W2 Lectures PDF - Biological Foundations of Mental Health

Week 2: Learning Outcomes By the end of Topic 1 you will be able to: Describe how astrocytes could influence behaviour in the healthy central nervous system (CNS) Explain the modulation of synaptic function (the 'tripartite synapse' and gliotransmission) Describe the structure o...

Week 2: Learning Outcomes By the end of Topic 1 you will be able to: Describe how astrocytes could influence behaviour in the healthy central nervous system (CNS) Explain the modulation of synaptic function (the 'tripartite synapse' and gliotransmission) Describe the structure of astrocytic networks and explain their possible functions Explain the intrinsic difficulties of research aimed at establishing the role of the astrocyte in psychiatric disorders By the end of Topic 2 you will be able to: Define the two main characteristics of a stem cell Identify the different locations of adult neural stem cells in the mammalian brain and recognise the importance of the neurogenic niche Explain examples of the molecular control of adult hippocampal neurogenesis Discuss the possible functions of adult hippocampal neurogenesis Discuss some environmental factors that can influence adult hippocampal neurogenesis By the end of Topic 3 you will be able to: Explain what iPSCs are and how they are made. Understand how neurons can be generated from iPSCs. Explain the types of experiments that can be carried out, using iPSC- derived neurons, to study brain disorders. Give an example of what we have learned about brain disorders from using iPSC technology.  10/06/2019 glicsentric vie! INSTITUTE OF PSYCHIATRY, PSYCHOLOGY & NEUROSCIENCE Module: Biological foundations of mental health Dr Isabella Gavazzi - Week 2: Topic 1 Neuron-glial interactions and Building blocks of the brain mental health Part 1a of 2 new take on Mental H. issus - Introduction (1) What is the biological basis of behaviour? Figure 1: Neuron Figure 2: Glial cell (astrocyte) = - - Week 2 · Building blocks to the brain Neurocentrism. · G Topic 1: Neuron-glial interactions andWeek fundamental 2 –health mental players Lorem ipsum. 2 of 7 1  10/06/2019 Introduction (2) Part 1: Astrocytes in the healthy CNS Astrocyte networks H - The modulation of synaptic function (the ‘tripartite synapse’) Part 2: Astrocytes in CNS pathology Depression - Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 3 of 7 Astrocytes in the Healthy Brain Visualised first by the use of histological staining, such as the silver impregnation method, developed by Camillo Golgi, 1873 19 Figure 3: Astrocytes visualised by silver impregnation method Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental intung Lorem ipsum 4 of 7. 2  10/06/2019 The rising stars of neuroscience Do glial cells affect behaviour? Mice are smarter with human astrocytes! perform better in cognitive tests show enhanced long term potentiation (LTP) of synapses I d strengthening synapticaction Figure 4: Human astrocytes Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 5 of 7 addem How can astrocytes affect behaviour? ~ influence indirect - Homeostatic role E -- Ability to release neurotransmitters (gliotransmission) Formation of astrocytic networks Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 6 of 7 3  10/06/2019 dent re Gliotransmission and the tripartite synapse - calienensmitte D Ca++ increases in astrocytes elicit the regulated release of gliotransmitters e.g. - glutamate - - GABA - ATP and adenosine (purines) Ahoyan - D-serine ~ F Figure 5: The tripartite synapse Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 7 of 7 4  10/06/2019 INSTITUTE OF PSYCHIATRY, PSYCHOLOGY & NEUROSCIENCE Module: Biological foundations of mental health Dr Isabella Gavazzi Week 2: Topic 1 Neuron-glial interactions and Building blocks of the brain mental health Part 1b of 2 - Consequences of gliotransmission What are the consequences of astrocyte modulation at the - tripartite synapse for brain function and behaviour? There is some evidence for a possible role in memory and sleep regulation. LTP - activity. · · streghering of