Neuroscience Michaelmas 2013 Notes

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 2^ND 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 developingbrain. 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 asRADIAL GLIAL CELLSsimultaneously 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 re-innervated 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 theextracellular matrix, andcadherinsor 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...

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