BIPN 152 Midterm 3

covers part of LE 9 - not all of LE 13, (no DI slides were posted), MB review session info(?), MB practice questions (posted in Canvas Inbox)

ALS stands for… (& another name for it) which is a __ __ disease

• def. ALS

  • describe (1 w/ 2) (1)

• age of onset is __ to __ years, but can occur in people younger and older than this range

• it causes (2)

  • symptoms (4)

  • when symptoms begin in arms, is called __ onset; when first notice the mouth-related problems, is called __ onset

amyotrophic lateral sclerosis / Lou Gehrig’s disease, is a motor neuron disease

• is a chronic neurodegenerative disease that attacks upper & lower motor neurons (aka motor neurons in the motor cortex of brain and spinal cord or brainstem)

  • where attack of lower motor neurons:

    • attack of somatic motor neurons in SC will impair muscle control (of limbs)

    • attack of bulbar motor neurons in brainstem will impair speech & swallowing (by impairing oropharyngeal muscles)

  • where attack of upper motor neurons will affect the motor cortex

__

onset is 40-60 years

causes loss of muscle control & eventual paralysis

• muscles twitches & cramps

• tight and stiff muscles (aka spasticity)

• slurred and nasal speech

• difficulty chewing or swallowing

when symptoms begin in arms, is called limb onset; when first notice the mouth-related problems, is called bulbar onset

for ALS

t/f: bulbar onset ALS typically shows a poorer prognosis/result of survival (aka faster progression towards death) compared to limb onset ALS

__

most cases of ALS are __, but some are __

…

for familial ALS, most identified mutations occur in which 4 genes/proteins?

• which mutation of the 1 specific gene is focused on in class (b/c found in most ALS cases)?

  • approx. % found in sporadic vs. familial cases

  • describe (1)

  • how does it act/behave when it is a healthy vs. disease gene (1 / 1)?

    • what is interesting about this protein w/in disease genes?

___

although loss of normal protein function might contribute to ALS, the major factor that causes ALS and other neurodegenerative diseases is the (1), which is a __ __ of function

true

__

most cases of ALS are sporadic, but some are familial

…

for familial ALS, most identified mutations occur in the genes/proteins:

• C9orf72

• SOD1

• FUS

• TDP-43

TDP-43 mutation is found in most ALS cases

• 4% in familial, 1% in sporadic (where TDP-43 is likely made de novo)

• in ALS, TDP-43 gets mislocalized to the cytoplasm, instead of the nucleus which is where it normally is

• in health gene: TDP-43 acts as a RNA binding protein used in RNA processing

  • (^ is the normal function, and TDP-43 aggregates would be in the nucleus NOT cytoplasm)

• in disease gene: TDP-43 forms intracellular protein aggregates

  • (^ while is in cytoplasm b/c is a disease gene aka gene w/ TDP-43 mutation)

  • almost all patients have clumps/aggregates of TDP-43 in their motor neurons, including people who don’t have the TDP-43 mutation

___

although loss of normal protein function might contribute to ALS, the major factor that causes ALS and other neurodegenerative diseases is the aggregation of misfolded proteins, which is a toxic gain of function

---

remember that “aggregates” are accumulation/clumps of toxic misfolded proteins

def. LATE

__

t/f: LATE involves a different anatomical pattern/path for the spread of aggregate pathology compared to AD

• explain how (1)

• how will it affect normal vs. toxic function?

_

explain the hypothesis relating to spread and “seed” aggregates (1)

---

t/f: LATE dementia & ALS are different diseases, and are only related b/c they both involve TDP-43 pathology

is a type of dementia that involves the TDP-43 protein, NOT tau or amyloid

__

true

• TDP-43 is mislocalized from the nucleus → to the cytoplasm (as hyperphosphorylated TDP-43)

…

loses normal function (aka loses function as a RNA binding protein)

gains a toxic function (aka TDP-43 will aggregate)

__

TDP-43 pathology first occurs in a small subset of neurons BUT will spread progressively to other neurons via releasing seed aggregates & uptake

---

true

• LATE dementia & ALS are different diseases, and are only related b/c they both involve TDP-43 pathology

name 2 acute injuries to the brain

• def. acute vs. neurodegenerative

stroke & TBI (traumatic brain injury)

• ^ are acute injuries to the brain, where:

  • acute injuries have sudden/fast onset

  • vs. neurodegenerative disease that are chronic, long-lasting/slow, and progressive

def. stroke

• is one of the leading causes of (2)

• symptoms of stroke (5)

  • which 1 symptom is more common in hemorrhagic strokes?

def. infarct

__

loss of blood flow to the brain will deprive the brain of (2), which will form the __ source called (1)

__

name the 2 types of stroke

• def. each

• state how each stroke usually occurs (1 each)

• which type of stroke can cause swelling/edema? explain how ← but will also be explained in later flashcard

stroke — localized/focal loss of blood flow to the brain due to brain hemorrhage or vessel occlusion/blockage

• is one of the leading causes of death & long-term disability

• symptoms:

  • numbness or weakness of the face, arm, or leg ESPECIALLY unilaterally

  • trouble speaking or understanding words

  • vision problems

  • loss of balance & coordination

  • headache (more common in hemorrhagic strokes)

infarct — local area with dying or dead cell tissue, b/c lack of blood flow

__

loss of blood flow to the brain will deprive the brain of glucose & oxygen, which will form the energy source called ATP

____

ischemic stroke — localized loss of blood flow to the brain due to blocked blood vessel/vessel occlusion

• usually due to blood clots that get stuck in the vessel

• can cause swelling/edema

  • (b/c decrease of blood flow to the brain means less oxygen and glucose to the brain means less ATP is made, causing the cells in the vessel to have buildup of sodium → dep- → excess glutamate release into synaptic cleft → hyperactivation of NMDARs → excess Na and Ca influx into post- → excess Na brings in water & the cell swells)

    • ^ for buildup of intra- sodium b/c ATP power the Na/K pump to move sodium out of the cell

hemorrhagic stroke — localized loss of blood flow to the brain due to burst blood vessel

• usually due to high BP

what is the most common artery involved in strokes?