synaptic Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 2 of 8 1  a 10/06/2019 wide a nextmodel Evidence for a role of astrocytes in memory Cruise experimub- - 1. Cannabinoids bind to all CB1R (in black) 2. Astrocytes release glutamate (purple) 3. Glutamate binds to NMDAR 4. AMPAR is internalised 5. LTD is induced 6. The mouse is lost 2 1 1 3 4 1 2 - 1 3 5 6 Figure 6: Working Memory Impairment following cannabinoids exposure Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 3 of 8 · W. Memory impacted by Marijuana in humans o summatergic/Gabusic - neurons exiety inhibiting Evidence for a role on sleep regulation - DI Adenosine acts to suppress synaptic transmission, and its release would be linked to the regulation of sleep. - > Figure 7: ATP signalling via exocytotic release from astrocytes Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 4 of 8 * Adenjoine promotin sleep Latin-Astoastery. · Calline Promots wakefulness. 2  10/06/2019 ② Co-morbidities Many mental health disorders affect cognition and exhibit sleep co-morbidities. 14 Astrocyte networks Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 5 of 8 Gap junctions interconnect astrocytes in networks rede network. * & - Figure 8: Drawing of a gap junction Figure 9: Astrocytes can be directly coupled with neighbouring astrocytes via gap junctions 2 types of protiers. - Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 6 of 8 * Aicyho can from nehmis- ↑ Ase specific Permability [Resion specific. 3  10/06/2019 Astrocytic networks and neuronal - mi Gliotransmitters are released in astrocytes undergoing Ca++ rise Pre - Post Ca+ A B 1: Release of neurotransmitter 2: Neurotransmitter interacts with receptors on astrocytes Glutamate binds to receptors on astrocytes 3: Release of gliotransmitters - that influence neuronal activity Rise in Ca++ spreads to * 4: Glutamate and glutamine diffuse through astrocyte gap junctions neighboring astrocytes 5: Release of gliotransmitters at a remote synapse Figure 10: Calcium waves in astrocyte networks Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 7 of 8 : calcium naus. What can astrocytic networks do? - Regulate the generation of a rhythmic firing pattern in neurons, necessary for several vital functions, such as respiration and mastication Eg. Rhett syndrome Transdeeepmete Eden Act as a hub for integrating signals from different brain areas In part 2, the potential involvement of astrocytic network dysfunction in depression will be illustrated. - Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 8 of 8 4  10/06/2019 INSTITUTE OF PSYCHIATRY, PSYCHOLOGY & NEUROSCIENCE Module: Biological foundations of mental health Dr Isabella Gavazzi Week 2: Topic 1 Neuron-glial interactions and Building blocks of the brain mental health Part 2 of 2 - Introduction Astrocytes play an active, informational processing role in CNS - Astrocytic dysfunction may contribute to mental health disorders - A more gliocentric approach may lead to more effective therapeutic strategies Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 2 of 25 1  10/06/2019 Figure 11: Mental health ⑳ Syndrome characterised by clinically significant disturbance in: Cognition - Emotion Regulation Behaviour B Dysfunction in: Psychological Biological Developmental processes * Associated with significant distress in : Social Occupational Other important activities & Examples: & Depression L Bipolar disorder # Schizophrenia & Autism Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 3 of 25 Difficulties studying mental health in humans Very difficult to study in humans Figure 12: Mental health Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 4 of 25 2  10/06/2019 Main lines of evidence - Human studies: mainly post-mortem Animal studies, including use of genetically modified animals - In vitro studies > C L Astrocyte culture Brain Slice ↳ phamolocosia Focus on Major Depressive Disorder but information will also be provided of evidence available for schizophrenia. - - Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 5 of 25 What is depression? A common mental disorder that causes people to