brain can be “seen” by magnetic resonance imaging (MRI) Brodal: Sentralnervesystemet 2nd edition 1.4 Kg 4.8 Kg The brain is alone….fanthastic The brain contains ~100 billion (1011) nerve cells Each nerve cell connects to ~10000 others The total number of connections in the brain is ~1015 – rivalling the total number of leaves in the Amazonas rain forrest We loose nerve cells all the time ~1/sec, 31million/year It amounts to ~2% in a lifetime What is a neuron? What is a synapse? A nerve cell is called a neuron – after the Greek word for fibre, sinew – because they form long fibre-like processes, both in the brain and spinal cord (CNS) and in the peripheral nervous system (PNS) A synapse is a contact point between neurons Nerve cell = Neuron Nerve fibre = Axon Receiving part = Dendrite Nerurons are independent cells that form networks Contact points = Synapses In the cerebral cortex, pyramidal cells (green) project axons to local and distant sites, interneurons (red) project locally Synaptic transmitters Pyramidal cells: glutamate (excitatory) Interneurons: GABA (inhibitory) Glia Neurons are the ’main cells’ of the brain Glial cells comprise ’supporting’ cells of several kinds – named after Greek glia = ’glue’ Glia are many times as numerous as neurons Dendrites Dendrites (of Greek dendron = ’tree’) are branched like a tree. They receive information from other neurons Many neurons have spines on their dendrites (Latin spina = ‘thorn’), receiving excitatory synapses Axon Axon (after Greek axon = axle) is like a long cable. Many axons are insulated by a myelin sheath (myelin) The axon carries the nerve signal (electric impulse) to the nerve ending (nerve terminal), several thousand per nerve cell. The nerve terminal releases the transmitter into the synaptic cleft. nerve terminals Synapse When the nerve impulse (electrical signal) enters the nerve ending, it opens voltage sensitive calcium (Ca2+) channels. Calcium entering the nerve ending triggers the fusion of synaptic vesicles with the nerve terminal membrane, to release neurotransmitter from the vesicle to the synaptic cleft. The transmitter activates receptors on the surface of the dendrite of the next neuron Ca2+ How does the brain work? Glutamate Indeed a useful substance • Glutamate (gluten + amino + -ate) [gluten: akin to clay, Old High German kliwa bran, Latin gluten glue, Middle Greek glia] • Most abundant amino acid • Protein constituent • Metabolite • Nutrient • Umami taste (Japanese ‘savoury’) [savor: from Anglo-French savur, from Latin sapor, from sapere to taste; be wise sage; sapiens] • Signalling functions Nervous tissue Network of independent cells Web between cell bodies = Neuropil Approximate size of a red blood cell NC Danbolt The glutamatergic synapse VGLUT1 VGLUT2 VGLUT3 PAG SAT1, SAT2 Farrukh A Chaudhry SN1 GS EAAC1 Niels Christian Danbolt GLT GLAST Storm-Mathisen får medisinpris 24.aug 2006 13:55 Jon Storm-Mathisen tildeles Anders Jahres store medisinske pris for 2006. Han får prisen for banebrytende forskning på signalstoffer i hjernen. Does glia release glutamate? ? synaptiske vesikler nerveende ? glutamat synapse dendritt glutamatresepto r glutamat astrocytt V Gundersen Glial cells can act as servomotors enhancing the performance of synapses Nature Neurosci 10:331-9 http://www.cmbn.no/news.html Publication in Nature Neuroscience on the function of glial glutamate release [Announced 27 February 2007] CMBN researchers Linda H Bergersen and Vidar Gundersen publish in Nature Neuroscience on the function of glial glutamate release. Synaptic activation of granule cells by the perforant path (the main input to the hippocampus) is enhanced by glutamate exocytosed from astrocytes onto presynaptic NR2B containing receptors. The mechanism is triggered by neuronal activity dependent stimulation of P2Y1 purine receptors on the astrocytes. Jourdain P1, Bergersen LH1, Bhaukaurally K1, Bezzi P, Santello M, Domercq M, Matute C, Tonello F, Gundersen V2, Volterra A2 (2007) Glutamate exocytosis from astrocytes controls synaptic strength Nat Neurosci, 10, 331-339 1contributed equally; 2corresponding authors See also News and Views. Linda H Bergersen Vidar Gundersen The nerve impulse (= action potential) K,Na ATPase -makes ion gradients that drive other tramsmembrane events -consumes most of the energy produced in the brain Voltage dependet Na-channel makes (first part of) the action potential Synapses on spines are candidates for plastic changes A B P ||||||||||||||||||||||||||||||||||||||||||||||| PSD95 s s C d s = spine d = dendrite = postsynaptic density Per Andersen 2004 AMPA receptors are inserted on demand Activity can potentiate (LTP) or depress (LTD) synapses Simplified model of the intracellular pathways involved in LTD and LTP. LTD is triggered by a modest rise