Lecture 20 - Circuit building & repair review.pdf

Circuits Do not start out in their final format • During brain development tissues develop and specify for particular functions • Neuronal subtypes • Glia • Glial subtypes? • Tissues coalesce into brain regions with specific biochemistry, anatomy, function and unique patterns of connectivity. Circ...

Circuits Do not start out in their final format • During brain development tissues develop and specify for particular functions • Neuronal subtypes • Glia • Glial subtypes? • Tissues coalesce into brain regions with specific biochemistry, anatomy, function and unique patterns of connectivity. Circuits need cells to function •Six stages of brain development: 1. Neurogenesis—mitosis produces neurons from progenitor cells, forming the ventricular zone (250,000 new cells are “born” every minute) 2. Cell migration—cells move out of the ventricular zone toward their destination, where they express particular genes. Radial glial cells help with migration 3. Cell differentiation—cells become distinctive types of neurons or glial cells based on time cellular interactions. Circuits need cells to function 4. Circuit formation- axons of developing neurons grow toward their target cells Growth cones at the axon’s tip guide the axons Synaptogenesis- formation of functional connections (synapses) 5. Cell death- Elimination of excess neurons 6. Circuit pruning- Elimination of excess synapses (synaptic rearrangement): + Active synapses strengthened + Inactive synapse removed Neuronal migration •Without spatial cues, neurons will wander aimlessly until they hit something, so We need something to guide them to their proper location. •Cue is based on chemotaxis •Radial glia act as guiding structures to help guide neurons. •Chemotaxis: the use of a chemical signal to guide motion of a cell, or the ability of a cell to move toward a chemical signal Growth cones and connection making •As neurons establish connections, they utilize Growth cones at the leading edge of their neuritic process •Cytoskeletal proteins are added to the leading edge of a pseudopod like structure. The cell membrane grows forward to match the leading edge of the cytoskeleton. • Cytoskeletal rearrangement occurs behind the pseudopods to make a more stable neuritic shaft. Multiple means of guidance Contact guidance- multiple axons often travel together in a bundle, relying o nthier contact to guide them forward, with a few Pioneer cones leading the way and making “decisions”. Chemoattractants- attract the growth cone Chemorepellants- repel the growth cone Chemotactic signals can be free floating or attached the surface of other cells. Target trophic support- Once a leading growth cone arrives, signals for differentiation and cellular stability encourage it to stay in place instead of wandering while the transition to a more stable setup occurs Neural polarity revisited Neurons separate axons and dendrites by using repulsive chemotactic signals to ensure that the two domains move toward their own respective targets. Neural polarity revisited This allows complex neuronal networks to emerge. Without selfavoidance signalling, and regulation of synaptogenesis, neurons would collapse into themselves and be unable to form a network. Synaptogenesis • Complex process by which a transient connection becomes a long term fixture. • First step – adhesion. Cadherins/protocahderins anchor the two opposed cell membranes together, while maintain a spatial gap (becomes the synaptic cleft) • Cadherins’ intracellular domains form a spot for other proteins to attach and link to cytoskeleton Synaptogenesis • Second step- Induction. A complex cytoskeletal array is assembled to anchor synaptic proteins in place within the larger synaptic structure. • Third step – full synapse recruitment. With the skeleton in place, particular synaptic proteins can be recruited and localized to the synapse • -its like constructing a building. Start with the foundation, then build the frame, finalize with the finishes and functional units. Too many connections! • To ensure that all the needed connections are made, the brain overproduces connections during development. • Process is called polyneural innervation • Then, redundant connections are pruned away until all that is left is what’s needed • Process called Synapse elimination. • Generally, the strongest or most used synapses are kept while the “inferior” ones are pruned. (Competitive elimination) • Surviving connections strengthen their hold, taking over real estate left behind by the terminated connections. What if competitive elimination fails? • Abnormally heightened connectivity between regions can lead to multiple issues with neural processing. • Some issues linked to hyperconnectivity • Autism/ASD • Might also give rise to savant characteristics. • Seizure disorders • Synesthesia • Paraphilias (?) Experience-dependent plasticity in the developing brain Critical periods • The time when experience and the neural activity that reflects that experience have maximal effect on the acquisition or skilled execution of a particular behavior • Parental imprinting in hatchling birds • Certain specific experiences during a sharply restricted time • Critical periods for sensorimotor skills and complex behaviors • End far less abruptly and provide far more time for environmentally acquired experience • Communication skills in songbirds • Language in humans Effects of visual deprivation • Visual cortical neurons divided into seven ocular dominance groups based on their degree of response to either the contralateral or ipsilateral eye • Group 1 cells driven only by contralateral eye • Group 7 cells driven entirely by ipsilateral eye • Group 4 cells driven equally well by either eye • Normal adult cat: most cells activated to some degree by both eyes • This normal distribution of ocular dominance can be altered by visual experience Effects of visual deprivation • One eye of a kitten sutured closed early in life • Eye was opened at 2.5 months, and kitten matured normally to 38 months • Very few cortical cells could be driven from the deprived (previously sutured) eye • Recordings from the retina and LGN were normal • Deprived eye gets functionally disconnected from the visual cortex • Behaviorally blind in the deprived eye • This amblyopia or “cortical blindness” is permanent Strabismus • In humans, amblyopia is most often the result of strabismus • Convergent strabismus: esotropia (“crossed eyes”) • Divergent strabismus: exotropia (“wall eyes”) • These alignment errors both produce double vision • Very common: affect ~ 5% of children • Inputs to the LGN from