Midterm - Review Flashcards
Necrosis
Premature cell death where cells rupture, spilling their content into extracellular space
Results in inflammatory response
Apoptosis
Programmed cell death
Cells are dismantled into membrane-bound vesicles
‘Cell Suicide’
Traumatic Brain Injury
ABI which includes on damage to the brain caused by an external mechanical force
Cause of TBI
When a blow to the head is sufficiently forceful the CSF is unable to protect the brain resulting with a collision of the brain and skull
Coup TBI
Brain collides with skull on same side of impact
Contrecoup TBI
Brain collides with skull on opposite side of impact
TBI severity depends mostly on degree of _______
Rotational Force - skull rotates and brain is to slow to catch up
Can result in sheared corpus callosum or torn bridging veins
Site of Contact with skull in TBI
Swelling (edema) or Bleeding (hematome) which can lead to Intracranial Pressure (ICP)
Necrotic Death due to direct impat (causing cells to rupture)
Generalized Damage in TBI
Possible infection from penetration or open trauma
Diffuse injury throughout brain due to different density of white and gray matter
Diffuse Axonal Injury (DAI) - twisting and shearing forces cause axon to be torn from cell body (axotomy)
Energy Crisis faced in TBI
Disrupted blood flow leads to:
Lack of Oxygen (hypoxia) - causes switch to anaerobic metabolism which leads to overproduction of lactic acid (acidosis) which damages BBB
Lack of Glucose (Hypoglycemia) - leads to cognitive deficits and further reduction in ATP production
Excitotoxicity
Excess Glutamate
Glu continously binds to and activates post-synaptic receptors leading to Ca2+ influx, resulting in depolarization, Ca2+ get sequestered in Mitochondria which disrupts production of ATP
Causes of Excitotoxicity
TBI - Necrosis (Excess Glu due to rupturing cells)
Stroke - Neuronal Depolarization
HD & ALS - Decreased Glu reuptake
AD - Due to Atrophy
Immune Activation in TBI
Microglia secrete pro-inflammatory cytokines
Environmental stress increased toxic Reactive Oxygen Species (ROS) production which leads to Oxidative Stress
Oxidative Stress
Result of = ROS > AntiOX
Immune Privilege
Sites of body able to tolerate introduction of foreign substances without eliciting inflammatory response
Brain is NOT immune privileged due to interaction with peripheral immune system
Concussion
Mild TBI - a head injury with a temporary loss of brain function
- Upper brainstem & RAS* - Alterations of consciousness
- Corpus Callosum & Ant. Commissure* - Altered neurological function
- Vascular Injuries* - Headache, dizziness, fatigue
- Hippo. & Frontal Lobe* - memory, attention, concentration
- Amyg. & Basal Forebrain* - mood and emotion
Chronic Traumatic Encephalopathy (CTE)
Progressive degenerative disease found in an individual with a history of multiple concussions
Brain Changes: Decreased brain weight, enlarged ventricles, neuronal death, tau aggregates, beta-amyloid plaques
Symptoms: Memory impairment, erratic behavior, impulsivity, depression, suicidal thoughts
Neurocirculation
Brain’s blood supply comes from Common Carotid and Vertebral Arteries (form Circle of Willis)
Main arteries which rise to brain - ACA, MCA, PCA
Stroke
Interruption of blood flow to the brain
Ischemic Stroke
Blockage in blood vessels
Ischemia
Lack of blood flow to tissue or organ
Hemorrhagic Stroke
Rupture in blood vessels
Ataxia
Reuslt of Cerebellar stroke
Motor impairments, difficulty walking, balance and coordination problems
Brain’s Energy Supply
Brain relies on blood supply to get Glucose and Oxygen (energy supply)
What causes a stroke?
Narrowing of arteries in neck or brain (cholesterol deposits)
Genetic mutations which increase risk of hypercholesterolemia, damage blood vessel walls, or cause clotting disorders
Environmental/Experiental factors which increase inflammation of vessel walls (High BP, smoking, obesity, alcoholism)
Intracerebral Hemorrhagic Stroke
Blood vessel ruptures
Blood leaks into surrounding brain tissue and creates swelling (edema) and ICP
Necrosis
Causes: High BP and aging blood vessels
Subarachnoid Hemorrhage
Bleeding in subarachnoid space
Cause: Brain Aneurysm (blood-filled bulge in weakened blood vessel wall)
Prognosis not good - 40-50% mortality rate
Transient Ischemic Attack (TIA)
Mild Ischemic Stroke (Mini Stroke)
Similar to stroke - only lasts minutes-hours
Leads to more severe attack 15-30% of time
Could be adaptive (prepares brain for more severe attack)
Treatment - Anti-coagulants (blood thinners)
Core of Stroke
Area directly fed by occluded vessel
Less than 20% normal blood flow
Necrosis and Apoptosis
Penumbra of Stroke
Outskirts of lesion, receive blood flow from other vessels
20-40% of normal blood flow
Apoptosis - Ripple Effect
Stroke Necrosis
Lack of oxygen → switch to anaerobic glucose metabolism → Acidosis → decreased membrane permeability → Ions and water rush into cell → cells swell and rupture
Stroke Apoptosis
Lack of Glucose → no fuel for Na/K pumps → Cells Depolarize → flooding of Glu leads cells to initiate self-destruct
Damaged BBB in a Stroke
During Ischemia, epithelial cells are weakened (due to hypoxia and resulting acidosis) → during reperfusion peripheral immune cells can leak through and exacerbate immune response and inflammation
Increase Ca2+ in Stroke
Result of Neuronal depolarization
Triggers release of Glu
Excess Calcium results in production of ROS - as a result Mitochondria can’t deal with stress and release signals to induce apoptosis
Collateral Circulation
Blood flow through secondary pathways after the obstruction to the principle pathway occurs
