Neuroplasticity

Hebbian learning

"two cells or systems of cells that are repeatedly active at the same time will tend to become 'associated', so that activity in one facilitates activity in the other." (1949)

list some degenerative changes that can occur following axonal injury

(1) the axon terminal degenerates, (2) myelin breaks down and forms debris, (3) the cell body undergoes metabolic changes. Subsequently, (4) presynaptic terminals retract from the dying cell body, (5) postsynaptic cells degenerate. In this illustration the postsynaptic cell is a muscle cell.

list some challenges that CNS neurons must overcome for regrowth

*"bad" glial environment* - combat glial scars, - inhibitory extracellular matrix - blockers of myelin -> repopulate with neurons and "good" glia

what specific type of rehab training has shown to be most effective in producing long-lasting cortical reorganization in affected brain areas during the chronic phase post stroke?

** task specific training

describe neurons in the CNS capacity to regenerate axons

**limited capacity

CNS axons can regrow, BUT...

*Growth is impeded by negative elements in the environment* - Clean up is slow - myelin proteins (NOGO, MAG, OMGP) increase - inhibitory proteoglycans increase *Intracellular growth factors such as GAP-43* (important for intracellular signaling/growth cone advance) *are low* - growth factors have different distributions compared to young brain - normally growth-supporting extracellular matrix (laminin) is sparse

sensitization

*Increased response to 1 stimulus that is consistently preceded by a noxious stimulus* - Strengthening of responses to potentially injurious stimuli - recognized as a short-term memory response, but reflects structural changes in these cells.

how does an axon find its way?

*chemotaxis* 2 forms: - chemoattraction - chemorepulsion

the mechanisms involved in experience-dependent plasticity depends on what 2 things?

*type of synapse & location involved*

list some things that help CNS axons regrow

- *neurotrophins* (ex: increase cAMP levels to prime neurons to ignore myelin-inhibitors) - re-express "youth" proteins (ex: GAP-43)

describe the experience-dependent plasticity process

- During the *initial phases of motor learning*, large and diffuse regions of the brain are active. -When *tasks are repeated*, the number of active regions in the brain are reduced. --> more effective process - When a *motor task is learned*, only small, distinct regions of the brain show an increased activity when performing the task. --> optimized recruitment of neural system.

motor learning vs motor adaptation

- Motor learning is more structural long-term changes... - motor adaptation has more changes of route of signal processing, and shor-term changes performance.

after an initial ischemic insult, excessive intracellular Ca2+ concentrations result in 3 pathways of cellular destruction: - - -

- increased glycolysis - increased intracellular water - activated protein enzymes

silent synapse

- refers to a synaptic contact between two neurons where a presynaptic action potential fails to evoke a detectable postsynaptic signal. - A synapse can be presynaptically silent if the action potential invading the presynaptic bouton or terminal fails to evoke release of neurotransmitter.

describe the differentiation of neural stem cells during neurogenesis

- some stem cells become glial cells **only a small % actually become neurons** HALF of them die off

synaptic changes following injury to an axon in the CNS include the following: - - - -

- synaptic effectiveness - denervation hypersensitivity - hypereffectiveness - unmasking of silent synapses

the extent of deficits following axonal injury depends on what?

- the degree of damage to white fiber tracts in the spinal cord - vertebral level of the injury

2 main types of plasticity in learning and memory formation

1) long term potentiation.. or 2) long term depression.. of excitatory glutamatergic synapses

nerve injury grades

1) neuropraxia 2) axonotmesis 3) 4) NIC-neuroma in continuity 5) neurotmesis 6) mixed injury (1-5)

what occurs immediately (within minutes) after neuronal injury

1) synaptic transmission turned off 2) *cut ends pull apart and seal up, and swell*, due to axonal transport in both directions

