Lecture 18 - Repair and Regeneration of the Nervous System PDF

Repair and regeneration in the nervous system Aims • What is functional reorganization? • What are the 3 types of neuronal repair? • What barriers impede central nervous system regeneration? • Does neurogenesis happen in an adult mammalian brain? Functional reorganization without repair • After...

Repair and regeneration in the nervous system Aims • What is functional reorganization? • What are the 3 types of neuronal repair? • What barriers impede central nervous system regeneration? • Does neurogenesis happen in an adult mammalian brain? 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, guidance, and 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 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) 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 Three types of neuronal repair 1. Peripheral nerve regeneration 2. Restoration of damaged central nerve cells 3. Genesis of new neurons 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 • Schwann cells are the glial cells that myelinate peripheral axons • Macrophages are the immune system cells that clear the degenerating remains of severed axons • Both secrete molecules that are essential for successful regeneration • When a peripheral axon is severed: • Axon segment distal to the cut degenerates • Debris left by the dead axon is cleared by macrophages • Proximal axon stump transforms into a growth cone • Schwann cells proliferate & secrete growth-promoting signaling molecules • Regeneration is more efficient after crushing vs cutting a nerve 1. Peripheral nerve regeneration: Schwann cells are essential • The Schwann cell is the essential cellular mediator of peripheral axon regrowth 1. Peripheral nerve regeneration: Schwann cells are essential • CNS axon outgrowth from adult neurons using an impractical experimental approach • Severed axon in the optic nerve can be provided with a peripheral nerve graft that offers the Schwann cell and connective tissue components that support PN regeneration • Central axons grow through the peripheral nerve graft • Sharply limited effects: low # of synapses and functional capacity to restore vision 1. Peripheral nerve regeneration: reinnervation of appropriate target tissues • Extension of axons is the first step in peripheral nerve regeneration • Next essential event: reinnervation of appropriate target tissues and reestablishment of synaptic connections • Fair degree of imprecision in the reinnervation of specific targets • Subsequent regeneration can (or cannot) be fairly faithful to the original pattern Three types of neuronal repair 1. Peripheral nerve regeneration 2. Restoration of damaged central nerve cells 3. Genesis of new neurons 2. Nerve regeneration in the central nervous system • Very little long-distance axon growth or reestablishment of functional connections within the CNS following injury • Relatively poor prognosis following brain or spinal cord damage https://www.youtube.com/watch?v=lU9QH7pB6nU 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 2. Nerve regeneration in the central nervous system: Immune activation Three types of neuronal repair 1. Peripheral nerve regeneration 2. Restoration of damaged central nerve cells 3. Genesis of new neurons 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 3. Genesis of new neurons • Neural stem cells are often found in close proximity to blood vessels • Suggests they may be regulated by circulating as well as local signaling molecules • Neuron replacement is gradual • The limited capacity to replace neurons in an adult brain has offered some promise that, under the right conditions, neuron replacement might be used to repair the injured brain • The CNS likely puts a premium on the stability of connections to ensure that learned behaviors are maintained Nuclear Weapons and Neurogenesis • When are cortical neurons generated over an individual’s lifetime? • Fluctuations in environmental exposure to radioisotopes from nuclear weapons testing • Normally steady state isotope carbon-14 in Earth’s atmosphere was dramatically altered for a brief period between the mid 1950s and early 1960s • Many countries conducted multiple tests of nuclear weapons • Experimental birth-dating technique • People of varying ages had been naturally exposed to a ‘bolus’ of 14C Student-led Summary • “What? So what? Now what?” • What? • What did we learn today? • So what? • Why does it matter? How is it useful, relevant, or important? • Now what? • How do we connect this to our previous learning? What else do we need to know? Summary • The ability of the brain to alter, renew, or repair itself • Functional reorganization without repair • Three types of neuronal repair • Peripheral nerve regeneration • Restoration of damaged central nerve cells • At least 4 barriers: neuronal death, glial cells actively inhibit axon growth, neural stem cells are constrained, immune responses further inhibit extensive regrowth • Genesis of new neurons • Goal: develop potential therapies for brain repair following injury/degeneration Review sessions for Exam #2 • Wednesday 10/26 @ 8:30 (in class) • Friday 10/28 4:00-5:00 pm on TEAMS • Saturday 10/29 7:00-8:00 pm on TEAMS • EXAM 2 on motor systems & plasticity is Monday October 31 @ 8:30 (class time) on eLearning