• this artery is involved in most (over half) of __ strokes

why is this artery the most common?

• explain the type of effects (1)

__

middle cerebral artery (MCA) is most common artery involved in strokes

• involved in most ischemic strokes

is the most common b/c the MCA supplies blood to a large area of the cortex, thalamus, and basal ganglia

• SO it has a wide range of symptoms depending on which branches/structures are affected

name the 2 categories of stroke risk factors (& def. each)

• state the risk factors in each category (4 ← describe / 5)

__

def. mini-strokes

• another name for it

• describe (1)

__

what does the “BE FAST” acronym for stroke stand for?

non-modifiable risk factors: ← can’t change its risk of causing strokes

• age (risk increases w/ age)

• sex (more young men than young women are affected, BUT young women w/ stroke have higher mortality)

• race (higher risk in POC)

• genetics (i.e. cardiovascular factors)

__

modifiable risk factors: ← can change the risk of causing stroke (either increase or decrease the risk)

• smoking

• alcohol consumption

• diet & obesity

• physical inactivity

• hypertension aka high BP

__________

mini-strokes / transient ischemic attack (TIA)

• the temporary loss of blood flow to the brain due to a blood clot that reverses itself w/in a day

are warning signs for stroke risk, where 1/3 of people who experience TIA will experience a stroke w/in a year

__

Balance (loss of balance, headache, dizziness)

Eyes (blurred vision)

Face (unilateral face drooping)

Arms (arm or leg weakness or numbness)

Speech (trouble speaking or understanding speech)

Time (to call ambulance)

for ischemic stroke

explain how the area impacted by the stroke grows AKA spatiotemporal expansion of the infarct

• minutes after the start of a stroke, will have a small infarct core surrounded by ischemic penumbra, where:

  • cells in the core will always die (← dead tissue, irreversible, death is via cell edema)

  • cells in the penumbra is only partially damaged AND can be rescued/saved IF intervention/treatment occurs w/in an early period of time before the core expands to include the penumbra

• over hours, the core will expand to encompass/include the penumbra

• days to weeks after the start of a stroke, the core takes over the penumbra completely, SO all the cells in the infarct will die

for ischemic stroke

term for blood vessel?

what is the term defined as emergency ischemic stroke treatment that aims to restore blood flow in the vessel?

• name the 2 approaches to this & briefly def. them

• describe each approach of this ischemic stroke treatment (3, each w/ 2-3 more / 1)

thrombus = blood clot

recanalization — emergency ischemic stroke treatment that aims to restore blood flow in the vessel

• thrombolysis — breaking apart blood clots

• thrombectomy — removing blood clots

__

thrombolysis

• ischemic stroke patients will receive tPA (tissue plasminogen activator) if:

  • diagnosed w/ ischemic stroke

  • is w/in 4.5 hours from the start of the (ischemic) stroke

• cannot receive tPA if:

  • diagnosed w/ hemorrhagic stroke

  • have high BP

  • had recent head trauma or head surgery

• 2 tPA treatments are:

  • Alteplase

  • Tenecteplase

__

thrombectomy ← done when the clot/thrombus is too large for tPA OR if after the 4.5 window

• insert stent into femoral artery (of thigh) that will move through blood vessels to get to the brain, where the stent will grab the thrombus/blood clot & pull it out

for ischemic stroke

b/c spatiotemporal expansion of the infarct occurs over time, what happens at early vs. later times? (← use a specific term for each & def. it)

state the 3 ~stages that occur over time

• describe 1 of them (1)

• in early time, neurons die via cytotoxic edema ← pathological cell swelling that is a type of necrotic cell death

  • (^ cytotoxic edema/swelling is what happens before the onset of necrosis)

• in later time, neurons die via apoptosis ← a type of programmed cell death

__

excessive infarct depolarization, where this excessive excitation will destroy neurons — called excitotoxicity (where cytotoxic edema & necrosis can occur)

→ inflammation

→ apoptosis

for ischemic stroke

explain cytotoxic edema, which occurs in the early stage after stroke (2)

explain how a normal cell/neuron can undergo either apoptosis or necrosis

• apoptosis is a __, __-__ process

__

t/f: cell death through apoptosis occurs throughout the body as a normal part of development; it also occurs in neurodegenerative diseases like AD

cytotoxic edema is seen as the swelling of organelles & forms membrane blebs, which are bulges in the membrane

cytotoxic edema makes the membrane leaky b/c the neuron loses control of membrane permeability (as seen w/ the membrane bleb)

__

if normal cells does apoptosis, then membrane blebs will form → then, the cell breaks apart into apoptotic bodies that are phagocytosed by microglia & astrocytes

• apoptosis does NOT cause inflammation

if normal cells does necrosis, then the cell swells → then, the plasma membrane bursts (lysis)

• necrosis causes inflammation

…

apoptosis is a controlled, energy-dependent process

• (^ energy-dependent meaning that apoptosis relies on ATP for energy)

__

true

for ischemic stroke

differences b/w necrosis & apoptosis, in terms of:

• affected cells are

• induced by

• inflammation or no inflammation

• effect on cytoplasm & nucleus or mitochondria

• effect on plasma membrane

• energy & passive or active

which one has a key feature of calcium overload?

necrosis (N), apoptosis (A)

• N affects groups of cells vs. A affects individual cells

  • (b/c N is uncontrolled, passive process, while A is controlled, energy-dependent (active) process)

• N is caused by pathogens/toxins vs. A is caused by physiological stimuli (i.e. development)

  • (b/c physiological events occur over time, like how N is a delayed process that occurs over/after longer period of time)

• N causes inflammation vs. A doesn’t

• N does swelling of cytoplasm + mitochondria/organelles vs. A does shrinking of cytoplasm (b/c breaks into apoptotic bodies) & condensation of nucleus

