Psych 261 Midterm 2

Neuroplasticity

Modification of the tissues of the brain throughout the lifespan

Neurogenesis

Formation of new neurons in the NS

Neurogenesis Locations

1) Subventricular zone by the lateral ventricles

2) Denate gyrus of the hippocampus

3) Striatum (likely via. adjacent subventricular zone)

Neurogenesis Process in the denate gyrus of the hippocampus

Type 1 Radial Stem Cells (astrocytes) divide

Type 2 Non-Radial Stem Cells formed

Type 2 cells multiply and give rise to immature neurons

Immature neurons differentiate to form mature neurons that are integrated into the neural architecture

% turnover + # of neurons generated in the adult hippocampus

1.75% turnover (~700)

Neurogenesis Process in the subventricular zone by the lateral ventricles

Ependymal cells form the ventricular zone.

Beside the ependymal cells, there are 3 types of cells (B, C, A)

Type B cells (astrocyte) can self-renew and also give rise to Type C cell

Type C cells are proliferative precursors that form type A cells which are new neurons.

Difference & similarity b/w neurogenesis in denate gyrus vs. SVZ

1st step for both involves glia

DG - Type 2 non-radial stem cells (2nd step) can either multiply or give rise to immature neurons

SVZ - Type B (astrocyte) (1st step) can self-renew or give rise to neurons

Where do type A cells (neurons) go after being formed in the SVZ

In rodents & other mammals, Astrocytes bundle up the new neurons and migrate them to the olfactory bulb via the rostral migratory stream

In humans, they make their way to areas close to the SVZ, such as the striatum.

Evidence that neurogenesis occurs in the SVZ in humans

Astrocytes w/ neural stem cell characteristics identified

SVZ has the ability to produce neuroblasts (stem cells)

3 Ways to increase neural plasticity

Exercise

Diet
Learning

How does exercise influence neural plasticity

Increases neurogenesis + growth/complexity of existing neurons by triggering the release of brain-derived neurotrophic factor(BDNF)

Brain-derived neurotrophic factor (BDNF) functions (4) + how is it transported

Major neuron growth molecule (supports the growth of neurons and synapses)

• Transported retrogradely & anterogradely

Potentiates synaptic transmission

Involved in gene transcription

Modifies synaptic morphology

Enhances neuronal resilience

(PIME)

What happens when BDNF binds to their TrkB receptors?

Presynaptically - Modify transmitter release

Postsynaptically - Modify postsynaptic sensitivity (ex. w/ NMDA receptors)

What does exercise enhance in addition to neural plasticity?

Cognitive performance (executive control, controlled processing, visuo-spatial ability, response speed)

(EC VR)

Does decreasing your energy intake increase neuronal growth?

Yes.

mRNA for growth factors of BDNF increased w/ energy intake reduction. Additionally, higher neurogenesis is observed.

Dietary restriction increases (4)

Neurotrophins (ex. BDNF), antioxidants, removal of damaged molecules, and reduction of inflammation/oxidative stress

(NADIO)

What phenomenon allows dietary restriction to have positive effects?

Hormesis/preconditioning - exposure of cells/organisms to a mild stress results in adaptive responses that protect against more severe stress

(think of going to the gym - body builds back stronger after a stressor)

Types of dietary protocols (4) & which are the most effective?

Western (3 large meals w/ snacks interspersed)

Caloric restriction (CR) (eating smaller meals - cutting caloric intake by ~30%)

Time Restricted Feeding (TRF) (eating a normal amount, but restricting that to a 4-8 hour period)

Intermittent Energy Restriction (IER) (interspersing days of normal eating w/ days of energy restriction)

• Beneficial effects on the brain even when the overall # of calories remains the same as a normal diet (TRF/IER)

Including periods of fasting might have greater benefits than simply reducing caloric intake.

HFS vs LFCC diets influence on brain plasticity

(High saturated fat/refined sugar vs low saturated fat + complex carb)

Inc BDNF & performance

What brain change occurred when squirrel monkeys trained a dexterous grasping task?

The motor cortex finger‑representation area enlarged after ~12 days of training.

What neural changes occur after 3 months of juggling training?

Increased gray matter in the left posterior intraparietal sulcus and mid‑temporal motion‑processing areas.

How does long‑term violin training change somatosensory cortex?

