Module 3 Neuroanatomy

What are chemo-attractants and their function?

stimulates positive chemotaxis (movement of molecules along a chemical gradient); when cell membrane is interacting, it will grow towards these chemicals

What are chemo-repellants and their function?

inhibit axons from growing in this direction

What are contact-attractants and their function?

stimulate growth of axons

What are contact-repellants and their function?

inhibit axons from growing into this territory

What proteins are in the ECM that influence axon growth cone migration in the developing (embryonic) human nervous system?

laminin, fibronectin, tenascin, collagen, nebrin, CSPG

What is the function of the proteins in the ECM?

embryonic development: stimulate axon growth

adult development: some of them will inhibit, like CSPG

Where is the source of neurotrophic molecules while the axon growth cone is actively migrating?

axon itself produces neurotrophic factors

Where is the source of neurotrophic molecules once the growth cone establishes a connection with its target?

after connection with target, the target cell will produce neurotrophic factors

What is metalloproteinase? What does it do?

enzyme that degrades connective tissue/ECM proteins; functions to degrade these so that the growth cone can penetrate/migrate through

What are filipodia?

they are foot-like extensions from an axon growth cone with a lot of actin present; they act more as "sensory" probes that will probe the environment

What are lamellipodia?

these are more of the "webbing" in between filipodia, also with actin present; they act more like "motors" that push the migrating cell forward

What are the mechanisms of how nerve growth factor (NGF) and its receptor can influence the nucleus of an innervating neuron?

1. NGF from post-synaptic cell will be released --> the axon terminal will internalize the NGF and its receptor --> retrograde axonal transport to the nucleus to basically say "keep cell alive and stimulate growth of axon"

2. NGF binds to receptor and causes a phosphorylation pathway, which will then cause transcription factors to target nucleus to tell it to "keep cell alive and to continue with axon growth"

What are the different neurotrophins and their ligand binding preferences in the trk receptor family?

these are molecules that will stimulate axon growth and survival of a neuron by stimulate nucleus --> if this can't occur, then mechanism for death of neuron and thus neurodegenerative diseases such as ALS

types:

NGF --> trkA

NT-4, BDNF, NT-3 --> trkB

NT-3 --> trkC

What are the four steps observed during development of neuronal circuits and formation of synapses?

- specification of distinct neuronal cell types

- directed outgrowth of developing neurons via molecules

- selection of appropriate synaptic partners

- refinement of connections through elimination of certain neurons, axons, and synapses during "critical periods" of development via environmental cues

What is observed during the original formation of synapses of motor neurons contacting skeletal muscle fibers?

motor neuron will go to multiple different muscle fibers and different motor neurons will also join. There is only one input (motor neuron) is kept at each muscle fiber - one motor neuron per muscle fiber

What is observed during re-innervation following injury?

cut through axon, target becomes denervated

axon regenerates and grows to target cell and the motor neuron will go to the muscle fiber and different motor neurons will go to different fibers (more than one at a fiber)

then we allow for only one input to be for each muscle fiber, and this occurs after 32 weeks

What is the concept of the punishment theory?

highly active receptor gives off signals that eliminate weaker synapses by surrounding vicinity of other receptors and protecting more active synapses

What is the concept of the protective theory?

protective cloud under more active synapses via post-synaptic density 95

What is the normal anatomical pathway of axons that project form the retina to the occipital lobe?

nasal half of R eye: will start at the nasal half of the right eye, and then will go into the optic chaism and then into the left optic tract, where it will then go into the lateral genicular nucleus, and then to the visual cortex of the L cerebral hemisphere

temporal half of L eye: will start at the temporal half of the left eye, and then will go into the optic chaism and then will stay along the left optic tract and then into the lateral genicular nucleus, and then to the visual cortex of the L cerebral hemisphere

What is an ocular dominance column in the visual cortex of the occipital lobe?

action potentials from light signals will travel to layer 4 of the cerebral cortex in the occipital lobe, and then go to other regions of the cerebral cortex and create these ocular dominance column

normally they will be the same size width for the left and right eyes

How does suturing the right eye two weeks after birth cause a perturbation in light activity during a critical period affect ocular dominance columns?

it will decrease the width and will be darker for the R eye, and will have increased width and brightness in the L eye

What is an experimental treatment that might promote structural and functional recovery from early monocular deprivation in adult rats?

degrade ECM (perineural net) and see if anything will change (CSPG is inhibitory in nature so get rid of this and see if sprouting of axons can occur

