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Neuroscience Michaelmas 2013 Notes

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This is an extract of our Neuroscience Michaelmas 2013 document, which we sell as part of our Neuroscience Notes collection written by the top tier of Oxford students.

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Neuroscience Michaelmas 2013- Experimental and clinical evidence CNS Development:???

GENERATION OF SECOND BODY AXIS: classic experiment by Spemann showed that transplanting the "ORGANIZER" to a region of the ectoderm that normally gives rise to epidermis (before it was called the notochord) forms a 2 nd body axis and thus a 2ND NEURAL TUBE. Shows that the notochord has the capacity to dictate the presence of the CNS anywhere in the ectoderm but that this is physiologically restricted to the dorsal lip of the blastopore. FAILURE OF NEURULATION: if the rostral end of the neural tube fails to close ANENCEPHALY results. This is characterised by a mass of UNDIFFERENTIATED nervous system, with much of the cerebral hemisphere being absent: terminal. If the caudal end fails to close SPINA BIFIDA can result: this ranges in severity from a MENINGOCELE where there is a herniation of the meninges to a MENINGOMYELOCELE, where the spinal cord itself herniates. HOLOPORESENCEPHALY results from the partial/complete failure of the PROMESENCEPHALON TO SEPARATE into the diencephalon and paired telencephalic vesicles. ? As this process overlaps with facial formation, there may be marked facial abnormalities e.g. a single midline eye with a rudimentary nose above it - CYCLOPIA. (most births result in a miscarriage). See below for HYDROCEPHALUS. The pseudostratified neuroepithelium is where the MULTIPOTENT PROGENITORS ("neuroblasts") are situated that are able to make neurons and glia. The formation of the neural tube polarizes the neuroepithelial cells by orienting the apical side of the cell to face inward, which later becomes the ventricular zone, and the basal side is oriented outward, which contacts the outer surface of the developing brain. The cells begin to self-renew (through symmetric division to give two progenitors, which causes an EXPANSION of the surface area of the brain; or through asymmetric division to give one progenitor and one neuron) at the VENTRICULAR ZONE and give rise to non-stem cell progenitors, such as RADIAL GLIAL CELLS simultaneously by undergoing asymmetric division- these are what the neural progenitors are called in more mature neural tube. Radial glia cell bodies lie in VZ and have LONG processes that extend to the PIAL surface, and thus are placed in a favourable position to serve as a scaffold for migration of neurons emerging from the neural progenitor population in the VZ. It has been demonstrated by experiments using SELECTIVELY LABELLED FLUORESCENT DYES that these can ultimate generate both postmitotic neurons, astrocytes (in "gliogenesis") and also intermediate progenitors. Newly generated neurons extend a LEADING PROCESS that wraps around the shaft of the radial glial cell. Adhesion is mediated by INTEGRINS. Microtubules are attached to the leading process, and link it to the nucleus which is held in a microtubular 'CAGE'. ? Nucleus moves in a STEP-WISE manner (nucleokinesis).