Enlarged representation of LEFT‑hand digits in RIGHT S1 (the hand used).

Stroke/cerebrovascular accident def’n

Disruption of normal blood delivery to brain tissue

Two types of strokes & which is more common

Ischemic (more common) & Hemorrhagic (10-20%)

Ischemic strokes

Arteries/capillaries blocked by either:
Floating debris

Buildup of material inside the blood vessels

Constriction of the blood vessels

Prevents nutrients from getting to brain cells, ultimately resulting in death of the cells in the region supplied by the blocked blood vessels.

Hemorrhagic strokes

a.k.a Intracerebral hemorrhage (ICH)

Involves a RUPTURE of a blood vessel in the brain

Occurs due to either a traumatic brain injury or other factors, including high blood pressure.

Severity depends on the amount of blood lost. (>150 mL) results in blood pressure in cerebral vessels that is insufficient to supply the remainder of the brain, leading to death.

Hematoma

A large blood mass in the brain, which can put pressure on critical parts of the brain, can lead to death (just as blood loss from the arteries/capillaries can at the same time).

What % of hemorrhagic strokes result in death soon after

40%

Death caused by ischemic stroke reason

Exitotoxicity - over-activity of nutrient-starved cells

Exitotoxicity mechanisms mechanism #1

Cerebral blood flow drops b/w critical lvl
Energy demands outweigh nutrient availability

Energy-dependent ion channels (ex. Na+/k+ pump) work less efficiently, causing Na+ buildup in the cells

Cells are depolarized and inc NT release into the synaptic cleft

Exitotoxicity mechanisms mechanism #2

Astrocyte (involved in tripartite synapse) have transporter proteins (some are also present on neurons) responsible for clearing glutamate

As the levels of glutamate increase - they can’t keep up

Additionally, transporters begin to malfunction & can even reverse (ejecting more glutamate into the synaptic cleft) as a result of insufficient energy supply

Exitotoxicity mechanisms mechanism #3

An increase in glutamate - even 100x (caused by inc Na+ in cells & less being cleared by transporters on astrocytes) leads to more positive ion influx into local cells

Furthers the problem - even more glutamate is release

Glutamate receptors let what ions into the cell - what effect does this have?

In addition to Na+, NMDA receptors allow Ca2+ into the cell (glutamate gated calcium channels)

Calcium enters in large amounts due to excess stimulation of these receptors (from elevated lvls of glutamate)

Impact of excess calcium influx on cells

Impairs mitochondrial function, disrupting the production of ATP

Further compromising energy supply to active mechanisms (ex. Na+/K+ pump)

A series of chemical reactions occur that lead to the production dangerous free radicals such as nitric oxide (NO), which causes dmg to nearby cells

Problematic roles of nitric oxide (3)

Destroy organelles inside the cell (ex. proteins, nucleic acids, and liquid membranes)

Triggers more glutamate release

Precursor to a molecule involved in triggering apoptosis

Main NT of interest in stroke pathology

Glutamate (excitatory)

Cytotoxic Edema Mechanism & Impact

Positive ions accumulate in BOTH neurons & glia - water is osmotically drawn in from extracellular regions. Leads to swelling.

Disrupts protein function & physically stresses cells

Ultimate result of ischemic stroke (2)

Necrosis - ishcemic cells rupture, spilling their contents into intercellular space.

Apoptosis - dissolution of the contents of the cell

Necrosis seems to occur first

Summary of the effects of ischemic stroke

Decreased nutrient supply

Increased Na+ in cell

Increased glutamate release (due to elevated Na+ & astrocyte transporters being overwhelmed by glutamate to pick up & reversing when they do not have sufficient nutrient supply)

Calcium lvls elevate as glutamate binds to NMDA receptors (which allow Na+ to enter the cell but also calcium when there is sufficient glutamate)

Calcium results in NO (free radicals) - which destroy organelles, release more glutamate, & release precursors to apoptosis.

Ultimately necrosis &/or apoptosis

Hemorrhagic Stroke Additional Counterintuitive mechanisms

Blood pools outside of the ruptured blood vessels, creating a hematoma which mechanically puts pressure on the surrounding cells, disrupting their function.

Lower blood flow in the surviving arteries leads to similar events seem w/ ischemic stroke

Can cytotoxic edema be caused by both ischemic & hemorrhagic strokes?

