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Bio 222 Cell/Molec Neuroscience > Exam 4 > Flashcards

Exam 4 Flashcards

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1
Q

timing of behavior/physiology tightly correlated w/

A

environment (i.e. day and night)

optimal times for behavior vary, but there’s a general pattern

behaviors cycle in oscillatory pattern

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2
Q

how to demonstrate circadian rhythm experimentally

A
  • Put animal in constant environment (temp, noise, light)
    • example: constant darkness (DD)
  • Measure activity (wheel running)
  • Results: every day, activity starts a little sooner (cycles, but slightly less than 24 hours)
    • Activity is circadian (periodic) but not exactly 24 hours
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3
Q

circadian pattern of humans in constant darkness

A

circadium rhythm slightly longer than 24 hours (but there’s genetic variation)

those w/ most genetic variation likely to have sleep disorders

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4
Q

circadian rhythm in constant light

A

rhythm of more than 24 hours (unlike less than 24 hours in constant darkness)

causes more health problems than in dark since nocturnal

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5
Q

properties of circadian rhythms

A
  • Found in all organisms
  • Period in constant conditions is close to, but not exactly 24 hours
  • Can depend on light dark cycle and other cues (zeitgebers)
  • Many single cells can display circadian rhythm; multiple cells release hormones to synchronize
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6
Q

nocturnal, diurnal, and crepuscular animals: definition + example

A

nocturnal: sleep during day (mice)

diurnal: sleep at night (humans)

crepuscular: sleep middle of day and middle of night, active dawn and dusk (fruit flies)

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7
Q

who discovered molecular mechanisms controlling circadian rhythms

A

Hall, Rosbash, Young

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8
Q

Konopka

A

identified gene that when mutated, change cycle duration

called period (per mutants)

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9
Q

Hall and Rosbash

A

discovered the function of the per gene

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10
Q

Young

A

determined function of a second clock gene, called timeless (tim)

found that per and tim proteins bind to each other

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11
Q

observations about per protein made by Rosbash

A
  • per mRNA levels vary in cyclic fashion
  • mRNA cycling is circadian (cycle b/w high mRNA and protein levels)
  • per protein levels are also cyclic, peak level reached several hours after mRNA peak
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12
Q

initial model proposed by Rosbash about per protein function (5 steps)

A
  1. Transcribe per mRNA
  2. make per protein in cytosol
  3. import per protein into nucleus
  4. Per protein inhibits its own promoter (mRNA and protein levels fall)
  5. Inhibition is relieved, begin making per mRNA again
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13
Q

what is the actual mechanism w/ per and tim proteins that regulate timing of cycle

A

proteins clock (dCLK) and cycle (CYC) are required to activate transcription of per and tim

per and tim proteins dimerize, are phosphorylated, then enter the nucleus

phosphorylated dimer inhibits transcription of per and tim mRNA

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14
Q

how is timing of clock mechanism regulated

A

via phosphorylation of per and tim proteins by Doubletime (per) and crytochrome genes (tim)

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15
Q

Doubletime gene

A

produces kinase that regulates per protein in cytosol

degrades per: extends cycle duration by preventing dimer formation

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16
Q

Cryptochrome (Cry) gene

A

produces kinases that regulate tim proteins in both cytosol and nucleus

degrading tim in cytosol: extends cycle duration by preventing dimer formation

degrading tim in nucleus: destroys dimer, removing inhibition, next cycle starts

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17
Q

how does light entrain the clock

A

in flies (not mammals): cryptochrome is light sensing protein

light activated cryptochrome promotes rapid degradation of tim protein in cytosol (can’t form dimer, cycle stops)

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18
Q

phase shifting from travel

A

normally: light during day breaks down cytosolic tim, extends cycle duration

travel: light during night breaks down nuclear tim, advancing onset of next cycle (shortens cycle duration, phase advance)

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19
Q

how is mammalian clock different from flies

A

there are proteins homologous in structure/function to dCLK, CYC, and PER

PER forms dimer with CRY, not TIM (timeless lost)

cryptochrome (CRY) not light sensing

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20
Q

light input in mammals is different from flies how

A

CRY isn’t light sensitive

light input based on retinal projections to the SCN (suprachiasmatic nucleus)

