Brain Functional Organization & Neurotransmission PDF

Functional organization and neurotransmission in the brain Mohammad K. Hajihosseini BIO-5004A [email protected] October 2024  Lecture Outline Gross development of the brain Functional subdivisions of the brain Topographical organisation of the cerebral co...

Functional organization and neurotransmission in the brain Mohammad K. Hajihosseini BIO-5004A [email protected] October 2024  Lecture Outline Gross development of the brain Functional subdivisions of the brain Topographical organisation of the cerebral cortex Neuronal and neurotransmitter types in the cerebral cortex  Gross anatomy of human Brain Anatomically, the brain is divided into 6 main regions The brain contains an intricate ventricular system filled with the cerebrospinal fluid Nourishment of the central nervous system The blood brain barrier (BBB) 650 Km; 10-20 m2 * Selective transport of molecules into the nervous system * Major obstacle for delivery of drugs into the nervous system Three major cells involved: * Endothelial cells * Microglia and some immune cells can * Astrocytes negotiate their way passed the BBB, but * Pericytes only in certain disease conditions. Nourishment of the central nervous system The choroid plexus system * The brain/ CNS is surrounded by, and contains, fluid-filled cavities (called ventricles: Lateral, 3rd and 4th) The fluid inside is called cerebrospinal fluid (CSF) - 500 ml produced each day! * The fluid circulates, provides physical support, buoyancy and nourishment to the brain/ Spinal cord  CSF is produced by the Choroid Plexus system - composed of a special population of ependymal cells Scanning EM of Ventricular space The choroid plexus ependymal cells  CSF’s contents give important information about the health status of the central nervous system Sample obtained by Lumbar puncture e.g. Detection of lymphocytes or bacteria – is indicative of infection or autoimmune disease e.g. as in Multiple Sclerosis Or high levels of protein: transferrin - indicative of ‘leaky’ choroid plexus The brain forms from disproportionate growth and flexure of the ‘neural tube’ during embryonic development The forebrain (cerebral cortex) becomes the largest part of CNS, and ‘obscures’ other parts of the brain Development of the human brain  Functional subdivisions of the brain Medulla oblongata – Major relay centre Reticular formation – Integration and “filtering” – Involuntary functions Vital reflex centre (eg. breathing, blood pressure) Non-vital reflex centre (eg. swallowing, coughing, vomiting) Cerebellum – Coordination of movement and balance Integration of information – Receives nerve inputs from motor areas of cerebrum as well as muscles, joints, skin, Source: MediaPhys 2.0 An Introduction to Human eyes, ears and viscera. Physiology. McGraw-Hill  Functional subdivision of the brain Diencephalon – Thalamus Relay station Awareness / states of arousal – Hypothalamus Major homeostatic control centre – Regulation of Autonomic N.S. and endocrine system Controls secretion of reproductive hormones by the pituitary gland Neural centres controlling behaviour (appetite, thirst, sexual behaviour) – reward pathways Forms part of the limbic system (emotion and memory) Circadian rhythms (sleep)  Functional Integration in the brain The Limbic System Interconnecting group of structures Controls basic emotions (fear, anxiety, pleasure, anger) Olfaction (smell) Hippocampus – processing of memory  The Cerebrum Consists of the cerebral cortex and the sub-cortical nuclei (basal ganglia)  The Cerebral Cortex Consist of a shell of grey matter covering a mass of white matter (axonal tracts) Has two Hemispheres, which are not completely symmetrical in structure, nor equivalent in function Each hemisphere controls the contra-lateral side of body – Hemispheres themselves are connected via the corpus callosum Concerned with “higher functions” including sensory analysis, motor coordination, language and intellect Corpus callosum  The Corpus Callosum Consist of a shell of grey matter covering a mass of white matter (axonal tracts) Has two Hemispheres, which are not completely symmetrical in structure, nor equivalent in function Each hemisphere controls the contra-lateral side of body – Hemispheres themselves are connected via the corpus callosum Concerned with “higher functions” including sensory analysis, motor coordination, language and intellect Corpus callosum  Correlation between evolution and cortical size/ gyrification Humans have the largest and most convoluted cerebral cortex  partJohn of the brain called O’Keefe the