• N has ruptured membrane vs. A has membrane blebbing, where membrane is intact

• N doesn’t require energy / is passive vs. A is energy(ATP)-dependent / is active

N involves calcium overload

for ischemic stroke

t/f: a stroke triggers neuronal cell death

what are the immediate cellular changes after a stroke? (7)

the delayed cellular changes? (2)

true

__

immediate cellular changes:

• ATP depletion (b/c stroke is loss of blood)

• excess depolarization

• excess glutamate (b/c of excess dep-/excess excitation)

• increased intra- Ca2+

• get cytotoxic edema that causes necrosis is in the core

• get cytotoxic edema that does NOT cause immediate necrosis is in the penumbra

• make ROS (reactive oxygen species)

_

delayed cellular changes:

• inflammation

• apoptosis of the penumbra

for ischemic stroke

ischemia includes a __ of subcellular & transcellular events

state the general events above (~2/3 parts)

ischemia includes a cascade of subcellular & transcellular events (← ischemic cascade)

__

• excess Na+ and Ca2+ influx through NMDARs

• excess Ca2+ → causes mitochondrial damage → causes apoptosis, WHILE excess Na+ → causes excess depolarization & cell swelling/edema

for ischemic stroke

explain the immediate cellular effect after stroke: ATP depletion (2)

swelling is caused by (2), which (function ← 1)

• loss of blood flow to the brain will bring less glucose & oxygen to the brain, SO less of these 2 will makes less ATP (energy)

• the Na+/K+ pump uses a lot of ATP b/c the pump maintains the RMP by using ATP to move ions against their concentration gradient

…

swelling is caused by depolarization & excess Na+ influx, which brings water into the neuron

for ischemic stroke

explain the immediate cellular effect after stroke: excess depolarization (4)

dendritic beading is a sign of __ __

t/f: Excitatory networks are especially vulnerable during ischemia

__

explain the immediate cellular effect after stroke: excess glutamate (2)

• also contributes to excess intracellular __ (← step where get increased/excess intra- Ca2+)

• the core of the infarct experiences a loss of blood flow (and glucose + oxygen)

• core doesn’t make ATP so has no energy

• core will excessively dep- (aka excess excitation), which releases glutamate out of the core into the penumbra

• the penumbra triggers neighboring cells to dep- via dendritic beading, which might expand the infarct

^ called “spreading depolarization”

__

dendritic beading is a sign of cytotoxic edema/swelling

__

true

---

• glutamate buildups in the synaptic cleft faster than it can be removed

• so, glutamate spills over to the extrasynaptic NMDARs which are coupled up w/ death pathways

also contributes to excess intracellular calcium (← step where get increased/excess intra- Ca2+)

for ischemic stroke

how does excess intra- Ca2+ damage mitochondria?

__

t/f: healthy mitochondria always make ROS in small amounts, but impaired mitochondria makes too much

t/f: excess unregulated production of ROS are bad for the cell b/c it leads to cellular damage & many types of disease

__

what do ROS do? (2)

Ca2+ is stored in ER and mitochondria in order to maintain a certain level of cytoplasmic Ca2+, BUT mitochondria is easily overloaded by calcium

→ SO, get decreased membrane potential & formation of ROS (b/c mitochondria stop making ATP, which increases ROS production) ← where ROS damages proteins & lipids

__

true

true

__

ROS have unpaired electrons that react w/ proteins, lipids, and nucleic acids, which impairs their function

you can slightly improve their functions w/ diet via antioxidants, like vitamin C and E

for ischemic stroke

for the delayed cellular effects after stroke: inflammation & apoptosis of the penumbra

damaged mitochondria initiate __ cell death by releasing (1 ← def.)

• aka apoptosis is a __ form of cell death that is caused from (1)

_

(2 ← aka the 2 acute brain injuries mentioned) induce inflammation, which is triggered by BOTH (2)

• for 1 of the triggers, explain how it activates inflammation (~4 steps/parts)

• for the other trigger, explain how it controls inflammation:

  • BBB is part of the __ __ made of (3), whose signals will (1) in order to (1)

damaged mitochondria cause delayed cell death by releasing apoptotic factors/bodies (are proteins that trigger apoptosis)

• aka apoptosis is a delayed form of cell death that is caused from damaged mitochondria

^^ this specifically refers to apoptosis w/ ischemic stroke, while the ATP failure, excess Na and Ca, etc. refers to necrosis w/ ischemic stroke

_

stroke & TBI induce inflammation, which is triggered by BOTH injured neurons & damage to the BBB

(^ cytotoxic edema/cell swelling is injured neurons, rupturing of membrane is damage to BBB)

• injured neurons will release DAMPs (damage associated molecular patterns), which will bind to Rs of immune cells → activate signaling pathways (in immune cells) → immune cells release cytokines & chemokines → inflammation

  • specifically, sterile inflammation (is inflammation caused w/o pathogens)

• BBB is part of the neurovascular unit made of neurons, astrocytes, and pericytes, whose signals will control the diameter of blood vessels in the brain → in order to control rate of local blood flow

---

(pic shows that astrocytes make contact w/ astrocytes & neurons, so is like the “in-between” structure of the two)

def. TBI (& stands for what?)