experience depressed mood anhedonia. Loss of interest or pleasure - Feelings of guilt or low self-worth Disturbed sleep (insomnia or excessive sleep) Low energy Poor concentration. What are the neurophysiological processes underlying a depressed state? Week 2 there-- C Building blocks to the brain neurocentic neuroned distinction Topic 1: Neuron-glial interactions andWeek underactively 2 –health mental Lorem ipsum 6 of 25 #) - eatiin - at antidep-I aim to seratin. Cincina 3  10/06/2019 Astrocytes may play a role in depression? - - Evidence comes from: Studies in animal models = = Post-mortem human tissues Astrocytes in culture (in vitro) - Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 7 of 25 Examples of studies um Animal models Figure 13: Mouse Astrocyte pathology is present in animal models of depression - Treatments that revert astrocyte pathology also revert symptoms of depression in animal models - - Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 8 of 25 4  10/06/2019 Chronic unpredictable stress (CUS; a model of depression) ① E Stressors W Cage rotation Light on A significant decrease of mRNA Light off levels is seen for the glial- specific marker GFAP. Cold stress Isolation The effect of stress can be reversed by the glutamate- Crowding modulating drug riluzole. Cold swim stress - B : Control C : Chronic stress 8 - S Figure 14: Effects of chronic unpredictable stress (CUS) and riluzole on mRNA levels of glial-specific markers measured by in situ hybridization Animals are subjected to a sequence of two stressors per day over an extended time period - Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 9 of 25 Sucrose preference test - Anhedonia is considered a symptom of depression - Water Sucrose solution Figure 15: Sucrose preference test Reduced preference for sucrose solution represents anhedonia Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 10 of 25 5  10/06/2019 Chronic unpredictable stress causes anhedonia in rodents Chronic unpredictable stress affects animal S behaviour in the sucrose preference test, leading to anhedonia. This is reversed by riluzole, in parallel with the E reduction observed in glial pathology. Rilusole increases glutamate uptake by astrocytes - and this results in increased glutamine production. 15 days 35 days Figure 16: Chronic unpredictable stress effects animal behaviour in sucrose preference test, leading to anhedonia. Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 11 of 25 Examples of studies Human Post-mortem material Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 12 of 25 6  10/06/2019 Decreased GFAP expression in depression suicides - Scanned brain images GFAP mRNA levels GFAP protein levels Figure 17: Decreased GFAP expression is also observed is observed in the medio dorsal thalamus and caudate nucleus but not in the primary motor and visual cortex of depressed suicides. indicating J - Decreased GFAP expression (mRNA and protein) is also observed in depressed suicides. Attractic pathology - This loss is present in the mediodorsal thalamus and caudate nucleus but not in the - primary motor and visual cortex, nor in the cerebellum. Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 13 of 25 Example of studies - 3 Studies conducted on cultured astrocytes. - Various types of pharmacological - and non pharmacological treatments for depression can act directly on astrocytes. Figure 18: Glial cell (astrocyte) Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 14 of 25 7  10/06/2019 - >erzad independent Direct effect of fluoxetine on cultured astrocytes seratorin. ----- Figure 19: Fluoxetine induces the production of trophic factors by cultured astrocytes (Prozac Fluoxetine (Prozac), a commonly used antidepressant, induces the production of trophic factors by cultured astrocytes in serotonin independent manner. - Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 15 of 25 effect adger several weeks by. Astrocytic networks in Major Depressive Disorder A role for astrocytic networks in Major Depressive Disorder (MDD)? Evidence from studies on post-mortem human material and animal models