??If a notochord is GRAFTED DORSALLY to the neural tube, an extra floor plate and motor neurons are produced, and DORSALIN EXPRESSION is suppressed ?
the notochord induces a midline floor plate which in turn induces motor neurons, as well as also supressing genes expressed in the dorsal neural tube.
? Shh patterns the neural tube as a MORPHOGEN: this morphogenic influence lays down the influence for subsequent signalling gradients. CRANIAL NERVES are associated with branchial arches, and each arch identity is defined by the spatial distribution of HOX GENE EXPRESSION. For example, in the absence of Hoxb1, cells in rhombomere 4 generate motor neurons that innervate TRIGEMINAL rather FACIAL targets. ? SPATIAL IDENTITY provided by Hox genes. Three possible ways of making TOPOGRAPHIC MAPS- example is retinotopic map: 1) retinal axons migrate in in a TEMPORAL sequence; 2) retinal axons migrate in a RANDOM manner and later become refined; 3) retinal axons could connect in a more SPECIFIC manner to specific regions. Classical experiment demonstrated that the THIRD option is correct: Roger Sperry experiment- he severed the optic nerve in a frog and then rotated the eye in its socket by 180 degrees before the nerve regenerated ? the frog exhibited an orderly response to visual input, the behaviour was reversed. Therefore retinal axons reinnervated their original targets, suggesting there is an ESTABLISHED MAP. "Chemoaffinity hypothesis" suggests MOLECULAR CUE-MEDIATED MATCHING was involved rather than validation and immediate refinement of random connections. ? Relevant for all developing axons in CNS, involving both chemoattraction and chemorepulsion by short and long-range queues- however, the crude map that is generated in this way is then REFINED to be more precise- PLASTICITY. Integration of molecular guidance: Growing axons rely on a variety of guidance cues in deciding upon a growth pathway. The growth cones of extending axons process these cues in an intricate system of signal interpretation and integration, in order to ensure appropriate guidance. These cues can be functionally subdivided into:Adhesive cues that provide physical interaction with the substrate necessary for axon protrusion. These cues can be expressed on glial and neuronal cells that the growing axon contacts or be part of the extracellular matrix. Examples are laminin or fibronectin, in the extracellular matrix, and cadherins or Ig-family cell-adhesion molecules, found on cell surfaces.Tropic cues that can act as attractants or repellents and cause changes in growth cone motility by acting on the cytoskeleton through graded intracellular signalling (the receptors to these cues are DIFFERENTIALLY expressed at the growth cones- this in turn is determined by axon position). For example, netrins and ephrins, and semaphorins play a role in guiding axons through the midline, and forming chemotropic gradients that form retinotopic maps acting as both an attractant and a repellent.


Modulatory cues, that influence the sensitivity of growth cones to certain guidance cues. For instance, neurotrophins can make axons less sensitive to the repellent action of Semaphorin3A.

Given the abundance of these different guidance cues it was previously believed that growth cones integrate various information by simply SUMMING the gradient of cues, in different valences, at a given point in time, to making a decision on the direction of growth. However, studies in vertebrate nervous systems of ventral midline crossing axons, has shown that modulatory cues play a crucial part in tuning axon responses to other cues, suggesting that the process of axon guidance is nonlinear. For example, commissural axons are attracted by Netrin and repelled by Slit. However, as axons approach the midline, the repellent action of Slit is suppressed its Robo-3/Rig-1 receptor. Once the axons cross the midline, activation of Robo by Slit silences Netrinmediated attraction, and the axons are repelled by Slit. ? Robo/Slit LOSS-OFFUNCTION MUTATIONS result in axons crossing the midline multiple times. (Indeed, Robo1 one has been found to be a candidate gene for DYSLEXIAimportance of these cues in ultimately wiring up the enormous functional complexity of the brain).?Axon guidance across the midline during the formation of the OPTIC CHIASM represents a "decision point": the nasal half of the axons of each orbit cross to the other side of the brain. This is regulated by a selective long-range CHEMOREPULSIVE cue mediated by Ephrin-A, to which the axons are differentially sensitive as they have different levels of EphA expression. The receptor, is expressed only by those that DON'T CROSS (i.e. those from the TEMPORAL HEMIRETINA). ? Ephrin-A MUTATIONS lead to ABNORMAL tectal terminations of the retinal ganglion axons. The inhibitory Eph and Ephrin ligands also make up RECTANGULAR COORDINATES across DIFFERENT AXES so that the retinotopic map can be made SMOOTHLY. The DEGREE to which they are repelled is set by their own particular level of Eph expression, which is in turn set by the POSITION of the neuronal cell body in the retina. Thus, axons from the anterior retina, expressing the lowest level of Ephs, can project to the posterior tectum, even though this is where Ephrins are highly expressed. Posterior retinal cells express high Eph level, and their axons will stop more anteriorly in the tectum. Experiments which show this are KNOCKOUT and OVEREXPRESSION experiments, and those where BIOASSAYS are produced from explants of defined portions of the retina are laid on substrates of tectal membrane fragments. Strategies for molecular guidance cues: 1) axons can "solve the problem" of long-distance navigation by DIVIDING the journey into short segments through the use of INTERMEDIATE TARGETS- these could represent 'decision points' where the axons need to diverge, and at defined points the axons could CHANGE THEIR SENSITIVITY in response to each cue, so it could move on with the next part of the journey. 2) FIRST axons reach their targets when the EMBRYO IS SMALL and the distance to cover is SMALL: these "PIONEER