• t/f: can appear w/o physical evidence

• symptoms are classified as (3)

• t/f: TBI and stroke have sim. cascades

concussion is a __ TBI

• describe (1)

__

def. CTE

• symptoms (3)

• affects __ __ of the neocortex, which progressively spreads

CTE is a __ (def. term)

• CTE tau tangles begin in __ __

• CTE tauopathy is prominent around __ __

• t/f: pattern of CTE tauopathy is distinct from other tauopathies

traumatic brain injury — is damage to the brain tissue caused by an external force

• true (i.e. whiplash)

• symptoms can be mild, moderate, or severe

• true

concussion is mild TBI

• usually have change in consciousness (i.e. disoriented, feeling dazed, foggy thinking), NOT loss of consciousness

__

CTE (chronic traumatic encephalopathy) — is a permanent, progressive neurodegenerative disease caused by repeated blows to the head / TBI (i.e. repeated concussions)

• symptoms:

  • aggression

  • memory loss

  • depression & suicide

• affects deep sulci of the neocortex, which progresively spreads

CTE is a tauopathy (NFTs containing abnormal tau aka tau that is hyperphosphorylated & mislocalized)

• CTE tau tangles begin in deep sulci

• CTE tauopathy is prominent around blood vessels

• true

def. Zika

t/f: pregnant women advised not to travel to regions where Zika virus were present

---

the NS forms during embryonic development, where (embyronic brain regions → brain structures in adult and children)

• forebrain → (2) → (1) (2)

• midbrain → (1) → (1)

• hindbrain → (2) → (2) (1)

__

how are ESCs formed?

Zika — a mosquito-borne virus that can cause microencephaly (small brain size) in infants

true

---

forebrain

• → tele|encephalon → cerebrum

• → di|encephalon → thalamus, hypothalamus

midbrain

• → mes|encephalon → brainstem

hindbrain

• → met|encephalon → pons, cerebellum

• → myel|encephalon → medulla

___

fertilized egg → embryo → blastocyst w/ ICM (inner cell mass) → harvested ICM → ESCs

def. stem cell (2)

def. neural stem cell (2)

• another name

• can undergo either __ or __ cell division (← def. each)

t/f: cells cannot self-renew if they are differentiated

stem cells are self-renewing (aka replicate itself) & can differentiate into multiple cell types

neural stem cells also self-renew BUT can ONLY differentiate into neurons, astrocytes, or oligodendrocytes (← only structures present in the CNS)

• (aka neural progenitors)

• can do either symmetric or asymmetric cell division

  • symmetric — makes 2 SAME daughter cells

  • asym. — makes 2 DIFFERENT daughter cells: 1 stem cell & 1 other differentiated kind

true ← cells cannot self-renew if they are differentiated

how do you know whether sym. or asym. division is done?

cell-fate determining proteins will be separated either symmetrically or asymmetrically

summary of neural tube formation in vertebrates (3)

__

what migrates away to/& gives rise to PNS neurons, melanocytes, and neuroendocrine cells?

neural tube closure starts in the center & proceeds in the __ & __ directions

__ __ results from failing to complete neural tube formation/closure

• describe (1)

__

after development of neural tube, what occurs?

• form the neural plate & 3 germ layers: ectoderm, mesoderm, endoderm

• neural plate folds to → form neural tube (w/ ectoderm surrounding/encasing it)

• form neural crest cells & somites (somites from mesoderm)

^^

neural crest cells migrate away & differentiate into PNS neurons

neural tube closure starts in the center & proceeds in the caudal & rostral directions

spina bifida results from failing to complete neural tube formation/closure

• cause defects in SC and spinal bones

__

after development of neural tube, fore/mid/hindbrain will differentiate into the brain structures that are present in children & adults (← picture in prev. flashcard)

neural progenitors (aka precursor for neurons & glia) form in the __ __

• name a key neural progenitor (1)

  • explain how cell differentiation occurs w/ these neural stem cells (← aka name the 2 stages)

    • what kind of division involved in each stage

    • what occurs in each stage

    • each stage’s relation to expansion/growth of neural tube

neural progenitors (aka precursor for neurons & glia) form in the neural tube

• radial glial cells (RGCs)

  • proliferative stage ← mainly sym. division

    • 1 RGC will produce another RGC → SO have 2 RGCs (same daughter strands)

  • neurogenic stage ← mainly asym. division

    • 2 RGCs will differentiate into different things from e/o: neurons, oligodendrocytes, astrocytes

proliferative stage does lateral expansion of neural tube (more w/in the neural tube / concentrated)

neurogenic stage does radial growth (thickening) to increase specialization of tissue

---

note that for neurogenic stage, the ventricular end (apical surface) is deepest end & pial end (basal surface) is shallowest end where newly differentiated cells go

for neuronal differentiation

layers of neurons develop in an __-__ manner, where (1) b/c …

• rel. migrating neuron & RGC

t/f: neurons in diff. layers of cortex have distinct circuit connectivity & function

inside-out manner, where oldest neurons are the deepest / closest to ventricular end (apical surface)

• b/c the more recent neurons migrate past the earlier born neurons to reach the cortical plate

migrating neurons OFTEN will move up the RGC towards the cortical plate at pial end

__

true

t/f: specific mutations disrupt cortical cell migrations

• state example of gene that’s mutated to disrupt migrations (← more mentioned about this gene in later flashcard)

during migration, neurons also begin to develop __

__

primate brains have subtypes of neural progenitors called (2), which will (1)

what type of neurons will also migrate from the __ __ (which is…) in the __ & __ regions of developing embryonic brain INTO the developing cortex

true

• Reelin gene mutations will cause disorganization of migrating neurons

during migration, neurons also begin to develop axons

__

primate brains have subtypes of neural progenitors called intermediate progenitors (IPs) & basal radial glial cells (bRGCs), which will form a new zone of proliferation (aka new area/layer of proliferation)

inhibitory interneurons will also migrate from the progenitor zones in the ventral & medial regions of developing embryonic brain INTO the developing cortex

^^

progenitor zones are where neural progenitors aka neural stem cells are located

developing cortex (is area w/ lots of neurons)

how does Zika virus relate to microencephaly & neural progenitor development? (general statement & describe ← 4)

Zika virus disrupts neural progenitor development → leads to microencephaly in mice, where:

• Zika virus replicates in embryonic mouse brain

• infects neural progenitors cells (NPCs)

• leads to defects in differentiation

• induces immune response (inflammation) in the brain AND apoptosis of post-mitotic neurons

