Transcript NeuroReview3

Development and refinement
of CNS
Earliest form of neuroplasticity
Stages of NS development
• Induction of neural plate
• Birth or proliferation of neurons and glia
• Migration of cells to their eventual
locations in NS
• Axon growth and formation of synapses
between neurons
• Death of particular neurons and
rearrangement of neural connections
Neuralization, or Induction of the
Neural Plate
Cell Proliferation
• Cells in the neural tube begin to proliferate
(multiply, divide and increase in number)
• Most of cell division occurs in ventricular
zone of neural tube
• Cell division occurs through mitosis
• After about 7 weeks of development one
daughter cell will remain in ventricular
zone and one will migrate outward and
become a neuron or glial cell
Types of Cell Migration
Methods of Cell Migration
Cell Migration con’t
• The layers of the cerebral cortex develop
at different times
• Cells in outermost layers must migrate
through innermost layers first
• Development proceeds in an inside-out
fashion
• Cells in the neural crest will develop into
neurons and glial cells of the peripheral
nervous system
Formation of axons and dendrites
• Growth cones: structures that form at the
end of developing axons and dendrites
• 3 main features: main body; filipodia;
lamellipodia
• Filipodia and lamellipodia can move and
pull the growing processes along with
them
• Chemoaffinity hypothesis
• Guidance molecules
Axon formation, con’t
• First axons to reach their target have pioneer
growth cones, and use guidance molecules to
guide them
• Later axons use trail blazed by pioneer growth
cones
• Fasciculation: tendency for developing axons to
stick together and grow along established
pathways
• Cell adhesion molecules (CAMs): on surface of
growing axons that cause axons proceeding in
the same direction to stick together
Synaptogenesis
• Formation of new synapses
• Requires coordinated activity of at least 2
neurons
• Requires presence of glial cells, particularly
astrocytes
• Structures of the synapse must form (receptors,
neurotransmitters etc)
• Many processes promote or inhibit synapse
formation so that best connections are made
Neuron Death
• Cell death can be necrotic or apoptotic
• Necrosis: passive cell death, results in
inflmmation
• Apoptosis: programmed cell death (cell
suicide), much neater
• Cell death during NS development is
apoptotic
• Failure to get adequate NGF leads to
apoptosis
Synapse Rearrangement
• When neurons die they leave space on
postsynaptic membrane
• Sprouting axons of surviving membranes
will take over space
• Rearrangement seems to focus output of
each neuron on a smaller number of postsynaptic cells and increases selectivity of
synaptic transmission.
Time course of development
• Most neurons in adult brain are present by 7
months post conception
• Volume of brain quadruples after birth
• Due to synaptogenesis, myelination of axons
and increased branching of dendrites
• Primary visual cortex, auditory visual cortex
undergo burst of synpatogenesis at 4 months of
age until a maximum is reached at 7 months,
synapses in prefrontal cortex develop steadily
up to age of 2
Myelination
• Sensory cortex gets myelinated first (first
few months of life)
• Motor areas are next
• Prefrontal cortex is last, continues into
adolescence
• Myelin is composed of 15% cholesterol,
which is why doctors recommend milk for
babies
Dendritic Branching
• Deeper layers of cortex develop their
branches earlier than outer layers
• Just like time frame of migration of
neurons in cortex (inside-out manner)
• This pattern of development occurs the
same way in all cortical regions
Plasticity
• If the nervous system is still being formed after
birth then that means our brain’s connections
are plastic (can be rearranged)
• Environment influences which neurons survive
and which ones are lost
• “Use it or lose it”: can be good and bad.
Enriched environments can be helpful,
deprivation can have permanently damaging
effects
• Period of plasticity appears to be limited in some
cases (critical period) and unlimited in some
cases
End points to plasticity?
• Critical periods imply that the brain is not always
going to be plastic
• What ends critical periods? End of period of
axon growth? Maturation of synaptic
connection? Beginning of inhibitory input?
Presence or absence of neurotrophins (nerve
growth factors)?
• Mature neurons maintain nearly all of the
machinery necessary for restructuring their
synaptic connections (e.g. recovery after motor
nerve injury involves axonal sprouting at
neuromuscular junction)
End points to plasticity?