of depression Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 16 of 25 8  10/06/2019 Disruption of astrocytic networks play a role in depression C: control A B S: suicide case Quantitative polymerase chain reaction (PCR) data from Cx30 (A) and Cx43 (B) NB: suicide completers had C D diagnosis of MDD, Bipolar disorders or schizophrenia. There was no difference in Cx30 and 43 levels between pathologies. Quantitation of band intensity of western blot images for Cx30 (C) and Cx43 (D) with β-actin used as a loading control. Figure 20: Dysfunction of connexins in the dorsal Lateral prefrontal cortex of suicide completers The expression of the components of astrocytic GAP junctions Cx30 and Cx43 is reduced in dorsal lateral prefrontal cortex from suicide completers compared with control subjects, suggesting a dysfunction of astrocytic networks in depressed individuals. Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 17 of 25 Antidepressants reverse connexin 43 decrease in the prefrontal cortex of stressed rats CTR: control group CUS: Chronic unpredictable stress group Protein levels mRNA levels CF: CTR+fluoxetine group SF: CUS+fluoxetine group CD: CTR+duloxetine group SD: CUS+duloxetine group Figure 21: Antidepressants reverses connexin 43 decrease in the prefrontal cortex of stressed rats Chronic unpredictable stress in rats causes decreased connexin 43 (Cx43) protein and mRNA levels in the prefrontal cortex (PFC), analogous to what was observed in suicides. Antidepressants reverse this decrease. Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 18 of 25 9  10/06/2019 Chronic unpredictable stress disrupts astrocytic networks Antidepresent S - grup untreated CTR: control group Representative dye CUS: Chronic unpredictable stress group coupling images from CF: CTR+fluoxetine group animals of all groups SF: CUS+fluoxetine group CD: CTR+duloxetine group SD: CUS+duloxetine group Figure 22: Chronic unpredictable stress disrupts astrocytic networks Chronic unpredictable stress (CUS) disrupts astrocytic networks, as shown by a significant decrease in the distance of diffusion and the number of coupled cells in the prelimbic cortex of CUS-exposed rats as compared with control group, following Lucifer yellow dye injection. Treatment with antidepressants significantly reversed the effect of CUS on intercellular coupling. Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 19 of 25 Gap junction induces depressive-like behaviour O - ---- Figure 23: Gap junction induces depressive-like behaviours - - Gap junction blockade in the prefrontal cortex (PFC) with carbenoloxone induces depressive-like behaviors. I measured put Week 2 Building blocks to the brain test. ( dep. Topic 1: Neuron-glial interactions andWeek sympt 2 –health mental because Lorem ipsum 20 of 25 sucrose move apparentl increased doses. 10  10/06/2019 - A role for astrocytic networks and/or gliotransmission? Decreased levels of connexins were identified in both MDD and in experimental stress. Fluoxetine and other antidepressants can reverse these changes in animal models. Blocking GAP junctions in the prefrontal cortex is sufficient to induce depressive behaviour in animals, suggesting astrocytic network dysfunction may be sufficient to induce the onset of depression. The mechanisms whereby dysfunctional astrocytic networks may affect mood have not been established yet. Therefore astrocytic network dysfunction may be sufficient to induce the onset of depression. Sleep deprivation X -is a potent, if short-term, antidepressant. The antidepressant effects of sleep deprivation require astrocyte-dependent adenosine mediated signalling, i.e. gliotransmission. ↳ requires - gliotmsittin release. Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 21 of 25 E What causes astrocyte pathology in depression? Stress (acting on the Hypothalamic-Pituitary-Adrenal Axis) may be a causative factor in depression - Acute and chronic stress alter astrocyte morphology and physiology, - and most of these alterations can be prevented by antidepressants or other protective treatment Further, correlative, evidence supports a role for astrocytes in most if not all psychiatric disorders Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 22 of 25 11  10/06/2019 In conclusion O Much circumstantial evidence supports the hypothesis of a role for astrocytic dysfunction in psychiatric disorders - Often the most obvious astrocyte pathology appears to& be atrophy - It is currently impossible to determine whether astrocytic pathology is the primary cause of psychiatric disorders or it is secondary to neuronal pathology - Targeting astrocytic pathology appears in some cases to be sufficient to ameliorate behavioural disturbances - Future research into the neurobiology of psychiatric disorders should shift its focus from a neurocentric perspective to, at least, a neuro-glial one - Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 23 of 25 Figure references (1) Usage of all figures is covered by the College Copyright Licensing Agency (CLA) Higher Education License and associated reciprocal international agreements 1. Figure 3: Downloaded from: 7. Figure 9 & 10: Christian Giaume, Annette Koulakoff, Lisa Roux, David https://openi.nlm.nih.gov/detailedresult.php?img=3541578_CroatMedJ_5 Holcman & Nathalie Rouac. Astroglial networks: a step further in 3_0518-F1&req=4 neuroglial and gliovascular interactions. Nature Reviews 2. Figure 4: Human astros make you brighter Neuroscience 11, 87-99, doi:10.1038/nrn2757 Image downloaded from: http://www.dailymail.co.uk/sciencetech/article- 8. Figure 14: Banasr M, Chowdhury GM, Terwilliger R, Newton SS, 2856096/Intelligent-mice-created-half-human-brains-Scientists-make- Duman RS, Behar KL, Sanacora G. Glial pathology in an animal rodents-SMARTER-injecting-human-cells.html model of depression: reversal of stress-induced cellular, metabolic 3. Figure 5: Nicola J. Allen & Ben A. Barres. Glia — more than just brain glue and behavioral deficits by the glutamate-modulating drug riluzole. (2009). Nature 457, 675-677 doi:10.1038/457675a Mol Psychiatry, 15(5):501-11 (2010) 4. Figure 6: Han J, Kesner P, Metna-Laurent M, Duan T, Xu L, Georges F, Koehl 9. Figure 15: Ana I Domingos, Jake Vaynshteyn, Henning U Voss, M, Abrous DN, Mendizabal-Zubiaga J, Grandes P, Liu Q, Bai G, Wang W, Xueying Ren, Viviana Gradinaru, Feng Zang, Karl Deisseroth, Ivan E Xiong L, Ren W, Marsicano G, Zhang X. Acute cannabinoids impair working de Araujo & Jeffrey Friedman. Leptin regulates the reward value of memory through astroglial CB1 receptor modulation of hippocampal LTD. nutrient. Nature Neuroscience 14, 1562–1568 (2011) Cell. 2012 Mar 2;148(5):1039-50. doi: 10.1016/j.cell.2012.01.037. doi:10.1038/nn.2977 5. Figure 7: Dustin J. Hines, and Philip G. Haydon Phil. ATP signalling via 10. Figure 16: Banasr M, Chowdhury GM, Terwilliger R, Newton SS, exocytotic release from astrocytes. Trans. R. Soc. B 2014 369 20130591 Duman RS, Behar KL, Sanacora G. Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic 6. Figure 8: Downloaded from and behavioral deficits by the glutamate-modulating drug riluzole. http://163.178.103.176/Fisiologia/general/activ_bas_3/An%20Electron%2 Mol Psychiatry, 15(5):501-11 (2010) 0microscopic%20view%20of%20membranes.htm Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 24 of 25 12  10/06/2019 Figure references (2) 11. Figure 17: Torres-Platas SG, Nagy C, Wakid M, Turecki G, Mechawar N. Glial fibrillary acidic protein is differentially expressed across cortical and subcortical regions in healthy brains and downregulated in the thalamus and caudate nucleus of depressed suicides. Mol Psychiatry, 2015. doi: 10.1038/mp.2015.65 12. Figure 19: Allaman I, Fiumelli H, Magistretti PJ, Martin JL. Fluoxetine regulates the expression of neurotrophic/growth factors and glucose metabolism in astrocytes. Psychopharmacology (Berl). 216(1):75-84 (2011). 