AXONS" can then serve as guidance paths for subsequent axons in a process called FASICULATION. ? Studies in ZEBRAFISH RETINA showed that inhibiting neural differentiation of early retinal progenitors prevents axons from exiting the eye. 3) Following a MOLECULAR GRADIENT, as mentioned above, is a way which axons are able to smoothly reach their PROPER TERMINATION ZONE by DIFFERENTIAL EXPRESSION of the chemotropic cue receptors (still, is initial "crude map" is subsequently fine-tuned by neural activity). The maintenance of the progenitor pool is achieved by: 1) LATERAL INHIBITION- the neuronal precursor upregulates a pro-neural gene (triggered by environmental conditions), and this alos UPREGULATES DELTA, which binds to its receptor NOTCH on adjacent precursor cells so that these are INHIBITED from also DIFFERENTIATING into neurons in response to the environmental cue. 2) CONTROLLING THE PLANE OF DIVISION (inheritance of the apical membrane complex appears to be the determinant). 3) INTERKINETIC NUCELAR MIGRATION: the progenitors undergo this process of periodic movement of the nucleus in phase with the progression of the cell cycle- mitosis exclusively occurs at the APICAL SURFACE ? function appears to be to BALANCE the EXPOSURE of progenitor nuclei to neurogenic vs proliferative signals. In the retina of ZEBRAFISH MUTANTS lacking the Dynactin-1 motor protein, the interkinetic nuclei migrate more rapidly and deeply to the basal side, and more slowly to the apical side. Because Notch signalling is predominately activated on the apical side, the mutant progenitors are less exposed to Notch and exit the cell cycle PREMATURELY. ? This results in the OVERPRODUCTION of early-born retinal ganglion cells AT THE EXPENSE of later-born interneurons and glia.?

INTERMEDIATE PROGENITORS are formed from radial glua in the subventricular zones (also one of the areas of adult neurogenesis- in this case they migrate to the olfactory bulbs by the rostral migratory stream; other example is in the dendate gyrus of the hippocampus) are more fate-restricted than radial glia. They divide symmetrically to give neurons, and they express Tbr2. ? Tbr2 KNOCKOUT MICE have reduced progenitor numbers and a smaller cortex; autosomal recessive silencing of Tbr2 in humans shows MICROCEPHALY; demonstrates its importance in NEURONAL AMPLIFICATION during neurogenesis. FLUORESCENT LABELLING of one cell in the earliest stages of the DEVELOPING RETINA shows us that the clone of cells derived from that one cell contains ALL RETINAL CELL TYPES- thus THE MORPHOGEN MODEL WON'T WORK HERE in enabling different types of neurons to be made like it did in the neural tube. Subsequent analysis showed that different cell types arise in a strict TEMPORAL order, and that this does not occur though an environmental signal ? "old" retina progenitors cultured with "young" retina progenitors couldn't make "young" cell types; addition of candidate "young" or "old" environmental signalling didn't have an effect on cell type. Instead it is time-dependent intrinsic changes in progenitor cells which ONLY THEN allows