→ altogether: infected NPCs, differentiation defects, immune response, and apoptosis will cause microencephaly that ranges in severity

summary of early cortical development (from RGCs to differentiated neurons and glia) ← ~2/4

_

the mammalian cerebral cortex is said to have _#_ layers

• describe the layers (3)

____

t/f: neuronal migration brings neurons from their birthplace near the ventricular zone (VZ) up to the marginal zone (MZ) (near the pia) to ultimately form the cortex

• neural progenitors/neural stem cells do sym. division → 2 RGCs

  • intermediate progenitors (IPs) & basal radial glial cells (bRGCs) form a new zone of proliferation

  • migrating neurons move up RGCs

• do asym. division → 2 different daughter cells that are a upper layer neuron & a lower layer neuron

__

the mammalian cerebral cortex is said to have 6 layers

• layer 1 — has NO cell bodies

• layers 2 & 3 — mostly upper layer neurons (closer to pial end / basal surface) that do communication b/w the 2 hemispheres

• layers 4 & 5 — mostly deep layer neurons (closer to ventricular end / apical surface) that will project to subcortical regions

(layer 6 isn’t mentioned)

____

true

axon pathfinding, where axon reach target areas, will require spatiotemporal __ __ __ that determine when to __, __, and __

• name the 2 types of cues (& 2 things from each)

t/f: these guidance molecules/cues are located OUTSIDE of the cell

VS.

how do growth cones steer the direction of the axon w/ INSIDE the cell mechanisms? (← mention 2 specific structures)

__

__ is the first guidance molecule/cue discovered that’s used in the spinal cord

• how does it function?

t/f: this specific guidance cue is both NECCESSARY & SUFFICIENT for guiding axons

neuron migration is also guided by extracellular (OUTSIDE) cues, such as __

• (optional: summarize what this cue is overall)

axon pathfinding, where axon reach target areas will require spatiotemporal axon guidance molecules that deter. where to extend, turn, and stop

• short range cues: direct repulsion or direct attraction ← direct contact

• long range cues: are chemoattractants or chemorepellants ← for the axon

VS.

growth cones steer the direction of the axon by polymerizing microtubules/MTs towards attractive cues & away from repulsive cues, where F-actin look for axon guidance cues in the environment & MTs polymerize to extends towards or away from certain cues

__

Netrin is the first axon guidance cue discovered

• cells w/ DCC (Netrin R) extends down to the floorplate that secretes Netrin (on one side of the SC) → the axon crosses over the midline → cells moves away from the floorplate w/ Netrin (on other side of SC)

  • (^ Netrin is a chemoattractant, then cells get less attracted/repulsed by Netrin after crossing over)

true ← Netrin is NECCESSARY & SUFFICIENT for guiding axons

• (as seen w/ experiments w/ knockout cells & adding Netrin to normal cells that initially don’t have Netrin)

neuron migration is also guided by extracellular (OUTSIDE) cues, such as Reelin

• (Reelin is both an extra- axon guidance cue & a gene that will disrupt the organization of neuronal migration when mutated)

RGCs (radial glial cells) act as a structural __ to guide initial neuron migration

• specifically, what aspect of MTs is key in neuronal migration? (1 & def. “term”)

SO mutations in several __ genes are associated w/ brain malformations, like microencephaly

…

3 roles of MTs in brain development

• mutations in tubulin genes or MT-association proteins like (2) will disrupt these 3 functions above

…

a growth cone & leading tip of migrating neuron are similar in that (~1/2)

t/f: classifications of brain malformations are basically the abnormal functions of MTs

• state the 3 classifications of brain malformations

RGCs (radial glial cells) act as a structural scaffold to guide initial neuron migration

• specifically, microtubule cell motility (is a key mech. in neuronal migration)

  • is the transportation of neurons along MTs via motor proteins, like kinesin & dynein

SO mutations in several tubulin genes are associated w/ brain malformations, like microencephaly

…

MTs do:

• cell division (proliferative stage: sym. & asym. division)

• cell migration (neurogenic stage)

• neurite outgrowth aka extension/growth of axons and dendrites (for axon pathfinding)

  • is related to post-migration cortical organization

mutations in tubulin genes or MT-associated proteins like LIS1 & DCX will disrupt these 3 functions above

…

a growth cone & leading tip of migrating neuron are similar in that they require MTs that coordinate w/ F-actin

true

• abnormal cell proliferation or apoptosis

• abnormal neuronal migration

• abnormal post-migration cortical reorganization

Lissencephaly is a type of brain developmental abnormality characterized by (2)

• it results from abnormal / defective __ __ during cortical development, specifically what happens is __ __ aka …?

Type 1 lissencephaly has many unknown genetic defects, but the known genetic mutations are (5)

Lissencephaly seen to have:

• large ventricles

• missing sulci & gyri

it results from abnormal / defective cell migration during cortical development, specifically improper layering AKA abnormal/misorganization of the 6 layers of the mammalian cerebral cortex

_

Type 1 lissencephaly has many unknown genetic defects, but the known genetic mutations are:

• PAFAH1B1 (aka LIS1 protein) gene mutation

• DCX (X-linked doublecortin) gene mutation

• Miller-Dieker syndrome (← involves LIS1/PAFAH1B1 genes)

• XLAG

• RELN (aka Reelin)

(^ where DCX and LIS1 are tubulin-associated proteins; LIS1 for Type 1 lissencephaly)

for Type 1 lissencephaly cause: Miller-Dieker syndrome & LIS1/PAFAH1B1 gene mutation

def. Miller-Dieker syndrome

…

MTs have __ of a __ end & __ end (where both ends differ structurally and functionally)

• which end is the (rapidly) growing end?