10 Principles of Experience-Dependent Plasticity

1. Use it or lose it 2. Use it and improve it 3. Specificity 4. Repetition matters 5. Intensity matters 6. Time matters 7. Salience matters 8. Age matters 9. Transference 10. Interference

what occurs within hours of a neuronal injury

3) *synaptic terminal degenerates* - accumulation of neurons-filaments, vesicles 4) *astro-glial cells surround terminal* normally; after axotomy, astroglia interpose btwn terminal and target and cause terminal to be pulled away from postsynaptic cell

what occurs within days/weeks of neuronal injury

5) *myelin breaks up and leaves debris* (myelin is hard to break down) 6) *axon undergoes Wallerian degeneration* 7) *chromatolysis*

chemoaffinity hypothesis

= *Proposal that neurons or their axons and dendrites are drawn toward a signaling chemical/ molecular marker that indicates the correct pathway.* Note: - axons reach their targets in a series of discrete steps - diff cells respond to the same guidance cues differently - chemical cues exist at multiple point along the axon guidance pathways

habituation

= *decrease in response to a repeated, benign stimulus* - Reduction in the amplitude of synaptic potentials (ESPS) produced by the sensory neuron on the interneuron and motor neuron. - One of the simplest forms of neuroplasticity. - Cellular mechanisms that are responsible for habituation are not completely understood.

define neuroplasticity

= *the ability of neurons to change their function, chemical profile* (amount and types of neurotransmitters produced), *or structure* forming neuronal connections in response to info derived from experiences in the environment, sensory stimulation, and normal development

Denervation Hypersensitivity

= sharp increase of sensitivity of post-synaptic membranes to a chemical transmitter after denervation. It is a compensatory change. - occurs when presynaptic axon terminals are destroyed and new receptor sites develop on the postsynaptic membrane in response to the reduction in neurotransmitter released. When neurotransmitters are released from other nearby axons, an increased or hypersensitive response occurs owing to the additional receptor sites on the postsynaptic membrane

experience-dependent plasticity

= the process through which neural connections are created and reorganized throughout life as a function of an individual's experiences - a complex process involving persistent, long-lasting changes in the strength of synapses between neurons and in neural networks

growth cone

A distinctive structure at the growing end of most axons. It is the site where new material is added to the axon.

proteoglycans

A glycoprotein in the extracellular matrix of animal cells, rich in carbohydrate *make up the "filler" substance btwn cells*

neurapraxia

An injury to a nerve that results in temporary neurologic deficits followed by a complete recovery of function. mildest level of injury

true or false? many of the same mechanisms responsible for brain plasticity during learning are involved in recovery period following neuronal injury.

TRUE!!!

axonotmesis

The axons and their myelin sheath are damaged in this kind of injury, but the endoneurium, perineurium and epineurium remain intact. recovery = full (grade 2) -- slow/incomplete (grade 3)

NMDA

Type of receptor site for Glutamate that is difficult to stimulate, and often requires AMPA to first hypo-polarize cell N-methyl-D-aspartate

AMPA

Type of receptor site for glutamate that is ionotropic and easy to stimulate

unmasking (disinhibition) of a silent synapse

When a synapse is silent, only NMDA receptors are present on the postsynaptic membrane (and NMDA receptors only change activity **within the neuron.) -> synaptic transmission does not usually occur The *synapse becomes unmasked when AMPA receptors move into the postsynaptic membrane and the synapse becomes active.*

neuroplasticity was introduced by what american psychologist and philosopher

William james (1842-1910) -> brain functions are not fixed throughout life

is neural development plasticity?

YEP!

can excessively vigorous rehab of motor function too soon after a stroke/injury be counterproductive?

YES!

collateral sprouting

a denervated neuron attracts side sprouts from nearby undamaged axons

long-term depression (LTD)

a long-term decrease in the excitability of a neuron to a particular synaptic input caused by stimulation of the terminal button while the postsynaptic membrane is hyperpolarized or only slightly depolarized • mobile AMPA receptors are removed from the postsynaptic membrane, making the postsynaptic membrane less likely to be depolarized when glutamate is released from the presynaptic neuron.