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21
Q

evidence for role of SCN to generate circadian rhythms

A
  • isolated SCN cells are sufficient to generate circadian rhythms
    • electrical synapses b/w SCN neurons synchronizes entire nucleus
  • intact SCN is necessary for whole animal rhythms
    • hamsters w/o SCN have no circadian rhythm
    • when transplant SCN back in, circadian rhythm comes back
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22
Q

melatonin and the SCN

A

melatonin (hormone) gives feedback to SCN

melatonin can phase shift SCN clock depending on when it’s present

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23
Q

circadian control in mammals by SCN: what are 4 things SCN can affect

A

autonomic innervation

body temperature

glucocorticoids

feeding

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24
Q

drosophila and melatonin

A

drosophila also use hormones to synchronize brain to body, but NOT same hormones as mammals

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25
Q

sleep definition

A

reversible quiescence

increased arousal threshold (need more intense sensation)

homeostatic regulation

related to circadian clock

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26
Q

sleep and circadian rhythm experiment w/ fruit flies

A

if sleep deprive fruit flies, they rest a lot more

example of homeostatic regulation

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27
Q

neuron firing during stages of sleep

A

during slow wave sleep: action potentials (in cortical or thalamic neurons) occur in bursts; high amp, low frequency

during REM sleep: APs and EEG look like wake; no communication b/w thalamus and cortex

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28
Q

experiment with rats sleep deprivation

A

experimental rats: turntable moves whenever rat shows EEG signs of beginning of sleep

control rats: can sleep, less sleep deprived

all experimental rats died after a month

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29
Q

sleep deprivation and cognitive tasks

A

performance worse on selective attention and arithmetic tasks after 1 night of sleep deprivation

activation is less

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30
Q

synaptic homeostasis hypothesis (SHY)

A
  • when awake, more synapses are potentiated than depressed
  • during sleep, synapses downscaled to lessen metabolic burden
    • problem: some pathways show net LTP during sleep
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31
Q

glymphatic system: how does it work?

A
  • materials brought to brains via arteries
    • nutrients flow out
  • waste goes into vein from interstitial fluid (extraceullar fluid)
    • glymphatic system function varies if sleep or awake
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32
Q

glymphatic system: proposed role in sleep

A

awake: reduced interstitial space, restricted CSF flow, metabolites accumulate

asleep: increased interstitial space, better CSF flow, get rid of waste

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33
Q

what triggers sleep

A

interaction b/w thalamus and cortex

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34
Q

narcoleptic dogs: mutated gene

A

orexin (peptide, aka hypocretin)

essential for normal wakefulness

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35
Q

5 parts of somatosensory system

A

touch

temperature

pain

itch

propioception

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36
Q

sensation: 3 overall steps

A
  1. sensory fiber activation
  2. processing in spinal cord and brain
  3. perception of pain, touch, etc.
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37
Q

where are the bodies of sensory neurons located

A

dorsal root ganglion (DRG, sensation of body): located in spinal cord

trigeminal ganglion (TG, sensation of face): located in brainstem

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38
Q

sensory neurons’ two axons

A

each has unique termination pattern of peripheral axon in skin/organs, but also projects its central axon to specific laminae of spinal cord (DRG) or brainstem (TG)

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39
Q

4 main types of somatosensory fibers and where in spinal cord they terminate

A

Aα: muscle spindle; terminate in central/ventral spinal cord

Aβ: hair follicle, merkel cell; terminate in lamina IIv-V

Aδ: free nerve ending, D-hair follicle; terminate in lamina I,II,III, and V

C: free nerve ending; terminate in lamina I, II

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40
Q

which receptors sense touch

A

mechanoreceptors

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41
Q

mechanoreceptors function optimally w/:

A

light contact

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42
Q

two types of skin receptors based on speed of adaptation

A

slow adapting (SA) receptors: receptors that detect constant stimulus (e.g. pressure, skin stretch)

rapidly adapting (RA): detect only short pulses (e.g. initial contact, vibration)

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43
Q

4 types of mechanoreceptors in glabrous skin (no hairs)

A

merkel cell-neurite complex

meissner corpuscles

ruffini endings

pacinian corpuscles

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44
Q

merkel cell neurite complex

A

basal layer of epidermis, assoiate w/ nerve terminals branching from a single Aβ fibers

fine tactile discrimination, texture perception

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45
Q

meissner corpuscles

A

vibration, handgrip

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46
Q

ruffini endings

A

skin stretch

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47
Q

pacinian corpuscles

A

skin motion, skin slipping

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48
Q

touch circuit in central nervous system: how is touch info transmitted to brain for both glabrous and hair skin mechanoreceptors