hippocampus. discovered, in 1971, that certain nerve cells The Nobel Prize in Physiologyinplace orin the Medicine 2014 the brain were activated when a rat assumed a particular John O’Keefe discovered, in 1971, that certain nerve cells environment. Other nerve cells were activated at in the brain were activated when a rat assumed a particular Fig. 1 Nobel Prize in Physiology/ Medicine 2014 other places. He proposed that these “place cells” build up place in the environment. Other nerve cells were activated at an inner other places. map of the He proposed that environment. Place these “place cells” buildcells up are located in a an innerpart mapofof the brain calledPlace the environment. the cells hippocampus. are located in a The Nobel Prize in Physiology or Medicine 2014 part of the brain called the hippocampus. Fig.Fig. 1 1 Enotrhinal part of Hippocampus Cerebral cortex John O’Keefe discovered, in 1971, that certain nerve cells in the brain were activated when a rat assumed a particular place in the environment. Other nerve cells were activated at JohnotherO’Keefe discovered, places. in 1971, that He proposed certain that thesenerve cells cells” build up “place in the brain were activated when a rat assumed a particular May-Britt och Edvard I. Moser discovered John inan2005 that other nerve cells in in O’Keefe, place inner thethat map environment. of theOther environment. Place cells are located in a May-Britt och Edvard I. Moser discovered in 2005 other nerve cells in nerve cells were activated at a nearby part ofa nearby the brain, the entorhinal cortex, were part activated of the brain when called the hippocampus. rat passed certain locations. May-Britt Together, och Edvard passed certain locations. I. Mary part of the brain, the entorhinal other these Moserthese Together, locations discovered an Britt-Moser cortex, places. in 2005 inner map locations formed He were activated formed proposed & when the rat a that these hexagonal thatenvironment. ofa the othergrid, hexagonal nerve cells “place cells” build up grid, Placeincells are located in a each “grid cell” each “grid reacting a nearby cell” part in reacting of a unique the in a unique spatial brain, the Edvard spatial pattern. pattern. entorhinal part cortex, I.were Moser Collectively, Collectively, of the form a coordinate system that allows for spatial navigation. brain these grid activated called cells these the whengridthecells hippocampus. rat passedsystem certain locations. Together, these navigation. locations formed a hexagonal Fig. 2grid, Fig.form 1 a coordinate that allows for spatial each “grid cell” reacting in a unique spatial pattern. Collectively, these grid cells Fig. 2 Fig. 1 form a coordinate system that allows for spatial navigation. Fig. 2 A GPS system for spatial memory May-Britt och Edvard I. Moser discovered in 2005 that other nerve cells in May-Britt och Edvard I. Moser discovered in 2005 that other nerve cells in a nearby part of the brain, the entorhinal cortex, were activated when the rat a nearby part passed of the certain brain,Together, locations. the entorhinal cortex,formed these locations wereaactivated hexagonal when grid, the rat Cerebral cortex is subdivided into major functional lobes and sulci  What is the evidence for localised function? 1. Accidents and stroke (‘Ischemia’; damage to particular brain area perturbs particular function/s) 2. Studies in animal models (surgical removal or electrical recording from particular areas - most work on visual cortex) 3. More recently: PET scans and MRI analysis e.g. by Recording of electrical activity, increased blood flow and/or glucose metabolism  The Somatosensory Cortex The somatosensory cortex analyses inputs from mechanoreceptors (touch, stretch), thermoreceptors and nociceptors (pain) in the skin, muscle, joints and internal organs It is located in the parietal lobe of the cerebral cortex Receives information from receptors on the opposite side of the body There is a somatotopic organisation in the somatosensory cortex (sensory homunculus)  Evidence for topography: The Rodent Whisker ‘barrels’ * Each whisker is represented in a topographical fashion in the cerebral cortex * Connection from the whiskers to the brain are topographically preserved  The Somatosensory Cortex Source: Kandel, Schwartz & Jessell. Principles of Neuroscience. McGraw-Hill The area of cortex devoted to each area is proportional to the amount of information received from that area There is “plasticity” within the neurons of the somatosensory cortex (I.e. if one area receives extra stimulation or reduced stimulation the size of the