Neuroplasticity
Ability of the brain to reorganize and form new connections
Neuroplasticity after a Stroke
Following neuronal death and removal of death tissue, nearby undamaged neurons can migrate to affected area and take over some lost functions
Regrowth after a stroke
Endogenous Repair:
Axonal sprouting - new connections from surviving neurons
Angiogenesis - vascular growth, restores flow of nutrients to affected area
DNA
Packaged into Chromosomes in the cell’s nucleus
Can be copied - which allows for cell division and reproduction
Genes
Segments of DNA that code for the production of specific proteins
(Recipes for proteins)
Chromatin
DNA + Histones
DNA gets wrapped around proteins called Histones
This controls activity - if a gene is needed DNA qill unfrul to expose segments of DNA that must be processed (to mRNA then to Protein)
Alleles
Variants (alternative forms) of a gene
Dominant - only need one to produce a phenotype
Recessive - need two to produce a phenotype
Epigenetics
Changes in gene expression related to experience
The environment can cause certain genes to be turned on or off by changing accessibility via epigenetic markers
Acetylation - On, loosen
Methylation - Off, tighten
Huntington’s Disease
Neurodegenerative genetic disorder
Follows autosomal-dominant pattern of inheritance
HD Gene located in Chromosome 4
Symptoms of HD
Motor - chorea, occular movements, clumsiness, dystonia, athetosis
Cognitive - restlessness, agitation, irritability, lack of concetration, memory problems
Emotional - depression, apathy, anti-social behaviors, aggression
Dystonia
Persistent and intermittent muscle contractions causing abnormal and repetitive movements or postures
HD symptoms later in disease
Bradykinesia, rigidity, difficult initiating and maintaining voluntary movement
Unable to function independently
Cognitive issues worsen - progressive dementia
HD Prognosis
Death within 15-20 years of symptom onset
Cause of HD
HD Gene codes for htt (huntingtin)
HD Gene has a section containing repeat of the codon CAG, when there are more than 40 repeats this results in mutant htt which leads to HD
CAG codes for AA Glutamine (Gln) - long stretches of Gln result in misfolding and toxic protein aggregates in cells
HD Pathology cause
Increased mhtt function + Loss of WThtt function = HD pathology
Where does neurodegeneration occur in HD?
Basal Ganglia: Striatum → Medium-Spiny Neurons (MSNs) of caudate nucleus and putamen
Cerebral Cortex → Pyramidal Projection Neurons + Neurons with projections to motor cortex and limbic structures
Mutant htt in HD
Mutant htt accumulates in the nucleus of neurons (this is correlated with length of CAG repeats)
How do mhtt aggregates form?
When mhtt is produced, cell knows this is an irregular protein and releases factors to cut these proteins and dispose → some fragments end up sticking together and creating protein aggregates
GABA and HD
Upregulated in early stages, followed by marked reduction
Increased upregulated GABA activity + dysfunctional Glu activity in corticostriatal circuit → disruption of integrative processes by MSNs
GABA may initially by upregulated to deal with excess Glu
Glutamate and HD
Evidence of excitotoxic neuronal death in HD brains
Increased Glu receptor stimulation → symptoms of HD
Excitotoxcity due to decreased reuptake of Glu
Upper Motor Neurons
Originate in either the motor cortex or brainstem → axons extend to synapse onto LMNs
Bring motor commands to LMNs
May act directly or through interneurons
Release Glutamate
Lower Motor Neurons
Originate in brainstem or spinal cord → axons leave CNS and synapse onto muscles
Receive signals from UMNs and bring messages to muscles
Can pass through spinal nervs (limbs and trunk) or cranial nerves (head and neck)
Release ACh at NMJ
Corticospinal Tract
UMNs from motor cortex → Spinal Cord
Control muscles of limbs and trunk
Most axons decussate at medulla
Corticobulbar Tract
UMNs from motor cortex → LMNs brainstem
Contols muscles of head and neck
Some decussate and some remain ipslilateral
Upper Motor Neuron Damage
Failure to inhibit LMNs
Without inhibition LMN keeps telling muscles to contract → sustained contraction → stiffness and rigifity of muscles (spasticity) and hypertonia
Hyperreflexia - increase in muscle stretch reflexes
No muscular atrophy
Damage to Lower Motor Neurons
Unable to tell muscle to start contracting
Result is no contraction of muscles → flaccidity, hypotonia, fasciculations (twitching)
Hyporeflexia - decrease in muscle stretch reflex
Muscle atrophy
Amyotrophic Lateral Sclerosis
Degeneration of upper and lower motor neurons controlling voluntary movements
Use it or lose it → muscles that do not get ussed will atrophy (waste away)
Muscles are NOT dying first → wires connecting brain to muscle are degenerating and muscles are receiving signals
ALS Symptoms
Weakness in arms (sporadic) and legs (familial) first
Eventually - loss of control of all voluntary muscles in arms, legs, trunk, neck, and head
ALS prognosis
Fatal
3 years - 50%
5 years - 80%
only 10% live longer than 8 years
Riluzole
Treatment for ALS which increases life expetancy 2-3 months
Slows loss of muscles by blocking sodium channels and decreasing glutamate
LMNs and UMNs in ALS
LMN degeneration → muscle atrophy and fasciculations
UMN degeneration → spasms, increased muscle tone, abnormal reflexes
Astrocytes in ALS
Release toxins which lead to motor neuronal death
Necroptosis (programmed necrosis)
Glutamate and ALS
Decreased Glu transporters → Excitotoxicity
Action Potential
- Depolarization