13. Figure 20: Carl Ernst, Corina Nagy, Sangyheon Kim, Jennie P. Yang, Xiaoming Deng, Ian C. Hellstrom, Kwang Ho Choi, Howard Gershenfeld, Michael J. Meaney, Gustavo Turecki. Dysfunction of Astrocyte Connexins 30 and 43 in Dorsal Lateral Prefrontal Cortex of Suicide Completers Biological Psychiatry, Volume 70, Issue 4, 2011, 312–319 Week 2 Building blocks to the brain Topic 1: Neuron-glial interactions andWeek 2 –health mental Lorem ipsum 25 of 25 13  11/06/2019 INSTITUTE OF PSYCHIATRY, PSYCHOLOGY & NEUROSCIENCE Module: Biological foundations of mental health Dr Brenda Williams Topic 2 From embryonic neural progenitor Week 2: cells to adult hippocampal Building blocks of the brain neurogenesis Part 1 of 4 genever e Introduction necrepitin * Neuroepithelial cells * - Radial glial cells * Adult neural stem cells Figure 1: From neuroepithelial cells to adult neural stemcells generate radial glia generate neurons - DG SVZ = Week 2 Building blocks to the brain Week Topic 2: From embryonic neural progenitor cells to adult hippocampal 2 – Lorem ipsum neurogenesis 2 of 6 1  11/06/2019 Neuroepithelial cells are embryonic neural stem cells (NSC) spechstar cells ↳. - - Neuroepithelial / Embryonic NSCs can generate -1) Fig: 2 Neuroepithelial cells are NSCs A! ! Astrocytes Oligodendrocytes Neurons ! ! ! ! ! ! ! ! B! ! 2 Building blocks to the brain Week Week Topic 2: From embryonic neural progenitor cells to adult hippocampal 2 – Lorem ipsum neurogenesis 3 of 6 ! ! Aymetric !. ! ! ! Characterisation of embryonic neural stem cells ans ! ! C!! Embryonic stem cells are non-specialised cells ! Figure 3: Characterisation of embryonic neural stem cells Self-renewal Differentiation ! Ir ! ! ! ! ! Divide and generate more- specialised cell types ! RGC Make all of the different brain ! cell types ! D! ! ! genera Dedicated Progenitor Cell ! ! ! Week 2 Building blocks to the brain Week Topic 2: From embryonic neural progenitor cells to adult hippocampal 2 – Lorem ipsum neurogenesis 4 of 6 ! Figure! 5.1.! Composition! of! P0! cortical! neuron! cultures.! Primary! cortical! neuron! &/& cultures!generated!from!P0!Cln3 !or!WT!mice!were!stained!with!MAP2!and!NeuN!to!identify! neuronal! cells,! GFAP! to! identify! astrocytes,! CD68! to! identify! microglia! and! O4! to! identify! oligodendrocytes.! DAPI! was! used! to! visualize! all! nuclei.! Most! of! the! cells! were! (A)! MAP2! expressing,!or!(B)!NeuN!expressing!neurons.!(C)!Glial!contamination!was!mostly!due!to!GFAP! expressing!astrocytes!with!CD68!expressing!microglia!and!O4!expressing!oligodendrocytes!rarely! 2  11/06/2019 - Specialisation during differentiation Specialisation Figure 3: Specialisation during differentiation Neuron Dedicated um Progenitor cell we Radial glial cell (RGL) Neuroepithelial w Embryonic NSC -u Week 2 Building blocks to the brain Week Topic 2: From embryonic neural progenitor cells to adult hippocampal 2 – Lorem ipsum neurogenesis 5 of 6 may complain ZamaBeingen. so Lineage relationships ar masi 2. - never demands. A! Neuroepithelial ! cells/embryonic NSCs ! ! ! ! ! Figure 4: Lineage relationships ! Neurons ! ! Neural progenitor cell B! e.g. Radial glial cell ! ! ! Oligodendrocytes ! ! ! ! ! ! C!! Astrocytes - Adult Neural Stem Cells ! Week 2 ! Building blocks to the brain Week Topic 2: From embryonic neural progenitor cells to adult hippocampal 2 – Lorem ipsum neurogenesis 6 of 6 ! ! ! ! ! ! 3  11/06/2019 INSTITUTE OF PSYCHIATRY, PSYCHOLOGY & NEUROSCIENCE Module: Biological foundations of mental health Dr Sandrine Thuret Topic 2 From embryonic neural Week 2: progenitor cells to adult Building blocks of the brain hippocampal neurogenesis Part 2 of 4 Introduction Topic overview Adult Neurogenesis = Location/environment (niche) of Adult Neurogenesis -- Molecular control of Adult Hippocampal Neurogenesis Functionality of Adult Hippocampal Neurogenesis - Modulation of Adult Hippocampal Neurogenesis = Week 2 Building blocks to the brain Week Topic 2: From embryonic neural progenitor cells to adult hippocampal 2 – Lorem ipsum neurogenesis 2 of 12 1  11/06/2019 Adult neurogenesis? - “Once development was ended, the fonts of growth and regeneration of the axons and dendrites dried up irrevocably. In the adult centers, the nerve paths are something fixed, and immutable: everything may die, nothing may be regenerated.” Santiago Ramon y Cajal, 1928 Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. Altman & Das, 1965 - Week 2 Building