devoted area will change accordingly - e.g. blind people usually have a better developed/functioning somatosensory cortex) From the somatosensory cortex information passes to “association areas” where further processing occurs  Topography in the Motor Cortex The motor cortex is responsible for voluntary movement it is located in the frontal lobe Stimulation results in movement on the contralateral side Penfield (1950s) ‘mapped’ the motor cortex - the motor homunculus Much of the remainder of the pre-frontal cortex is involved in processing motor information  Cortical Areas involved in Language Language is considered to be the highest mental function in humans In 90% of people the left hemisphere is used in relation to language Distinct areas are specialised for the production and understanding of language: Broca’s area - involves the articulation of speech Wernicke’s area - involves interpretation of spoken language  Resources for Brain Anatomy/Function exploration > Gene Paint: https://gp3.mpg.de Info on gene expression in embryonic and adult brain Ø Allen Brain Atlas: https://portal.brain-map.org High resolution 3D images of rodent and Human brain Info on regional gene expression Ø Brain Facts: http://www.brainfacts.org Articles on brain facts: Current issue: Sexual dimorphism in the brain Cell type and common neurotransmitters in the brain  Connectivity and cell types in the C. cortex I VI Coronal section through adult rat brain - The two hemisphere are connected by the corpus callosum (carries myelinated axons) - Is a laminated structure: six laminae: I to VI -Two principle type of neurons: Projection and Interneurons -* Almost all of these neurons are generated during the embryonic or Early post-natal period  Cortical neuronal subtypes Projection/pyramidal Non-pyramidal/ interneuron Projection neurons appear pyramidal in shape; are excitatory and mainly use the neurotransmitter, Glutamate Interneurons are non-pyramidal in shape, are inhibitory and use the neurotransmitter, GABA (Gamma amino-butyric acid) but there are many different subtypes of interneurons Cholinergic signaling in brain is a negative regulator of appetite LETTER doi:10.1038/nature19789 A cholinergic basal forebrain feeding circuit modulates appetite suppression Alexander M. Herman1, Joshua Ortiz-Guzman1, Mikhail Kochukov2, Isabella Herman1,3, Kathleen B. Quast2, Jay M. Patel3,4, Burak Tepe1, Jeffrey C. Carlson1, Kevin Ung1, Jennifer Selever2,5, Qingchun Tong6 & Benjamin R. Arenkiel1,2,4,5 Atypical food intake is a primary cause of obesity and other activity was only altered once obesity became a burden (Extended Data eating and metabolic disorders. Insight into the neural control of Fig. 2b–k). feeding has previously focused mainly on signalling mechanisms We sought to determine whether conditional removal of cholinergic associated with the hypothalamus 1–5, the major centre in the neurotransmission selectively from the DBB, without cell death, led to brain that regulates body weight homeostasis6,7. However, roles of increased food consumption and obesity. We stereotaxically delivered non-canonical central nervous system signalling mechanisms in an EGFP-Cre-expressing AAV into the DBB of ChatloxP/loxP homozy- regulating feeding behaviour have been largely uncharacterized. gous mice (Fig. 2a), and evaluated ChAT knockout by immunohisto- Acetylcholine has long been proposed to influence feeding8–10 chemistry (Fig. 2b–k). Counts of ChAT-immunopositive neurons from owing in part to the functional similarity between acetylcholine and control and experimental brains showed a 72% and 55% decrease in nicotine, a known appetite suppressant. Nicotine is an exogenous ChAT expression in the DBB of Cre-expressing female and male mice, agonist for acetylcholine receptors, suggesting that endogenous respectively, compared to controls (Fig. 2l). Consistent with a role for cholinergic signalling may play a part in normal physiological cholinergic signalling in feeding behaviour, Cre-expressing animals regulation of feeding. However, it remains unclear how cholinergic displayed increased food intake (Fig. 2m) and subsequent weight gain neurons in the brain regulate food intake. Here we report that (Fig. 2n). Because knockout is restricted to the Chat gene, these data cholinergic neurons of the mouse basal forebrain potently influence imply that the observed effects on feeding and body weight were medi- food intake and body weight. Impairment of cholinergic signalling ated by cholinergic signalling, although it does not rule out a role for increases food intake and results in severe