• name 2 MT motor proteins & what each does

LIS1 is a MT-associated protein, specifically a __-associated protein that does __ transport b/c …

…

how is LIS1 and RELN (reelin) similar? (1)

microdeletion in Chr 17 of PAFAH1B1 genes that code for LIS1 protein

…

MTs have polarity of a “-” end & “+” end (where both ends differ structurally and functionally)

• “+” end is the end where MT polymerization occurs

• kinesin does anterograde transport towards the "+” end

• dynein does retrograde transport towards the “-” end

  • ^ think “kid” aka k | d

LIS1 is a MT-associated protein, specifically a dynein-associated protein that does retrograde transport b/c LIS1 protein forms a protein complex w/ dynein

…

LIS1 and Reelin function in the same pathway for cell migration, where Reelin promotes formation of the LIS1-dynein protein complex

---

(note that the MT “-” end is closer to soma, MT “+” end is closer to axon terminal)

for Type 1 lissencephaly cause: DCX (X-linked doublecortin) gene mutation

DCX (X-linked doublecortin) gene mutation results in (1) that resembles a __ __← def. a specific term w/in this

• more common in __ b/c …

• DCX is a __-associated protein

…

both LIS1 and DCX are involved in regulating MTs during cell migration, which includes __ (← def. term)

• SO mutations of either of the 2 MT-associated proteins lead to (1) and as a result __ __

____________

growth cones and tips of migrating neuron both require MTs coordination with F-actin, but what key thing distinguishes their "action"? (1 general w/ 2 specific)

DCX mutation results in subcortical band heterotopia, that resembles a “double cortex”

• ^ heterotopia — “out of place”

• more common in females b/c male fetuses die before birth due to having only 1 X chromosome (males have a more severe form of lissencephaly)

• DCX is a microtubule-associated protein

…

both LIS1 and DCX are involved in regulating MTs during cell migration, which includes nucleokinesis (the translocation of the nucleus as the migrating neuron crawls up the MT)

• SO mutations of either of the 2 MT-associated proteins lead to migration defects and as a result improper layering

(^ improper layering AKA misorganization of the 6 layers of the mammalian cerebral cortex)

____________

growth cones and tips of migrating neuron both require MTs coordination with F-actin, but they differ in what is being moved, where:

• growth cones move the axon

• migrating neurons move the nucleus

nearly all cortical malformations result in __ __ aka __

• def. the 2 terms

• describe (1)

nearly all cortical malformations result in seizure disorders aka epilepsy

• (^ cortical malformations refers to abnormal cell division, cell migration, and post-migration cortical organization (of layers))

• is a seizure disorder if they experience at least 2 seizures that are are separated by at least 24 hours

epilepsy — a chronic brain condition that causes seizures

seizures — a sudden disruption of the electrical communication b/w neurons (imbalance of excitatory & inhibitory inputs)

name 2 major types of seizures (& def. each)

• name the types of seizures that are classified w/in each major seizure type (2 ← w/ another name for each / 3) (← def. each)

can detect seizures w/ __

seizures are an imbalance of __ (1) and __ (2) inputs

…

there are rare instances where epilepsy can be caused by __ (← def. term) that lead to __/__ imbalance

• one treatment option of epilepsy caused by channelopathies is taking medications, where the medications target (1) or (1)

• other treatment options are (4)

generalized seizures — affect both sides of the brain

• absence seizures (aka petit mal seizures) — cause rapid blinking or a few seconds of staring into space

  • ^ think “petit” mal as having petit/not obvious symptoms

• tonic-clonic seizures (aka grand mal seizures) — cause a person to cry out, loss consciousness, fall to the ground, have muscle jerks or spasms

  • ^ think “grand” mal as having grand/very obvious symptoms

focal seizures (aka partial seizures) — affect ONLY 1 side of the brain

• simple focal seizures — affect small part of brain & causes twitching or change in sensation (i.e. strange taste or smell)

• complex focal seizures — cause confusion and dazed state, where the person can’t respond for up to a few minutes

• secondary generalized seizures — start in one part of the brain BUT spreads to both sides of the brain (aka person has a focal seizure that turns into a generalized seizure)

…

can detect seizures w/ EEG

seizures are an imbalance of excitatory (glutamate) and inhibitory (GABA, glycine) inputs

…

there are rare instances where epilepsy can be caused by channelopathies (mutations in ion channels) that lead to excitatory/inhibitory imbalance

• one treatment option of epilepsy caused by channelopathies is taking medications, where the medications target ion channels or GABA_A receptors

• other treatment options are:

  • surgery

  • devices

  • diet

  • new therapies

for ONE treatment option of epilepsy caused by channelopathies is taking medications, where the medications target ion channels or GABA_A receptors

how is GABA made? how is GABA transported? (2, 2)

which GABA Rs are iono- vs. metabotropic?

• for GABA_ARs:

  • GABA_ARs induce __ SO:

    • anti-seizure medications work to prevent seizures by (1)

    • (1) work to cause seizures by (1)

GAD w/ vitamin B6 co-factor converts glutamate into GABA, where GABA exits the cell into the synaptic cleft through GAT (GABA transporters) OR exocytosis (w/ vesicles)

• where GABA can either enter glial cells via GAT OR enter post- cell through GABA receptors (GABA_A Rs or GABA_B Rs)

GABA-A Rs — ionotropic; GABA-B Rs — metabotropic

• GABA_ARs induce IPSPs (inhibitory PSPs) b/c these receptors release Cl^- SO:

  • many anti-seizure medications prevent seizures by enhancing GABA transmission

    • b/c want to prevent E/I imbalance, so want to keep GABA_ARs normal function of releasing Cl- by activation of these receptors from GABA binding, SO want GABA production

  • many neurotoxins cause seizures by inhibiting GABA transmission

    • b/c want to cause seizures, so want E/I imbalance by preventing normal GABA_AR function, SO don’t want GABA production

for ONE treatment option of epilepsy caused by channelopathies is surgery

how does surgery treat epilepsy

ex. is w/ patient __

for ONE treatment option of epilepsy caused by channelopathies is diet

__ diet may help prevent seizure disorders aka epilepsy b/c …

• SPECIFICALLY, …

surgery cuts out the brain tissue where seizures originate/start in

• ex. is w/ patient H.M.