in calcium that activates protein phosphatase 2B (calcineurin) and protein phosphatase 1. This leads to the endocytosis of synaptic AMPA receptors as well as to their dephosphorylation. LTP is triggered by a large rise in calcium that activates CaMKII. This causes the delivery (exocytosis) of intracellular AMPA receptors to the synapse. CaMKII may also phosphorylate AMPA receptors directly, although this may not be required for their synaptic delivery. Malenka (2003) NY Acad Sci Glutamate neurotransmission and DNA damage and repair Centre of Molecular Biology and Neuroscience (CMBN) Ole Petter Ottersen The nerve impulse travels at high speed – 120 m/sec Det er helt avgjørende at farten til elektriske nerve impulser er rask De raskeste nerveimpusene har en fart på 120 m/sek (=432km/h). Raskere enn en Formel 1 bil. For at de elektriske impulsene skal være raske må aksonet (nervefiberen ) være isolert med myelin (fettlag) Myelin Hvis du brenner deg på fingrene er det svart viktig at du trekker til deg hånden raskt. Nerveceller sender sine signaler raskt via nervefiberutløperen og er dekket av et hvitt fettlag som vi kaller myelin. Myelinet virker som isolasjon rundt en elektrisk ledning og får nervesignalene til å gå 20 ganger raskere enn om myelinet ikke var der. I multippel sklerose ødelegges gradvis myelinet slik at nervecellene ikke kan sende elektriske impulser effektivt mellom hjernen og kroppen. The combined length of myelinated nerve fibres in the brain is 180000km – half the distance from the earth to the moon NMDA receptors are expressed in oligodendrocytesand activated in ischaemia Káradóttir, Cavelier, Bergersen, Attwell (2005) Nature First paragraph | Full text | PDF | Supplementary information See also: Editor's summary Article in UNIFORUM News from Science's STKE The myelinating processes of oligodendrocytes (needed by nerve fibres to conduct at high speed) are shown to have a class of glutamate receptors previously thought to be confined to neurons: NMDA receptors make cells 'learn' but can kill them if getting out of control. EM Localization Post-embedding immunohistochemistry reveals NMDA receptors in the myelinating processes of oligodendrocytes. (a) EM of cerebellar cortex showing immuno-gold (arrowheads) over the myelin. No labelling was seen with primary antibody omitted. (b) Gold particle density over myelin was comparable to that at mossy fibre post-synaptic density (psd), and much higher than at parallel fibre fibre psd or over axons or mitochondria in mossy fibre terminals. Scale 0.5mm Linda H Bergersen The brain hemispheres into four “lobes” The lobi share the work Parietal lobe: Body sensation, localization of touch, pain, etc Frontal lobe: Start of movements, speaking, decision making Occipital lobe: Vision Temporal lobe: Memory, sense of place, language, hearing, olfaction, initiative, spontaneity Cerebellum: Coordination of movement, balance http://en.wikipedia.org/wiki/Image:Brain-anatomy.jpg Brain stem: Connection between the brain and the rest of the body. Centres for control of respiration, cardiovascular function, etc Most brain functions are served by several brain regions. These are interconnected by bundles of myelinated axons. Therefore, localized brain damage usually does not completely destroy function, and function can be regained through training. Brain activity tunes brain blood flow, which can be recorded through imaging techniques Vision (flicker-board) Atle Bjørnerud, Rikshospitalet Brodal: Sentralnervesystemet 2nd edition Brodal: Sentralnervesystemet 2nd edition Finger-tapping Atle Bjørnerud, Rikshospitalet SENSASJON: En liten brikke gjør det mulig for Matthew Nagle å styre TV-apparatet ved hjelp av tankene. Foto: MICHAEL EDWARDS VG 04.04.2005 Neuronal ensemble control of prosthetic devices by a human with tetraplegia Hochberg et al. 2006 Nature Speach Broca's centre Wernicke's centre Atle Bjørnerud, Rikshospitalet Pathways for sensory coding & analysis Adapting to novel situations: Basic characteristics of events are stored as generalized classes. Abstracted beyond specific details of sensory inputs and motor outputs, they can be easily generalized and adapted to new circumstances. interact steer store Miller et al. (2003) Curr Opin Neurobiol 13: 198-203 / Per Andersen How can we maintain the brain? Use it – or loose it! The more you put into the brain, the more room there is And – physical exercise is good for the brain Physical training strengthens the brain (several reasons to be physically active) Though not everyone acts accordingly, most people know that physical activity counteracts the deterioration of the body during aging and protects against cardiovascular disease Now it turns out that physical exercise protects the brain against early aging and degenerative disease such