How does perturbation in light activity in eyes after the critical period of neural development affect width of ocular dominance columns?

if a neuron is treated with CSPG after the critical period, the ECM can be manipulated and used to promote a functional recovery and after 3 weeks, there can be a difference in the ocular columns

Two definitions of synaptic plasticity

1. an increase in synaptic efficacy due to increase in functional activity

2. changes in structure, connection, or function in a neural system in response to experimental manipulations or injury during development or in the adult, as well as changes that occur as a result of aging and disease

How does GAP-43 serve as a biomarker of axon growth during development of the human nervous system?

will be expressed at the tips of extending neuritic process during development

What are the relative levels of GAP-43 protein in soft-wired areas of the adult brain?

increased levels

What are the relative levels of GAP-43 protein in hard-wired areas of the adult brain?

down-regulation / not expressed

Where is the location of the GAP-43 protein during regeneration of axons?

axon terminals

What are the degrees of success for axon regeneration following axotomy in the PNS and CNS?

CNS = unsuccessful regeneration

PNS = successful regeneration

What are the reactions that occur in a neuronal cell body of a peripheral neuron immediately following axotomy?

- eccentrically located nucleus

- swollen cell body

- Nissl bodies have disappeared (due to being dispersed)

- induction of IEG expression (code for transcription factors which lead to regulation of gene expression for genes that promote functional recovery)

What events occur in the proximal stump of the PNS following axotomy?

- axon sprouting occurs

- new growth cones are formed

- re-expression of GAP-43 levels at the growth cone

What events occur at the distal stump of the PNS axon following axotomy?

Wallerian degeneration

- 24 hours = axon swells

- 48 hours = macrophages infiltrate tissue which cause disintegration of dystrophic axon, loss of synaptic connection, removal of myelin, transform schwann cells into neurilemmal cells

What is the origin of a neurilemmal cell? What are its functions?

- schwann cell

- act to guide the axon to its target cell by forming a regeneration tube which unites the distal and proximal stumps of the axon

What is the growth rate of a regenerating PNS axon following axotomy?

1-2mm/day

What factors in the CNS inhibit functional recovery following injury?

- weak expression of neurotrophic factors, potent neural growth inhibitors, axon sprouts and stops, and formation of impermeable gliotic scars

What factors in the PNS promote functional recovery following injury?

up-regulation of neurotrophic factors, expression of growth-promoting substrate molecules, neurilemmal tube will guide the axon

What molecules in the CNS are neurite growth inhibitory molecules are located in the ECM and myelin?

ECM: CSPG, tenascin, semaphosin 3A

myelin: MAG, NOGO A and B

How does a selective sema3A inhibitor affect the regenerative response and functional recovery of an injured spinal cord?

sema 3A itself is an inhibitory molecule that inhibits axon regeneration, so if this molecule will be inhibited, axonal sprouting and functional recovery can occur

What class of molecules are expressed by damaged cells and immune cells following injury to the CNS that function to promote astrocytic reactive gliosis?

cytokines --> these are cell signaling molecules that will coordinate other cells coming to the site of injury; they will stimulate astrocytes to migrate and form scar tissue where there is a lesion

What are some of the molecules that can directly stimulate astrocytes to form gliotic scar tissue?

fibronectin growth factor, TGF-beta, CNTF, interleukin 1, endothelin-1

Describe the experiment conducted by Dr. Martin Schwab in 1994

lesions were introduced to antibodies against NOGO A and B. these are inhibitory proteins, so inhibition of these molecules will cause axonal sprouting

used IN-1 and NT-3 --> combined offered the best sprouting

Describe the experiment conducted by Dr. Lars Olsen in 1996

PNS tissue was dissected out and then grafted into CNS tissue at the site of a lesion

the PNS offered a more permissive environment via a bridging graft that allowed for the axon to migrate and for re-innervation to occur

Describe the experiment conducted by Dr. Geoffrey Raisman in 1997

grafted olfactory cells into severed spinal tract because these have a lot of re-growth. this gave nerve fibers the pathway to grow back

What are the necessary biological ingredients that will probably need to be combined in order to promote successful functional recovery after SCI?

- providing neurotrophic factors

- neutralizing neurite growth inhibitory molecules with antibodies like IN-1

- inhibit the production of cytokines that mediate inflammation by use of steroids and/or related drugs

- provide bridging cells liek olfactory glia