• Now there is evidence of neuroplasticity in
adult brains in olfactory cortex and
hippocampus
• Goldman and Nottebohm (1980s) show
neurogenesis in bird brains. In 1990s
evidence of neurogenesis in adult rats and
primates
Neural stem cells: originate in
ependymal layer of brain’s
ventricles
Cells migrate to olfactory bulb
Hippocampal cells come from
neural stem cells near their
final location
“Recovery” of function
Neuroplasticity and brain damage
• CNS damage can trigger 4 neuroplastic
responses:
– Degeneration
– Regeneration
– Reorganization
– Recovery of function
Neural Degeneration
• Anterograde degeneration: degeneration of the
distal segment of an axon that has been cut (the
section between the cut and the synapse).
Occurs quickly
• Retrograde degeneration: degeneration of the
proximal segment (the section between the cell
body and the cut). Progresses gradually and
• Damage can spread to neurons that are linked
to damaged neurons: transneuronal
degeneration (can be retrograde or anterograde)
Neural Regeneration
• Regrowth of damaged neurons
• Does not progress very well in mammals
and higher vertebrates
• Virtually nonexistent in the CNS Of adult
mammals
• Does occur in the PNS of adult mammals
Three possibilities
• If Schwann cell myelin sheaths remain
intact, regenerating neurons grow through
them to original targets
• If nerve is severed and cut ends are
separated by a small space regrowth can
be directed to incorrect targets
• If severed ends are far apart or long
section of nerve is damaged functional
regeneration may not occur
Schwann cells
• Promote regeneration in the mammalian PNS by
producing neurotrophic factors and cell adhesion
molecules (CAMs)
• Neurotrophic factors stimulate growth of new
axons and CAMs on membranes of Schwann
cells provide the paths along which regenerating
axons grow
• In CNS oligodendroglia do not stimulate or guide
regeneration; actually release factors that block
regeneration
Neural Reorganization
• Could result from (1) strengthening of
existing conditions possibly through
release from inhibition and (2) establishing
new connections by collateral sprouting.
Treatment of NS Damage
• Neuroprotection: e.g. reducing brain
damage by blocking neurodegeneration
• Promoting CNS regeneration
• Neurotransplantation (fetal tissue, stem
cells)
• Rehabilitation training
Neuroprotection
• Brain injury is a complex cascade of
biochemical and structural changes of
varying duration each of which may
contribute to neuronal death or repair and
regeneration
• One therapeutic approach involves
administering compounds to protect neural
tissue from cytotoxic and excitotoxic
effects of the injury cascade
Inhibiting Cytotoxicity
• Neuroprotective agents that reduce
cytotoxicity tend to absorb damaging
molecules such as free radicals
• Free radicals can interact with cell
membranes, DNA and proteins, changing
their conformation and affecting their
function
• Free radical scavengers have not been
very effective in clinical trials
Inhibiting Excitotoxity
• Another approach is to try to prevent the
excitotoxic loss of neurons after injury
• Blocking hyperexcitation of receptors for
glutamate
• Treatments must target several pathways in the
injury cascade. Highly selective compounds may
lose their beneficial effect or become toxic by
pushing the injury cascade into alternative
pathways, which may be just as destructive
Neuroprotection
• Both the timing and the type of the
pharmacologic agent to be given can have a
significant impact on the success of therapy.
• With neuroprotective agents the general rule is
that the earlier they are given the better,
especially if the mode of action is increasing
inhibitory tone in the brain.
• Increased levels of inhibition that may be
needed to block excitotoxicity in the damaged
area may disrupt the subsequent recovery if
treatment is maintained throughout the course of
rehabilitation
Neural Regeneration
• How can the regeneration of neural tissue be
stimulated after injury?
• Trophic factors: agents that can stimulate the
repair, regeneration, elongation, and
reconnection of damaged axons or dendrites
• We are only beginning to understand the
multiple interactions that guide or block
regenerating axons to their targets, and how
behavioral experience can affect functional
outcomes in injury models
Reorganization through training
• Can physical therapy or exercise be used to
stimulate the brain to reorganize after a TBI?
• A good limb can be restrained, forcing use of
impaired limb, so that the impaired limb
‘relearns’ how to perform tasks
• Critical periods may exist for this type of
reorganization because brain will be differentially
sensitive to increased levels of activity following
injury