obesity, whereas GABAergic neurotransmission from cholinergic DBB neurons, which enhanced cholinergic signalling decreases food consumption. We have recently been reported to co-release GABA15 (Extended Data found that cholinergic circuits modulate appetite suppression Fig. 3a–c). on downstream targets in the hypothalamus. Together our data To test how acute inactivation of these neurons affected food intake, reveal the cholinergic basal forebrain as a major modulatory centre Chat-cre+/− mice were DBB-targeted for conditional expression of underlying feeding behaviour. hM4D-EGFP (Extended Data Fig. 4a). Following CNO treatment, The diagonal band of Broca (DBB) (Extended Data Fig. 1a–g) is a hM4D-EGFP-expressing mice consumed more food compared to con- major component of the cholinergic basal forebrain11. Studies have trols (Extended Data Fig. 4b), suggesting that both acute and chronic shown that cell types associated with feeding are connected with the inactivation of cholinergic DBB neurons were sufficient to increase  Amino acid Transmitters - Glutamate Glutamate is the major excitatory neurotransmitter of the CNS Is Synthesized via the Kreb’s cycle Glutamate Receptors are divided into 2 major sub-types: – Vast majority are ionotropic (NMDA-receptors (ion channel) (NMDA= N-methyl-D aspartate) – Minority are metabotropic (G protein-coupled Receptors) Critical role of glial cells in Glutamate receptor signalling Excess Glutamate is toxic to neurons and so it is taken up by Glial cells (astrocytes)  Amino Acid Transmitters: GABA (and Glycine) Both act by opening channels selective for Chloride ion (Cl-) causing a hyperpolarization of the membrane potential (IPSP) Benzodiazepines are sedatives and modulate the effects of GABA – eg. diazepam enhances Chloride ion conductance  Amino Acid Transmitters: Serotonin (a.k.a 5 Hydroxy-Tryptamine, 5HT) Serotonin is a derivative of amino acid Tryptophan Induces state of ‘ happiness’ Main mode of termination: Re-uptake back in to the pre- synaptic nerve terminal Clinical depression treated with serotonin re-uptake inhibitors Re-uptake also target of drug: ‘Ecstasy’ Effects of other ‘drugs’ on Glutamate and GABA signaling Neurotransmitter-related diseases of the central nervous system Disorder Cause Treatment Parkinson’s Dopamine deficiency Supply disease In substantia nigral L-Dopa/ neurons Dopamine Depression Multifactorial Inhibit re-uptake of Serotonin (5HT) (to increase the endogenous level of other neurotransmitters e.g. NE & Dopamine) Role of neurotransmission in addiction Neuron 2008 Volume 59, Issue 4, 621-633 Cocaine addiction involves an increase in dendritic spine density and sensitization of neurons through the regulation of the gene MEF2  ARTICLE Experimental modulation of brain function doi:10.1038/nature15257 Nature 2015 Volume 525 , 333-338 Labelling and optical erasure of synaptic memory traces in the motor cortex Akiko Hayashi-Takagi1,2, Sho Yagishita1,3, Mayumi Nakamura1, Fukutoshi Shirai1, Yi I. Wu4, Amanda L. Loshbaugh5,6, Brian Kuhlman5,6, Klaus M. Hahn5,7 & Haruo Kasai1,3 Dendritic spines are the major loci of synaptic plasticity and are considered as possible structural correlates of memory. Nonetheless, systematic manipulation of specific subsets of spines in the cortex has been unattainable, and thus, the link between spines and memory has been correlational. We developed a novel synaptic optoprobe, AS-PaRac1 (activated synapse targeting photoactivatable Rac1), that can label recently potentiated spines specifically, and induce the selective shrinkage of AS-PaRac1-containing spines. In vivo imaging of AS-PaRac1 revealed that a motor learning task induced substantial synaptic remodelling in a small subset of neurons. The acquired motor learning was disrupted by the optical shrinkage of the potentiated spines, whereas it was not affected by the identical manipulation of spines evoked by a distinct motor task in the same cortical region. Taken together, our results demonstrate that a newly acquired motor skill depends on the formation of a task-specific dense synaptic ensemble. ng-evoked a Protocol 1 rast, there 1,2 P28 Optogenetics P60~100 Day 1tool for is a powerful Day 2 controlling Dayneuronal 3 action0poten- day PA a Use of ‘optogenetics’ in living Enrichment Hot spot correlation AAV5 ,injection tials and has been usedPre- Cranial to demonstrate Post- Afterthe crucial role of cell ATG Stop mRFP Venus Merge 0 4 8 0 4 8 the control into M1 cortex surgery training assemblies in representing memory(0 day) tracesPA training 3. However, owing Protocol 2 to the + 1 day PA A ATG mice to