Neuroma-in-continuity (NIC)

a neuroma that results from failure of the regenerating nerve growth cone to reach peripheral targets. It occurs within an intact nerve in response to internally damaged fascicles, resulting in a distal portion of the nerve that no longer functions properly. recovery = poor to none grade 4

NMDA receptor

a specialized ionotropic glutamate receptor that controls a calcium channel that is normally blocked by Mg2+ ions; involved in long-term potentiation The NMDA receptor is unique, because to open the ion channel, glutamate must be bound to the receptor and the membrane must depolarize simultaneously. Thus the NMDA receptor is both voltage- and ligand-gated.

long-term potentiation (LTP)

an increase in a synapse's firing potential after brief, rapid stimulation. Believed to be a neural basis for learning and memory • repetition of a pattern of successful firing triggers additional chemical changes that lead, in time, to an increase in the number of receptor channels associated with successful synapses - the requisite structural change for long term memory.

what type of channels are the key mechanism involved in hebb's rule

calcium channels

chromatolysis

cell body swells nissl bodies break down

scientist discovered the synapse

charles sherrington

when an axon in the PNS or CNS is severed, the part connected to the cell body is referred to as the _____________ segment and the part isolated from the cell body is called the __________ distal segment

connected to cell body = *proximal* segment other end = *distal* segment

is damage to the nervous system considered plasticity? what about the recovery of the NS?

damage -- NO recovery -- YES!!

although axonal tearing and breakage occurs following SCI or TBI, most of the damage evolves when after the initial injury? owing to a cascade of cellular events

damage evolves *hours and days* following initial injury

is PT/OT techniques and exercises intended to increase or decrease the neural response to a stimulus

decrease

injuries that damage or sever axons cause __________________, but may not result in cell death bc *some neurons have the ability to regenerate the axon!*

degeneration

wallerian degeneration

degeneration of a nerve distal to an injury

who came up with the idea of synaptic plasticity?

donald hebb

Nerve Layers

epineurium, perineurium, endoneurium

lamellipodia

flat, sheetlike extensions from the core of growth cones located between the filopodia

define plasticity

from greek "plastos" *= the ability to be molded/shaped*

communication between *astrocytes and neurons* occur via the release of a neurotransmitter by the neuron that stimulates the release of _________________________ by the astrocyte

gliotransmitters

sprouting

growth of a new branch of an intact axon or the regrowth of damaged axon

Chemoattraction

growth of axons towards sources of diffusible attractive molecules = the process whereby a cell detects a chemical gradient of a ligand, called *chemoattractant* and, as a consequence, gets oriented and subsequently moves in the direction from a low to a high concentration of the chemoattractant

GAP-43

has been termed a 'growth' or 'plasticity' protein because it is expressed at high levels in neuronal growth cones during development, during axonal regeneration and is phosphorylated after long-term potentiation (LTP) and after learning (reference needed). This protein is considered a crucial component of the axon and presynaptic terminal, its null mutation leading to death within days after birth due to axon pathfinding defects.

scientist discovered neurotransmission, and ACh and its role

henry dale

how long after an injury can damage evolve following the initial injury due to a cascade of cellular events

hours and days

injury to what part of a neuron will lead to cell death?

injury that destroys the cell body

• In studies performed in the late 1800s, the pioneering neuroscientist Charles Sherrington observed that certain reflexive behaviors, including withdrawing a limb from a mildly painful stimulus, ceased after several repetitions of the same stimulus.

just a fun fact :)

_______ _______ ______________ is the biological basis of hebb's rule

long term potentiation (LTP)

is immediate changes in behavior considered plasticity?

mm YES and NO

gliotransmitters

modulate neuronal activity and synaptic transmission

neurotmesis

most severe grade of injury to a peripheral nerve. all components are damaged and irreversible. all motor and sensory loss is permanently impaired. grade 5

describe neurogenesis in the adult brain?

