final repair & regeneration

Question 1

What are the 4 major barriers to CNS regeneration?

Answer 1

Neuronal death
Glial cells actively inhibit axon growth
Neural stem cells have a limited ability to divide, migrate, and differentiate
Immune response: cytokines inhibit regrowth

Question 2

Describe the evidence in humans showing functional reorganization in the CNS without repair

Answer 2

Neuroplasticity allows for reorganization, and gain-of-function for an injured part of the cortex
Reorganization occurs with less used portions of the brain taking over for damaged ones
Seems to use primary and supplementary motor areas and visual cortex.

Question 3

What are the 3 types of neuronal repair? What do they each require? How successful are they?

Answer 3

Peripheral nerve regeneration (e.g., alpha motor neuron): requires reactivation of processes. Axon growth and guidance, Synapse formation, Most successful type of repair
Repair of existing neurons in CNS: sprouting–new dendrites, axons, and synapses grow from an existing cell body. Requires adhesion signals and trophic signaling, Hypertrophic glial cells inhibit neuron growth, Very limited type of repair
Genesis of new neurons E.g., olfactory receptor neurons Requires Maintenance of multipotent neural stem cells, NSC’s must be present an appropriate environment, Must be able to migrate and form synapses, Rarely occurs; mechanism is controversial

Question 4

Who is Henry Head and how did he contribute to the field?

Answer 4

1905–Henry Head performs nerve transection and reappositionon himself. Region that regained sensation after 2-6 months. Area normally innervated by the radial nerve

Question 5

What are the important cells and molecules for peripheral regeneration?

Answer 5

Schwann cells & Macrophages. Both secrete molecules essential for successful regeneration
Distal portion degenerates Proximal axon stump > growth cone > interacts with Schwann cells

Question 6

What factors contribute to increased nerve growth and more rapid recovery?

Answer 6

Activity > increased nerve growth and more rapid recovery
Regenerating peripheral sensory and motor axons express integrins–mediate recognition of matrix and intracellular signaling to facilitate growth. Integrins transduce ECM signals by interacting with cytoplasmic protein kinases and activating Ca2+channels

Question 7

Describe the results of transplanting a peripheral nerve and schwann cells into the CNS to promote central axon regeneration.

Answer 7

Schwann cells are essential for peripheral axon regrowth, create an environment that supports axon guidance and growth
Severed axons from the optic nerve apposed to a peripheral nerve graft. Ganglion cell axons grow through peripheral nerve graft

Question 8

What is the process of regeneration of peripheral synapses? Describe the specific molecules involved at the neuromuscular synapse.

Answer 8

When the axon degenerates, the Schwann cells and acetylcholine receptors (AChRs) remain in place. Increased expression of neurotrophins important for synaptogenesis (e.g., NGF and BDNF)
Specific molecules in the synaptic cleft and postsynaptic membrane preserve the neuromuscular synaptic sites and facilitate reinnervation and functional recovery
Regeneration of Peripheral Synapses: ColQbinds and localizes acetylcholinesterase (AChE) to the synaptic cleft, transmembrane receptor proteins(Lrp4 and MuSK) bind agrin(secreted by the presynaptic terminal of the ingrowing axon), agrinin the ECM àmuscle cell maintains AChR’s(rely on additional scaffold proteins)

Question 9

What are some ways the CNS can become damaged?

Answer 9

Physical trauma
Focal lack of oxygen(e.g.,stroke)
Global lack of oxygen (e.g., cardiac arrest)
Neurodegenerative diseases (e.g.,AD)

Question 10

What is TBI? What is CTE? What are common causes of CTE? What are long-term consequences?

Answer 10

TBI: Traumatic Brain Injury
CTE: Chronic traumatic encephalopathy. Neurological and behavioral deficits that follow TBI, paired with postmortem degenerative pathology. This occurs in athletes or soldiers who sustain repeated TBI. Long-term degenerative consequences: limited ability of CNS to repair itself once damage has occurred

Question 11

List stimuli that can cause neuronal apoptosis after injury in the CNS. What is the cascade for apoptosis?

Answer 11

Cell loss > enhanced activation of caspase-3 > causes cells to die by apoptosis
Neuronal apoptosis after injury can be caused by: Excess glutamate, Binding of cytokines, Loss of target connections (& loss of trophic support)
Lead to blocking Bcl2 (anti-apoptotic gene) > cytochrome c released from mitochondria > activates caspase 3 > apoptosis

Question 12

What are glial scars? How do they hinder axon growth?

Answer 12

Astrocytes, oligodendrocytes, and microglia grow and proliferate while neurons die > Major barrier for axon and dendrite regrowth
Myelin proteins produced by oligodendrocytes inhibit axon growth (e.g. myelin-associated glycoprotein (MAG))
Injured CNS axons express transmembrane receptors that interact with myelin proteins

Question 13

Describe the two major methods for neuronal birth-dating

Answer 13

Radioactive-labeled thymidine (H3-T)

Bromodeoxyuridine(BrdU)

Question 14

What 2 species were first shown to have neurogenesis in adulthood? In what areas of their brains does neurogenesis occur?

Answer 14

Neurogenesis in goldfish: Early 1970s, Teleost fish grow their entire lives (including eyes and brain) Stems cells form a ring at the margin of the retina. Generate all retinal cell types (except rods)
Songbirds: Radioactive thymidine incorporated into cells in the brain of adult canaries. Only occurs during cell division. Significant neurogenesis occurs in nuclei that control production and perception of song. Stem cells located in limited region around lateral ventricles. Radial processes(like radial glial) extend into song-control centers

Question 15

Where does neurogenesis occur in mammalian brains?

Answer 15

Neurogenesis occurs reliably in the olfactory bulb and hippocampus. Stem cells located close to the surface of the lateral ventricles (Subventricular Zone (SVZ)) > interneurons. most die before being integrated into existing circuitry

Question 16

What types of cells do NeuN and GFAP label? Why is it necessary to have these labels as well as a label for BrdU?

Answer 16

Antibodies against BrdUare conjugated to fluorescent markers
NeuN lables neurons
GFAP labels glia
Patients with skin cancers’ treatments include injections of thymidine analogs like BrdU and labels for NeuN and GFA to identify neurons post mortem.

Question 17

Does neurogenesis occur in adult humans? Why is this so difficult to study?

Answer 17

SVZ and SGZ are the only regions that give rise to new neurons in the adult brain that become functional.
Whether these limited examples of neurogenesis play a normal role in brain function is not yet clear. Manipulating neurogenesis is a challenge. Most methods for inhibiting neurogenesis have side effects. Radiation: kills dividing cells but might affect existing cells. Gene inactivation: inactivate genes involved in cell division is more specific, but most genes have more than one function

Question 18

Describe the experiment that took advantage of increased 14C in the atmosphere during 1955-1963 to examine neurogenesis in the adult cortex. What were the hypotheses of this study? What were the results?

Answer 18

From 1955-1963 many countries conducted nuclear weapon tests, Significant increase in atmospheric 14C, Provided a natural version of birth-dating techniques > 14C was incorporated into DNA synthesized during this time.
14C levels corresponded to the atmospheric level around the time of theses individuals’ gestations and births. Those born before 1955 have their levels go back to normal.

Question 19

Does neurogenesis occur in the adult human cortex? What is the evidence?

Answer 19

Patients with skin cancers–treatment included injections of thymidine analogs (e.g., BrdU). Examined cortical cells post mortem. Two studies combined provide strong evidence against neurogenesis in the adult cortex.