selectively disable Venus PaRac1 Stop limitations of spatial Day 1 resolution Day of 2 probes Day 3 currently Day 4 available, manip- * B PSDΔ1.2 Venus PaRac1 peed of the Rotarod training recently-activated synapses, *** *** Stop ulationPAof individual dendritic Pre- spines,Post-the major sites of excitatory Post- After Protocol 3 ATG C PSDΔ1.2 Venus PaRac1 DTE oactivation *** *** synapses 4–6 , has been training hindering unfeasible, training the training PA comprehensive + 2under- day PA a Fig. 8). Rotarod test standing of synaptic reorganization Day 1 (0 day) Dayduring 2 (+ 1 day) learning. Day 3 Thus, Day 4 for spine- Day 5 D can erase memory in skills- ATG Stop Venus PaRac1 DTE 1 day after specific light control, we took advantage of the structural properties of ATG Stop ing-evoked spines: the tight correlation Pre- between training Post- spine volume and training (0 day) Post- training (+ 2 day) After 4–7 function PA. E b trained mice PSDΔ1.2 Venus c Uncaging alone Uncaging/FSK DTE Uncaging/FSK/Ani Uncaging alone Uncaging/FSK oactivation Because b the prolonged activationc of the small GTPase d Rac1 induces e –30 0 5 60 (min) –30 0 5 60 –30 0 5 60 Uncaging/FSK/Ani Protocol 1 used a photoactivatable Protocol 2 Protocol ** spine shrinkage 8–11 , we form3 of Rac1 50 0Mg 1Mg 0Mg 1Mg 0Mg 1Mg 300 150 ** number of *** A)) TTX TTX TTX ) 100 ) **  ARTICLE Experimental modulation of brain function doi:10.1038/nature15257 Nature 2015 Volume 525 , 333-338 Labelling and optical erasure of synaptic memory traces in the motor cortex Akiko Hayashi-Takagi1,2, Sho Yagishita1,3, Mayumi Nakamura1, Fukutoshi Shirai1, Yi I. Wu4, Amanda L. Loshbaugh5,6, Brian Kuhlman5,6, Klaus M. Hahn5,7 & Haruo Kasai1,3 Dendritic spines are the major loci of synaptic plasticity and are considered as possible structural correlates of memory. Nonetheless, systematic manipulation of specific subsets of spines in the cortex has been unattainable, and thus, the link between spines and memory has been correlational. We developed a novel synaptic optoprobe, AS-PaRac1 (activated synapse targeting photoactivatable Rac1), that can label recently potentiated spines specifically, and induce the selective shrinkage of AS-PaRac1-containing spines. In vivo imaging of AS-PaRac1 revealed that a motor learning task induced substantial synaptic remodelling in a small subset of neurons. The acquired motor learning was disrupted by the optical shrinkage of the potentiated spines, whereas it was not affected by the identical manipulation of spines evoked by a distinct motor task in the same cortical region. Taken together, our results demonstrate that a newly acquired motor skill depends on the formation of a task-specific dense synaptic ensemble. ng-evoked a Protocol 1 rast, there 1,2 P28 Optogenetics P60~100 Day 1tool for is a powerful Day 2 controlling Dayneuronal 3 action0poten- day PA a Use of ‘optogenetics’ in living Enrichment Hot spot correlation AAV5 ,injection tials and has been usedPre- Cranial to demonstrate Post- Afterthe crucial role of cell ATG Stop mRFP Venus Merge 0 4 8 0 4 8 the control into M1 cortex surgery training assemblies in representing memory(0 day) tracesPA training 3. However, owing Protocol 2 to the + 1 day PA A ATG mice to selectively disable, Venus PaRac1 Stop limitations of spatial Day 1 resolution Day of 2 probes Day 3 currently Day 4 available, manip- * B PSDΔ1.2 Venus PaRac1 peed of the Rotarod training recently-activated synapses, *** *** Stop ulationPAof individual dendritic Pre- spines,Post-the major sites of excitatory Post- After Protocol 3 ATG C PSDΔ1.2 Venus PaRac1 DTE oactivation *** *** synapses 4–6 , has been training hindering unfeasible, training the training PA comprehensive + 2under- day PA a Fig. 8). Rotarod test standing of synaptic reorganization Day 1 (0 day) Dayduring 2 (+ 1 day) learning. Day 3 Thus, Day 4 for spine- Day 5 D can erase memory in skills- ATG Stop Venus PaRac1 DTE 1 day after specific light control, we took advantage of the structural properties of ATG Stop ing-evoked spines: the tight correlation Pre- between training Post- spine volume and training (0 day) Post- training (+ 2 day) After 4–7 function PA. E b trained mice PSDΔ1.2 Venus c Uncaging alone Uncaging/FSK DTE Uncaging/FSK/Ani Uncaging alone Uncaging/FSK oactivation Because b the prolonged activationc of the small GTPase d Rac1 induces e –30 0 5 60 (min) –30 0 5 60 –30 0 5 60 Uncaging/FSK/Ani Protocol 1 used a photoactivatable Protocol 2 Protocol ** spine shrinkage 8–11 , we form3 of Rac1 50 0Mg 1Mg 0Mg 1Mg 0Mg 1Mg 300 150 ** number of *** A)) TTX TTX TTX ) 100 ) **