as Alzheimer’s and Parkinson’s Physical exercise even enhances the performance of the healthy brain Didn’t we know? Marcus Tullius Cicero ~65 BC: “It is exercise alone that supports the spirits, and keeps the mind in vigor” John Adams, the second president of the United States, mid-1760s: “Exercise invigorates, and enlivens all the faculties of body and of mind . . . It spreads a gladness and satisfaction over our minds and qualifies us for every sort of business, and every sort of pleasure” Henry Ford (1863-1947) was of a different opinion (he sold T-Fords): “Exercise is bunk. If you are healthy, you don’t need it, and if you are sick, you shouldn’t take it”. Motion is natural…… was necessary to survive Hunters, gatherers, farmers, workers – human beings always had to be in motion to find their food, to earn their living Only during the recent 50 years our life style has changed to sedentary – we sit – in the car, in the truck, in front of the PC, in front of the TV, … Walking, jogging, running often enhance clear thinking Research in animals and humans show the brain works better in physically active than in inactive individuals Trening og hjernehelse Linda Hildegard Bergersen & Jon Storm-Mathisen Tidsskr Nor Lægeforen 2006; 126: 3253 http://www.tidsskriftet.no/pls/lts/pa_lt.visSeksjon?vp_SEKS_ID=1465573 Hippocampus (on the inner/lower side of the temporal lobe) is a part of the cerebral cortex involved in memory http://en.wikipedia.org/wiki/Hippocampus New neurons are formed continuously in certain parts of the mature brain Recently it was discovered that even in mature individuals new nerve cells are continuously being formed in certain parts of the brain, notably in hippocampus, a brain region needed for memory If the hippocampus is destroyed, you can read the same newspaper at breakfast every morning – you will remember neither what you read, nor what you ate Physical exercise enhances the formation of new nerve cells in the hippocampus – and imporves memory and the ability to learn What happens in the brain during physical exercise? Physical activity increases hippocampus dependent memory in adult rats, and leads to increased formation of new granule cells in the dentate gyrus, while the dendrites grow and get more spines, ie more synapses (Eadie et al. 2005 J Comp Neurol) New neurons continue to be formed in the dentate gyrus of hippocampus in mammals including man. The newly formed neurons are particularly sensitive to ’long term potentiation’ (LTP), ie enhanced efficiency, of active synapses. They may provide encoding of time into new memories (Aimone et al. 2006 Nat Neurosci; Kee et al. 2007 Nat Neurosci) Physical activity enhance by several fold the formation of new neurons, whereas ’enriched environment’ increases the survival rate of the new cells (Olson et al. 2006 Hippocampus) Exercise induces new cells, growth factors, and excitatory synaptic receptors Growth factor: BDNF NMDA type glutamate receptor: subunit NR2B AMPA type glutamate receptor: subunit GluR5 Internal control (‘house-keeping gene’): HPRT Green: neurons (NeuN) Blue: glial cells (S100b) Red: newly formed cells (BrdU) Farmer et al. (2004) Neuroscience Physical exercise can be used as a ’mood enhancer’ Depressive disorder may be caused reduced new formation of neurons in the dentate gyrus Antidepressive therapy (drugs or electroconvulsive shock) enhance this proliferation of neurons, which may explain the latency of the therapeutic effects Physical activity is antidepressant, partly through the same mechanisms, and has addional, faster mood enhancing effects (Ernst et al. 2006 J Psychiatry Neurosci) Antidepressive therapy enhances the production of endorphins (morphin-like hormones), which enhance the production of nerve growth factors, which then cause new neurons to form Physical exercise seem to work through the same mechanisms as conventional antidepressive therapy In addition physical activity has other, faster positive effects on mood – and probably no untoward side effects How much do you need to exercise? A little is much better than nothing. But you must feel the heart beat! The more the better, up to moderate doses. The curve levels off. The levels of nerve growth factors continue to increase during regularly repeated exercise for several months. For nerve growth factors optimal effect is attained by training only every second day, but the perspective is lifelong, training works at all ages. Regardless of outset – physical condition, body weight, handicap – everyone can find a form of training to benefit from. Even if you have been prevented from training during a period, you still have benefit from earlier training – provided you continue (as is the case for the muscles). KR Norum Joy! Paul Smaglik Naturejobs editor ISBN 978-82-995010-3-3