Yes

Dmg from a hematoma as well as ischemia caused by vasoconstriction can lead to cytotoxic edema

What enzyme does a hemorrhage produce - why & what effects does this have

Surrounding cells produce thrombin (criticial to clotting)

Helps stop bleeds via coagulation

High concentrations - make NMDA more responsive to glutamate, leading to excitotoxicity - often can cause apoptosis in glia + neurons

Thrombin triggers inflammatory responses from microglia, release pro-inflammatory markers & free radicals

Cell Dmg as a result of hemorrhagic stroke (from hematomes)

The immune system (microglia) considers blood spill an invader - inadvertently damaging local brain cells

Iron is released from hemoglobin from RBCs - creates free radicals that cause oxidative stress, damaging surrounding tissue

Plasma flows into interstitial space, causing vasogenic edema (water enters), putting further pressure on the cells, disrupting their function

Traumatic Brain Injury Unifying Factor

Brain dmg results from external forces (direct impact, rapid acceleration/deceleration, penetrating objects, blast waves, etc.)

The nature/intensity/direction/duration determine the dmg

Which type of TBI is most common w/ athletes & effect(2)

Impact deceleration injuries (head is moving and come into contact w/ stationary object)

Results in coup or countercoup (dmg is site directly adjacent to point of impact - skull is driven into brain OR dmg is on the opp side of the head where the brain and skull again make contact on the rebound)

Impact to the head Primary Damage (3)

Hematoma formation in the cerebrum or around the meninges

Contusion (local area of brusing involving small tears in blood vessels)

Diffuse axonal injury from general axonal shearing

Lead to various lvls of ischemia b/c of impaired blood flow caused by the injury

Primary Damage from TBI effect

PD (causes ischemia) - Contributes to swelling (edema).

Cytotoxic edema and/or vasogenic edema

Locally or throughout (diffuse traumatic brain edema) the brain

Swelling inc intracranial pressure & dec cerebral perfusion pressure, inc the likelihood of ischemia (reduced nutrient availability)

Ischemia, swelling, & bleeding big 3 effects

Inflammation

Exitotoxicity

Oxidative Dmg

Brain dmg associated w/ an acute traumatic brain injury is referred to as a

Concussion

Symptoms - headache, nausea, dizziness, and memory/attention problems (DHMAN)

May resolve w/i a week or two

Chronic traumatic brain injury Cause & Effect

Repeated impacts to the head

Associated w/ Alzheimer’s, Parkinsons, mood disturbances (impulsiviiy), and impaired cognition (memory/attention) (AP MC)

Dmg can effect cytoarchitecture of neurons, cerebral blood loss, and white matter atrophy

Following focal damage caused by an ischemic stroke, what occurs?

Necrotic (dead) tissue in the main area of the dmg is surrounded by a penumbra of live, but struggling cells.

Denervation - Cells in the penumbra that were connected to now dead cells lose axonal input

Spine collapse - dendrites of survive cells shrink b/c there is reduced input

What immediately happens to the surviving cells follow an ischemic stroke?

Decreased activity

Axons that are damaged by the stroke are prevented from re-growing by inhibitory signals

Spontaneous Recovery: Initial Events

Weeks 1-4 post-stroke

Brain kicks in adaptive plasticity mechanisms -

Considerable synaptogenesis

• Dendritic spines reappear (potentially in diff locations/shapes)

• Local axons begin to sprout axon collaterals that connect to denervated dendritic regions (even long-range axons)

Inc growth factors (ex. BNDF) - upregulated

Inhibitory GABA receptor activity dec

Excitatory NMDA receptor activity inc

Spontaneous Recovery: Network Reorganization

Weeks 4-8 post-stroke

Reorganization of cortical networks is already underway.

Network Reorganization Example (stroke to part of the somatosensory cortex previously represented by the forelimb)

Initial Effects & 1-4 weeks after

Some of the neurons representing the forelimb die + the surviving tissue is affected by dendritic spine collapse and less efficient neuronal functioning

One to four weeks after the stroke, more neurons are responsive to both fore- and hind-limbs.

• Increased growth factors, dendritic spine remodeling & axonal spouting, and excitability. Reduced sensory specificity.

• Increase in connections b/w the various limb regions of the somatosensory cortex.