?the cells to respond differentially to environmental signals- the COMPETENCE MODEL. ? Principle applies somewhat to cortical development, see below. TRANSPLANTATION STUDIES show that, in the development of the CORTICAL LAYERS, cells are specified to a particular fate by the end of S-phase ?
Transplanting a "young" ventricular progenitor cell EARLY in the final cell cycle (before S-phase) into a relatively 'old' developing cortex results in the cell ADOPTING the host fate ? therefore there is still plasticity at this stage. HOWEVER, transplanting the same 'young' ventricular progenitor LATE in the final cell cycle results in the cell MAINTAINING its ORGINAL IDENTITY. ? Here the 'competence' to respond to the environment become MORE RESTRICTED WITH TIME. ? As the intrinsic and extrinsic signals change, neurogenesis is followed afterwards by gliogenesis. DEVELOPMENTAL DEFECTS (first three are to do with radial migration):
?mutations in FILAMIN 1 (filaments that link the cell body of the neuron to the leading process) cause PERIVENTRICULAR HETEROTOPIA (heterotopia means clumps of grey matter located in the wrong place)- the neurons FAIL to form a leading process and don't leave the ventricles; form 'nodules' that lie along the lateral ventricles.
?Mutations in LIS1 and DCX, gene responsible for the CYTOSKELETAL microtubules involved in nucleokinesis (stepwise nuclear translocation mediated by a 'cage' of microtubules) causes LISSENCEPHALY (smooth brain): here the gray matter is thicker (4 layers rather than 6) and the majority of neurons are in deeper layers. Although the neurons mostly end up in the wrong layers, there is NO periventricular heterotopia. The organisation of the cells within each individual layer is also abnormal. Presumably cytoskeletal changes are affected in such a way that the neurons are unable to migrate through the already formed layers. ? Profound retardation from birth and susceptibility to CHILD EPILEPSY (applies to all cortical dysplasias).
? "REELER" mice have a mutation in the gene 'reeler' that codes the protein REELIN. These mice are characterised by MOVEMENT DISRODERS. It appears that reelin plays a role in regulating neural migration and the signalling required to stop migrated and start forming the correct synaptic connections at the right layers. The cytoarchitecture of these mice is REVERSED- the layers are INSIDE-OUT as the neurons pile up underneath the cortical plate, and it appears that the cortex and cerebellum are differentially affected.
? Foetal ALCOHOL EXPOSURE leads to reduced proliferation of VZ cells, increased cell death in VZ and thus inhibited neurogenesis.
? DISC-1 MUTATIONS are considered a generalized risk factor in major PSYCHIATRIC DISEASES and have also been implicated in memory deficits and abnormal patterns of brain activity ? increase the risk of developing schizophrenia, bipolar disorder, or major depression by about 50-FOLD in comparison to the general population. Functionally involved in several processes that regulate neural development and brain maturation such as neuronal proliferation, differentiation, migration, cAMP signaling, cytoskeletal modulation, and translational regulation via various signaling pathways: DISC1 may play an important role in neuroplasticity via interactions with molecules of the CYTOSKELETON and CENTROSOME, such as NUDEL and LIS1. The protein also enables the activity of dynein, a microtubule protein; controlling

?transport of microtubules is involved in neuronal migration, neurite outgrowth, and axon formation. It is HIGHLY EXPRESSED during critical periods of BRAIN DEVELOPMENT, particularly in the embryonic ventricular and subventricular zones of the cortex, where neural progenitor cells are found. This localization suggests that DISC1 is an important regulator of embryonic and adult neurogenesis, and may regulate proliferation and/or differentiation. Levels of the protein in neural progenitor cells undergoing INM affects whether they differentiate into neurons or remain as progenitors.
? Look up "Four Neurodevelopmental Models of Childhood Neuropsychiatric Disorders" section in "Development of the Cerebral Cortex: Implications for Neurodevelopmental Disorders". If the GANGLIONIC EMINENCES in the ventral telencephalon are DYED EXPERIMENTALLY, cells there appear to end up in the cortex. ? This represents the TANGENTIAL MIGRATION of GABA-ergic INHIBITORY INTERNEURONS from the medial ganglionic eminences (rather than from the VZ); this means they can be specified separately rather than being an additional type of neuron that has to be made from projection neuron progenitors as above. In this type of migration the axon tracts themselves serve as scaffolds, and mediate precise routes of navigation, thus connecting regions of neuronal generations with the final settling position of neurons. Indeed this may have evolved as a mechanism for increasing the COMPLEXITY of neuronal circuits.? Transcription factors are responsible for these ganglionic eminence neurons: KNOCKOUT MICE for Dlx1 and Dlx2 have greatly reduced numbers of GABA-ergic interneurons in the cortex. ? Disrupts formation of of most forebrain GABAergic neurons (including cortical interneurons, projection neurons of the striatum, pallidum, central nucleus of the amygdala, and the reticular nucleus of the thalamus). For the basal ganglia disruptions- affects habit learning and goal-directed behaviours, link with AUTISM? ? Mutations in some Dlx genes found in autistic patients!
PATTERNING CORTICAL AREAS: Rakic proposed the "RADIAL UNIT HYPOTHESIS": cohorts of cells generated by the progenitor cells within the VZ migrate up radial glia to populate ONLY ONE DOMAIN of the cortical plate: i.e. the horizontal location is already determined by the POSITION of the precursor cell in the VZ (thickness simply determined by birth order) ? Different cortical areas are patterned very early in the VZ- fact that we see REGIONAL DIFFERENCES in gene expression, namely Pax6 and Emx2, suggests this is true. These are expressed in complementary anteroposterior gradients in the V2 of developing neocortex- in KNOCKOUT MICE for Emx2 there is an expansion of the rostral neocortex at the expense of the more caudal auditory and visual areas; vice versa for Pax6 knockouts. ? Thus expected shifts of area identities in loss-of-function mutants observed. The local rostral course of FGF8 is in the right place to act as a signal for this patterning- it probably promotes one and represses the other. ? ECTOPIC EXPERIMENTS using FGF8 in mice neatly show its cortical morphogen action- it can cause a specific "barrel cortex" of the mouse somatosensory cortex to move posteriorly. The blood-brain barrier and cerebrospinal fluid:

???????????EARLY EVIDENCE FOR COMPARTMENTALISATION: dye injected into the separate compartments; when injected into the brain, the brain and spinal cord were stained whilst the peripheral organs weren't. Conversely, when injected into the periphery, the dye did not penetrate any CNS organs.
???????????BBB phenotype INDUCED BY THE CNS ENVIRONMENT: was shown that when avascular tissue from a 3-day old quail brain is transplanted into the coelomic cavity of chick embryos, the chick endothelial cells that VASCULARISE the grafts form a BBB PHENOTYPE. However, when avascular coelomic tissue was transplanted into embryonic chick brain, the endothelial cells that invade the tissue form LEAKY CAPILLERIES.
???????????The relative extraction of some LIPOPHILIC agents across the BBB may be LOWER THAN EXPECTED due to binding serum albumin, for example ? uptake of the anticonvulsants phenobarbital and phenytoin. Another reason is the action of ABC TRANSPORTERS ? MDR1 (multidrug resistance 1 ABC transporter) KNOCKOUT MICE died after being given usual worming drug; thus these transporters are physiologically useful in getting rid of potentially toxic compounds from the vulnerable CNS environment.
???????????Others may be higher than expected based solely on their lipid solubility; indicates the presence of SPECIFIC TRANSPORT MECHANISMS e.g glucose and L-DOPA.
???????????ENDOTHELIAL ENZYME SYSTEMS can form a "metabolic barrier" function particularly to render substances synaptically inactive. For example there are large amounts of DOPA decarboxylase and monoamine oxidase in endothelial cells that convert L-DOPA to 3,4-dihydroxyphenylacetic acid. ? EFFECTIVE THERAPY for PARKINSON'S requires that L-DOPA is given with a DOPA decarboxylase inhibitor for this reason.
???????????HYPERTONIC INFUSION OF MANNITOL (which doesn't cross the BBB) draws fluid from the CSF into the blood, thus dilating the vessels and 'opening' the BBB. ? Clinically effective in removing fluid from the brain during INCREASED INTRACRANIAL PRESSURE, and also very useful for DELIVERY VARIOUS DRUGS INTO THE BRAIN (e.g., in the treatment of Alzheimer's disease, or in chemotherapy for brain tumours).
???????????ELECTRICAL STIMULATION of PERICYTES causes local vasoconstriction involving Ca2+: they control CNS capillary blood flow where there is a lack of smooth muscle.
???????????CSF PRODUCTION at the CHOROID PLEXUS is very reliant on HCO3transport; KNOCKOUT MICE for this transporter results in a great reduction in CSF production. ? The HCO3- is recycled across the membrane, bringing Cl-.
???????????BRAIN TUMOURS contain vessels with poorly developed BBBs; as a consequence the abnormal permeability accounts for the vasogenic oedema that is commonly associated.
???????????The many adverse neurological effects associated with MENINGITIS are due to the abscesses and inflammation causing partial BBB breakdown. However this downside is also a clinical advantage in that it facilitates the DELIVERY of antibiotics.
???????????Increased CSF production, decreased CSF absorption (perhaps due to thrombosis of cerebral veins) or obstruction of CSF pathways (perhaps due to

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