blocks to the brain Week Topic 2: From embryonic neural progenitor cells to adult hippocampal 2 – Lorem ipsum neurogenesis 3 of 12 90'5 fill neurogenist in adult-brain for = until Neurogenesis in the adult brain is limited to specific neurogenic regions - * also in Hippocampus humans. of DG SVZ Subventricular zone of Subgranular zone of the lateral ventricles the dentate gyrus -- Figure 1: Neurogenesis limited to specific regions Week 2 Building blocks to the brain Week Topic 2: From embryonic neural progenitor cells to adult hippocampal 2 – Lorem ipsum neurogenesis 4 of 12 2  11/06/2019 Dynamics of Hippocampal Neurogenesis in Adult Humans N - Figure 2: Active neurogenesis throughout adulthood Figure 3 : Hippocampal Neurogenesis in Adult Humans 14C concentrations in hippocampal neuron genomic DNA correspond to a time after the date of birth of the individual, demonstrating neurogenesis throughout life. Source: Kirsty L. Spalding et al, "Dynamics of Hippocampal Neurogenesis in Adult Humans", Cell, Vol. 153, Issue 6, p1219–1227, 6 June 2013 Week 2 Building blocks to the brain Week Topic 2: From embryonic neural progenitor cells to adult hippocampal 2 – Lorem ipsum neurogenesis 5 of 12 Adult hippocampal neurogenesis - NeuN CAG GFP GFAP Figure 5: 4 to 6-week maturation period - - in rodants. Figure 4: Neurogenesis Week 2 Building blocks to the brain Week Topic 2: From embryonic neural progenitor cells to adult hippocampal 2 – Lorem ipsum neurogenesis 6 of 12 3  11/06/2019 Quantitative studies on adult neurogensis ~ zu year nee ≈700 new neurons in adult humans are added e a in each hippocampus per day ≈ 70% of the bulbar neurons are replaced during a 6-week period in an adult rodent Week 2 Building blocks to the brain Week Topic 2: From embryonic neural progenitor cells to adult hippocampal 2 – Lorem ipsum neurogenesis 7 of 12 Environment of Adult Neurogenesis Environment of Adult Neurogenesis Week 2 Building blocks to the brain Week Topic 2: From embryonic neural progenitor cells to adult hippocampal 2 – Lorem ipsum neurogenesis 8 of 12 4  11/06/2019 Adult neurogenic microenvironment (1) Transplantation studies provide evidence for regulation of fate determination by extrinsic signals in the environment Yener Figure 6: Adult neurogenic microenvironment NSC extracted from a non-neurogenic region i d No NSC derived from a non-neurogenic region produce neurons only when transplanted into a neurogenic region neues Week 2 Building blocks to the brain Week Topic 2: From embryonic neural progenitor cells to adult hippocampal 2 – Lorem ipsum neurogenesis 9 of 12 Adult neurogenic microenvironment (2) yes Figure 7: Adult neurogenic microenvironment nee - & neurogenic region NSC ~ - Xnerur Adult NSC derived from a neurogenic region will differentiate into neurons only in the neurogenic environment Week 2 Building blocks to the brain Week Topic 2: From embryonic neural progenitor cells to adult hippocampal 2 – Lorem ipsum neurogenesis 10 of 12 5  11/06/2019 Adult neurogenic microenvironment (3) C neurogenic niche- Endothelial cells - Astrocytes Blood vessels = Figure 8: Adult neurogenic microenvironment Week 2 Building blocks to the brain Week Topic 2: From embryonic neural progenitor cells to adult hippocampal 2 – Lorem ipsum neurogenesis 11 of 12 Astroglia induce neurogenesis from adult neural stem cells Reyplayer- Neurons Figure 9: Astroglia induce neurogenesis from adult neural stem cells Adult NSC derived from hippocampus co-cultured with adult hippocampal astrocytes can differentiate into neurons Adult NSC co-cultured with astrocytes from a non-neurogenic region rarely differentiate into neurons Source: Song, Hongjun, Charles F. Stevens, and Fred H. Gage. “Astroglia Induce Neurogenesis from Adult Neural Stem Cells.” Nature 417, no. 6884 (May 2, 2002): 39–44. doi:10.1038/417039a. Week 2 Building blocks to the brain Week Topic 2: From embryonic neural progenitor cells to adult hippocampal 2 – Lorem ipsum neurogenesis 12 of 12 6  11/06/2019 INSTITUTE OF PSYCHIATRY, PSYCHOLOGY & NEUROSCIENCE Module: Biological foundations of mental health Dr Sandrine Thuret Topic 2