Network Reorganization Example (stroke to part of the somatosensory cortex previously represented by the forelimb)

4-8 weeks after

A drop in the number of neurons responding to both limbs

Region of the cortex responsive to forelimb has expanded and taken over some of the territory of the hindlimb

Topographic reorganization of the somatosensory cortex after a stroke

Large Scale Network Reorganization

It can cross hemispheres

For example, people who experience a stroke to their subcortical motor pathway in one hemisphere might end up with increased connectivity between the ipsilesional motor areas and the motor areas in contralesional hemisphere.

At the same time they might show reduced connectivity between the thalamus of the ipselisional hemisphere and motor areas in the contralesional hemispheres.

Connectional Diaschisis

The reduced connectivity among areas distant from a stroke (that is beyond the penumbra)

Functional Diaschisis

Some brain areas further away from the stroke focal point might experience less activity in response to a stimulus or when they are involved in a given behavior.

Diaschisis General Meaning

Reduced activity in or reduced connectivity with areas that are relatively distant from the focal lesion, that is, those that are beyond the penumbral region.

Reorganization as a result of deprived input occurs when?

Somatosensory cortex/motor areas may be derived of their regular input.

May involve the loss of a limb)

Phantom Limb Syndrome

Continued sensations coming from the lost limb

Feeling like the limb is touched is rare - pain is common

Phantom Pain Mechanisms

Peripheral - injured nerve endings, altered activity in the dorsal root ganglion (contains sensory nerve bodies)

Can also occur due to the reorganization of the sensory & motor areas of cortex.

Ex. When amputees with phantom limb pain move their lips, activity appears not only in the face area of the motor and somatosensory cortex but also in the cortical region that previously represented the now‑amputated hand, showing expansion of the lip area into denervated hand territory. Brain doesn’t know that the sensations are now coming from the face and not the hand.

(amputees without phantom limb pain do not show activation of the hand area when moving their lips)

Spontaneous Recovery: Neurogenesis & Gliogenesis

In addition to network reorganization, the mammalian brain attempts to recover function after a brain injury by increasing the production of new cell

In rodent models of stroke, the source of new neurons that migrate to ischemic brain areas appears to be the subventricular zone.

One possibility is that newborn neurons migrate from elsewhere (such as the subventricular zone), using blood vessels as scaffolds for migration or as destination markers. Alternatively, these neurons could arise locally,

Neurogenesis after TBI

Neurogenesis mainly occurs in the peri-damaged brain regions after TBI in humans. However, it remains unclear whether these cells are born locally or from neurogenic regions.

Drug Therapies

Might mitigate the damage associated with brain injury and to speed recovery.

Would have to consider the timeline of brain injury and spontaneous recovery

(during and right after the injury, it would be helpful if the patient could take a drug that reduces neuronal overactivity. In contrast, after the initial damage, the problem is one of underactivity of the remaining neurons. Thus, some time after the injury, it would be useful to have a drug that increased the activity of underactive neurons.)

Injury = acute hyperactivity → you’d want to calm neurons.

Damage = chronic underactivity → you’d want to boost neurons.

The one drug therapy that has been shown to be useful

Ued as an early intervention during ischemic strokes

Tissue plasminogen activator (tPA) . . . tPA works by dissolving the clot and improving blood flow to the part of the brain being deprived of blood flow.

Administer w/i 3hrs

Training-Induced Recovery

Deficits associated with brain-injury can be ameliorated for up to a year post injury by applying rehabilitative training technique

Enriched environment and training induced dendritic growth in the spared tissue.

Stem Cell Therapy

Involves the introduction of stem cells into the post-stroke brain

• Shown to improve behavior and brain function

Stem cells from monkey embryos, intravenous injection from bone marrow stem cells… lead to formation of new glia & neurons.

Intravenous injection of peoples’ own bone marrow stem cells (harvested under local anesthesia) led to better recovery after ischemic strokes when compared to control stroke patients who did not receive the treatment.

Brain Stimulation For Motor Recovery Post-Stroke

After stroke, motor cortex activity becomes imbalanced across hemispheres: the lesioned hemisphere is underactive while the contralesional hemisphere over‑inhibits it.

Anodal tDCS over the lesioned motor cortex boosts activity and promotes neural growth, while rTMS or cathodal tDCS over the contralesional cortex reduces its over‑inhibition, allowing the damaged hemisphere to regain function.