the optimally aligned eye are competitively advantaged • More V1 territory • Suppressed eye eventually comes to have very low acuity that may render an individual effectively blind in that eye https://www.aoa.org/healthyeyes/eye-and-visionconditions/strabismus?sso=y Manipulating competition • Test the role of correlated activity in driving the competitive postnatal rearrangement of cortical connections • Activity levels in each eye remain the same but the correlations between the two eyes are altered • Cut one of the extraocular muscles in one eye during the critical period • Two eyes are no longer aligned (strabismus) • Objects in the same location in visual space no longer stimulate corresponding points on the two retinas at the same time • Differences in the visually evoked patterns of activity between the two eyes are far greater than normal • Unlike monocular deprivation, the overall amount of activity in each eye remains roughly the same Ocular asynchrony prevents binocular convergence • Input from both eyes remains active but highly asynchronous • Ocular dominance pattern is sharper than normal in layer 4 • Cells in all layers of V1 are driven exclusively by one eye or the other • Prevents binocular interactions in other V1 layers Cataracts • Render the lens or cornea opaque • Functionally equivalent to monocular deprivation in experimental animals • Left untreated in children, results in irreversible damage to visual acuity in the deprived eye • Largely avoided if treated before 4 months of age • Bilateral cataracts produce less dramatic deficits even if treatment is delayed • Similar to Hubel and Wiesel’s binocular deprivation in experimental animals • Unequal competition during the critical period for normal vision is much more deleterious than the complete disruption of visual input • Individuals monocularly deprived of vision after the close of the critical period are much less compromised Repair and regeneration in the nervous system Functional reorganization without repair • After stroke or injury to distinct brain regions, patients often recover some of the deficits seen immediately after the trauma • Physical therapy, speech therapy • In most cases, this does not reflect regrowth or replacement of damaged neurons • Most often the result of reorganization of intact circuits Three types of neuronal repair 1. Peripheral nerve regeneration 2. Restoration of damaged central nerve cells 3. Genesis of new neurons Three types of neuronal repair 1. Regrowth of axons Requires: • Reactivation of the developmental processes for axon growth and guidance • Synapse formation • Activity-dependent competitive mechanisms • Ensure proper matching of newly regrown afferents to temporarily denervated targets • Seen primarily when sensory and motor nerves are damaged in the periphery • Leaves nerve cell bodies in the relevant sensory and autonomic ganglia or spinal cord intact • Peripheral nerve regeneration • Most readily accomplished type of repair in the nervous system • Most clinically successful 1. Peripheral nerve regeneration • PNI results in a gradual but usually incomplete restoration of sensory & motor function • Can be facilitated by surgical reapposition of the 2 ends of the severed nerve • Restores continuity of the existing nerve sheath • Increases functional recovery Henry Head’s peripheral nerve regeneration experiment • Monitored the return of sensation • Gradual return of sensitivity to pressure & touch that was not well localized starting ~6 weeks into recovery • Light touch, temperature discrimination, two-point discrimination recovered more slowly and less restoration 1. Peripheral nerve regeneration: Schwann cells are essential • The Schwann cell is the essential cellular mediator of peripheral axon regrowth Three types of neuronal repair 2. Restoration of damaged central nerve cells • Cell bodies survive, while axons or dendrites of the neurons may be injured • Sprouting: new dendrites, axons and synapses must grow from an existing cell body • Repair requires the cooperative regrowth of exisiting neuronal and glial elements • Generally fails, except over limited distances • Fails often because of local overgrowth of glial cells and their production of signals that inhibit neuron growth (i.e., local inflammatory response that supports glial rather than neuronal growth) 2. Nerve regeneration in the central nervous system Damage to the CNS can occur in several ways: 1. Physical trauma (blunt forces to head) 2. Hypoxia (lack of oxygen, ex: stroke, drowning, cardiac arrest) 3. Neurodegenerative diseases (Alzheimer’s, Parkinson’s, ALS) Results in axonal and dendritic neuronal loss (immediately and/or over time) Differences between successful peripheral regeneration & limited regeneration in the CNS: 1. Damage to brain tissue engages the mechanisms that lead to necrotic and apoptotic cell death for nearby neurons whose processes have been severed 2. A combination of glial growth and proliferation and microglial activity (immune functions that lead to local inflammation) actively inhibits growth 3. Upregulation of growth-inhibiting molecules 2. Nerve regeneration in the central nervous system: Axon growth after brain injury • Local proliferation & extensive growth of processes from glial cells around the site of the injury leads to glial scarring • Local overgrowth & sustained concentrations of astrocytes & oligodendrocytes Three types of neuronal repair 3. Genesis of new neurons • Occurs rarely in adults • Peripheral olfactory receptor neurons Requires: • Nervous tissue must retain multipotent neural stem cells (can give rise to all cell types of the relevant brain region) • Stem cells must be present in a distinct region that retains an appropriate environment for genesis & differentiation of new nerve cells & glia • Regeneration must preserve capacity to recapitulate the migration, process outgrowth and synapse formation necessary to reconstitute local & long-distance connections 3. Genesis of new neurons • The ability of the adult central nervous system to generate new neurons in response to acute or degenerative damage to neural tissue • Several non-mammalian vertebrates do have the capacity for neurogenesis in response to brain injury • Fish & songbirds • There is always a balance between existing long-lived neurons and newly generated neurons (significant stability in the brain) • In humans, new nerve cells in the CNS are generated reliably in just 2 regions • The olfactory bulb & the hippocampus • These are primarily GABAergic interneurons • A low level of glial cell proliferation does continue throughout life • Astrocytes & oligodendrocytes