---

ketogenic diet helps prevent seizure disorders aka epilepsy b/c the mitochondria metabolism will produce ketone bodies, which are used as an alternative source of fuel when glucose levels are low

• SPECIFICALLY, the liver produces ketone bodies w/in the mitochondria & are used by the brain and heart as fuel

one POTENTIAL SOURCE of seizures disorders is __ __ __ (← def.)

• specifically, it is the classification of brain malformation where there is abnormal …

one POTENTIAL source of seizures disorders is focal cortical dysplasia (clumps of abnormal neuronal cells in the cortex)

• specifically, it is the classification of brain malformation where there is abnormal post-migration cortical reorganization

tuberous sclerosis is a type of cortical dysgenesis w/ abnormal cells, which are non-neoplastic

• t/f: it refers to the abnormal formation of the cortex due to disruptions in:

  • cell growth/proliferation

  • differentiation

  • migration

  • cortical organization

• def.

• describe (1 ← def. term)

• symptoms (3)

true

__

a rare autosomal dominant disorder that is secondary to mutations in the TSC1 and TSC2 tumor suppressor genes

• associated with formation of hamartomas (non-cancerous tumors)

• symptoms:

  • seizures

  • autism

  • intellectual disability

how are iPSCs (induced pluripotent stem cells) made?

• where the starting specific type of cells are added together with (#) __ __( ← name them)

iPSCs can differentiate in 6 possible types of cells (← name them)

• t/f: gene editing can control what type of neurons that iPSCs differentiate into

a method is used to reprogram / de-differentiate human somatic cells that are fully differentiated back into a stem cell-like state called induced pluripotent stem cells

• where the fully-differentiated adult somatic cells are added together with 4 Yamanaka factors: Oct4, Sox2, Klf4, c-Myc

iPSCs can differentiate in 6 possible types of cells:

• blood cells

• pancreatic cells

• motoneurons

• dopamine-producing neurons

• adipocytes

• cardiomyocytes

true

for gene editing can control what type of neurons that iPSCs differentiate into

name the 2 types of gene therapies

• describe each

t/f: gene editing, like CRISPR, can be used to treat diseases in humans

in vivo (done inside the body)

• gene turns into a viral vector, which is then directly delivered

ex vivo (done outside the body, then injected)

• gene turns into a viral vector, where the viral vector & isolated stem cells from the patient will come together to get a modified cell, which is then injected back into the patient

_

true

• first successful case done last year in an infant w/ CPS1 deficiency

def. intellectual disability (ID)

• def. the 2 things that are limited

  • another name for 1 of them

  • for the other one, describe the 3 aspects to it

IQ tests are done to measure intellectual functioning, where IQ of below __ indicates significant limitation in intellectual functioning

standardized tests are used to measure limitations in __ __

ID — condition where there is significant limitations in intellectual functioning & adaptive behavior before the age of 22

• intellectual functioning aka intelligence — general mental capacity for learning, problem solving, etc.

• adaptive behavior — the conceptual, social, and practical skills that are done by people in their daily lives

  • conceptual skills — language, money, time, etc. (← things we understand)

  • social skills — interpersonal skills, self-esteem, follow rules, etc. (← interacting with others & the social norms)

  • practical skills — personal care, healthcare, routines, etc. (← application of things we know)

IQ tests are done to measure intellectual functioning, where IQ of below 70 indicates significant limitation in intellectual functioning

standardized tests are used to measure limitations in adaptive function

for the genetics & underlying cellular properties of ASD and/or ID

t/f: All human traits emerge from an interaction of genes and environment

_

ID and ASD (autism spectrum disorder) are divided into 2 forms (← name & def. each)

• for 1 of them, give 2 examples

__

for ID:

• the causes usually unknown, but the known causes are divided into 2 categories (← name & describe each)

true

_

ID and ASD (autism spectrum disorder) are divided into:

• syndromic forms — ID and/or ASD is associated w/ other detectable anomalies / medical/behavioral signs and symptoms

  • ex: Down syndrome, fragile X syndrome

• non-syndromic forms — ID and/or ASD appear w/o other detectable anomalies

__

for ID:

• the causes usually unknown, but the known causes are divided into 2 categories:

  • environmental exposures

    • most common is fetal alcohol syndrome (mother exposed to/consumed alcohol while pregnant)

  • genetic abnormalities

    • most common chromosomal abnormality is Down’s syndrome

    • most common gene mutation is Fragile X syndrome

for Down’s syndrome

Down’s syndrome is syndromic to ASD and/or ID, where Down’s syndrome is a __ __, specifically a very common __ __

…

just recognize the below parts & picture:

• t/f: common physical signs include short neck, small head, flattened facial features, skin fold coming out from the upper eyelid

• t/f: common positive traits include natural affection, empathy, good short-term memory

• t/f: common cog./behavioral problems are short attention span, impulsive behavior, delayed language & speech dev.

t/f: people w/ Down’s syndrome are at increased risk for other health conditions, like ASD

Down’s syndrome is syndromic to ASD and/or ID, where Down’s syndrome is a genetic abnormality, specifically a very common chromosomal abnormality (b/c have trisomy Ch. 21)

all 4 are true

for Rett syndrome

Rett syndrome is syndromic to ASD and/or ID, where Rett syndrome is a __ __, specifically a very common __ __ __

• most cases are caused by mutations in the MeCP2 gene, which is located on the _ chromosome

  • SO Rett syndrome is more common in __ b/c …

t/f: is also associated with ASD symptoms

Rett syndrome is syndromic to ASD and/or ID, where Down’s syndrome is a genetic abnormality, specifically a very common single gene mutation

• most cases are caused by mutations in the MeCP2 gene, which is located on the X chromosome

  • SO Rett syndrome is more common in females b/c males will die before birth

true

for ASD (autism spectrum disorder)

characterized by (2)

more common in __, where ratio used to be higher b/c …

…

def. disorder vs. condition

def. ASD in terms of disorder vs. condition

relate to neurodivergence

char. by:

• persistent deficits/lacks in social communication & interaction

• restricted, repetitive behavior, interests, or activities

more common in males, where ratio used to be higher b/c didn’t account for sex differences where girls easily mask social inabilities & they also changed the qualities that diagnose ASD

…

disorder — deviation from the norm, has negative connotation

condition — state of being, is less stigmatized

…

ASD as a disorder — moderate to severe ASD interferes w/ daily life

ASD as a condition — mild ASD is not necessarily disruptive to daily life

neurodivergence: individuals w/ ASD process the world differently from neurotypical individuals (other ex: ADHD, OCD, etc.)

def. DSM-5

published by who, when

next edition expected to be published b/w __ and __

…

is the persistent deficits/lack in social comm. and iteraction across multiple contexts, name 3 general social deficits

diagnostic & statistical manual on mental disorders 5th edition (by APA, in 2013)

next edition b/w 2023-2028

…

• deficit in social-emotional reciprocity

• deficit in nonverbal communication

• deficit in developing, maintaining, and understanding relationships

for ASD (cont.)

t/f: people w/ ASD have a large range of intellectual abilities

• explain

ASD is a __ __ __; they are not made up of discrete/fixed subcategories

• meaning?

…

autism is not caused by 1 mech, BUT by a family of neurodev. processes that __ on __ brain circuit formation that occurs during __ and __ __development

• t/f: autism is highly genetically heterogenous

• the key biology involves brain development, esp. __ and __

• many autism-linked genes converge on a relatively __ number of cellular pathways

• t/f: environ. factors may contribute in some cases through interaction w/ genetics/biology

true

• range from extreme intellectual disability (extreme ID) to extraordinary intellectual abilities/specialized talents

ASD is a single heterogenous spectrum; they are not made up of discrete/fixed subcategories

• meaning that ASD is a spectrum (of severity of effects) that is caused by different genetic abnormalities

…

autism is not caused by 1 mech, BUT by a family of neurodev. processes that converge on altered brain circuit formation that occurs during fetal and early postnatal development

• true ← autism is highly genetically heterogenous

• the key biology involves brain development, esp. synapses and circuits

• many autism-linked genes converge on a relatively small number of cellular pathways

• true

for ASD (cont.)

t/f: ASD often has several common co-morbidities

def. co-morbid vs. syndromic

…

ASD has a strong genetic component w/ heterogenous causes, including specifically __ & __ (← what do they stand for? & def. 1 of them)

• state the genetic heterogenous causes of ASD (6)

• where ~ ½ variants are __, while other ½ are __

true

• co-morbid — 2 (distinct) medical conditions that occur in a person at the same time

• syndromic — collection of symptoms that often occur together & are linked to ONE genetic disease or cause

…

ASD has a strong genetic component w/ heterogenous causes (aka strong genetic heterogenous spectrum), including specifically CNVs (copy number variants) & SNVs (single nucleotide variants)

• genetics

• common variants

• rare inherited CNVs

• rare inherited SNVs

• de novo CNVs

• de novo SNVs

where ~ ½ variants are heritable/inherited, while other ½ are environmental

__

CNVs (copy number variants) — parts of chromosome are deleted or duplicated

genes ass. w/ ASD are often involved in __ brain development

__

Why do we know so much more about genes compared to the environment when it comes to ASD & ID? (3)

__

ASD is ass. w/ a range of _(3)_natal factors, where the highest magnitude associations are with __ __ use & neonatal __

__

we are confident that autism is NOT caused by childhood vaccines & SO we can conclude that …

• evidence for strong genetic component to autism (2)

• t/f: autism can be diagnosed earlier and earlier

  • give example of this & explain

__

syndromes ass. w/ ASD can be __ (due to __) or the result of __

genes ass. w/ ASD are often involved in early brain development

__

• the environment includes a very broad range of factors

• the exposure to environmental factors are often transient (short / temporary)

• studies to look at environ. factors are too expensive & time-consuming

__

ASD is ass. w/ a range of prenatal, perinatal, and postnatal factors, where the highest magnitude associations are with maternal medication use & neonatal seizures

__

we are confident that autism is NOT caused by childhood vaccines & SO we can conclude that correlation b/w childhood vaccines & developmental abnormalities are NOT the same as causation

• evidence:

  • twin studies: identical twins are likely to get it if the other has it; BUT likelihood for fraternal twins is the same chance as w/ non-twin siblings

  • animal & human studies: changes in brain circuit ass. w/ autism genes occur in utero/prenatal or in early perinatal developmental period

• true

  • use eye tracking in young children, where visual preference for geometric shapes is an early biomarker/indicator of an ASD subtype w/ more severe symptoms

__

syndromes ass. w/ ASD can be monogenic (due to SNVs) or the result of CNVs

use syndromic ASD to study cellular mechanisms underlying ASD b/c we know the genetic causes

one of the syndromic forms of ASD and/or ID: fragile X syndrome (FXS)

fragile X syndrome (FXS) is the most common __ cause of ID and ASD

def. FXS

• is caused by a __ __in the gene __ that encodes for (1), SO have __ of __ expression ← is what causes Fragile X syndrome

what are the 3 states depending on the amount of the specific trinucleotide repeats?

symptoms (5)

draw out how it looks like

fragile X syndrome is the most common hereditary cause of ID and ASD

a trinucleotide repeat expansion disease of CGG

• is caused by gene mutation of gene FMR1 that encodes for the Fragile X Messenger ribonuclear protein (FMRP), SO have lack of FMRP expression

  • ^ the lack of FMRP protein expression is what causes Fragile X syndrome

typical (→ get normal FMRP expression), premutation (→ have some defects), mutation (→ lack of FMRP expression)

symptoms:

• ASD

• ID

• enlarged testicle

• flat feet

• seizures (in ~10% of patients)