neurogenesis in adults is **limited thought to occur in the hippocampus - involved in long-term memory

hebb's rule

neurons that fire together wire together fire apart, wire apart

does functional axon regeneration occur in the CNS axons?

no

neurogenesis largely occurs when?

occurs mostly in the developing brain (as kids grow up)

synaptic hypereffectiveness

occurs when only some branches of a presynaptic axon are destroyed. The remaining axon branches receive all of the neurotransmitter that would normally be shared among the terminals, resulting in the release of larger than normal amounts of transmitter onto postsynaptic receptors.

neural migration

process whereby neurons extend from their place of birth to connect to far reaching areas of the brain.

damaged neurons must form growth cones and assemble axons by overcoming the hostile CNS environment. once the axons are assembled, axons need to be ______________ for proper functioning and signaling within the nervous system

re-myelinated

Recovery of Synaptic Effectiveness

return to normal cellular function after edema that interfered with action potential conduction has resolved

• Researchers map functional areas of the cerebral cortex by recording neuron activity in response to sensory stimulation or during active muscle contractions. - Cortical maps can be modified by what? - Cortical plasticity and reorganization are likely mechanisms driving functional recovery after a stroke; how long does reorganization take?

sensory input, experience, learning, and brain injury. reorganization can take years

_________ cells may provide another method of treating white matter injuries such as SCI and demyelinating diseases such as MS

stem cells

Neurotrophins

support the growth, survival, and differentiation of both developing and mature neurons

neurogenesis

the formation of new neurons stem cells are involved

regenerative sprouting

the injured axon issues side sprouts to form new synapses with undamaged neurons.

the recovery and neuronal function after brain injury is influenced by what factors of rehab, relative to the injury

the intensity and timing of rehab! -> early rehab is necessary for improved outcomes prolonged inactivity following cortical injury may lead to subsequent loss of function in adjacent, damaged regions of the brain!!!

Excitotoxicity

the property by which neurons die when overstimulated, as with large amounts of glutamate

describe how astrocytes likely influence synaptic plasticity

through modulating neurotransmitter release and receptor expression at the postsynaptic membrane

True or false? cerebral cortex Reorganization after a nerve injury may be a factor in some chronic pain syndromes.

true

true or false? - different forms of LTP and LTD can occur simultaneously, depending on the type and location of the synapse

true

true or false? - in addition to the damaged neuron, the pre and postsynaptic neurons around it are also damaged

true

true or false? - the same processes that follow a peripheral axonal injury also occurs following a spinal cord injury

true

true or false? - there are drugs currently in development that block the effects of NOGO and other growth inhibitors and could become useful in CNS recovery

true

true or false? - when a neuron dies, the NS promotes recovery by altering specific synapses

true

true or false? during the development of the cortical layers, nuclei/cells move up and down according to their cell cycle phase

true

true or false? • Some types of rehabilitation are beneficial even if initiated during the chronic stage post stroke, because plasticity can occur with rehabilitation after months or years following neurologic injury.

true

true or false? - both habituation and sensitization can happen at the same time

true and in the same place or diff place --> = *re-organization of structure*

true or false? - astrocytes play a critical role in brain and spinal cord plasticity

true may also be important for new synapse formation following stroke

true or false? neuroplasticity is a general term used to encompass the following mechanisms: - habituation/sensitization - experience-dependent plasticity; learning and memory - cellular recovery after injury

true!!

chemorepulsion

turning or directing of axons away from sources of diffusible repulsive molecules

filopodia

very fine, tubular outgrowths from the growth cone also how neurons find each other assist in neuron migration

Principles of Experience-Dependent Plasticity - describe the *"use it or lose it"* principle

• Failure to drive specific brain functions can lead to functional degradation.

Principles of Experience-Dependent Plasticity - describe the *"use it and improve it"* principle

• Training that drives a specific brain function can lead to an enhancement of that function.