A
  1. Post synaptic dorsal column (PSDC) neurons in dorsal spinal cords get info from glabrous and hairy skin LTMR
  2. Project to dorsal column nuclei (DCN), which synapse on to ventral posterior nuclear (VPN) complex of the thalamus
  3. Thalamus to somatosensory cortex
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49
Q

touch circuit in central nervous system: circuit exclusive to hairy skin

A
  • spinocervical tract (SCT) neurons get info exclusively from hair skin
  • synapse onto lateral cervical nucleus (LCN)
  • LCN neurons snapse onto ventral posterior nucleus (VPN) complex of thalamus
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50
Q

mechanosensitive neurons in DRG

A

most DRG neurons are mechanosensitive:

some quickly desensitize

some are slow, have sustained current

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51
Q

piezo 2

A

peripheral mechanotransduction channel: mediates rapid adapting current

only piezo 2 is expressed in DRG

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52
Q

piezo 2 is expressed in

A

merkel cells, which are slow adapting (also DRG)

piezo 2 KO (merkel cell KO): loss of slow-adaptive firing

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53
Q

piezo 2 KO: main deficit

A

loss of touch sensation (major mechanoreceptor in DRG and merkel cells)

loss of mechanical pain

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54
Q

Piezo 1 KO: main deficits

A

broadly expressed in internal organs

vascular development deficits, sickle cell disease

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55
Q

thermoreceptors are:

A

free nerve endings

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56
Q

2 classes of thermoreceptors

A

cold fibers: respond to a decrease in temp

heat fibers: respond to an increase in temp

each fiber has a preferred temperature

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57
Q

what channels detect temperature change

A

thermal TRP channels

different TRP channels detect different temperatures and chemicals

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58
Q

TPRA1

A

NOT a cold sensor in vivo

cold sensing remains intact in KO mice

59
Q

TRPV1

A

hot channel

activated by capsaicin (gives spicy hot sensation)

capsaicin and heat both trigger Ca influx

60
Q

TRPV1 KO mice

A

impaired pain sensation (latency for withdrawing from heat pain)

worse heat detection, but can still detect some heat

61
Q

what are the hot channels

A

TRPV1, TRPM3, TRPA1

TKO (triple knockout): complete loss of withdrawal response from heat

62
Q

cool channel

A

TRPM8

KO mice can’t detect cold (mouse has no preference for cold vs hot chamber)

63
Q

GluK2

A

Kainate (KA) glutamate receptor

cold channel

GluK2 KO almost completely loses ability to detect cold

64
Q

acute vs chronic pain

A

acute (nocioceptive pain): good pain

chronic (pathological pain): abnormal changes to somatosensory system, bad pain

65
Q

fast vs slow pain

A

fast pain: transmitted by myelinated A𝛿 fibers

slow pain: transmitted by unmyelinated C fibers

66
Q

different methods of testing pain

A

mechanical pain: von frey assay

hot pain: hargreaves assay

cold pain: 0oC

67
Q

sodium channel specifically expressed in nociceptor

A

Nav1.8+

68
Q

4 types of nociceptors

A

mechanical

thermal

chemical

polymodel (combination of pain)

69
Q

peripheral vs central terminals of sensory neurons

A

peripheral terminal: detects noxious stimuli (tranduction)

central terminal: transmits noxious info to brain (transmission)

70
Q

labelled line hypothesis

A

specific DRG and spinal neurons process noxious information

different neurons transmit different sensations

71
Q

simple labellined line hypothesis cannot explain:

A

noxious stimuli evoke pain in most cases, but not always

pain can be evoked by innocuous stimuli in chronic pain patients

72
Q

gate control theory of mechanical pain

A

pain transmission neuron (T neuron) in spinal cord receives peripheral inputs from C/A𝛿 nociceptors to transmit acute pain

LTMRs activate T neurons, but inhibitory interneuron inhibits T, prevents touch from causing pain

under pathological conditions, inhibitor gate is gone, touch can trigger pain

73
Q

gate control circuit: what properties of T neuron and inhibitory interneuron

A

Somatostatin (SOM) expressed in excitatory interneruons in dorsal spinal cord

Dynorphin (Dyn) expressed in inhibitor interneurons

74
Q

mechanisms of chronic pain

A

peripheral sensitization: overactivate TRPV1, excitate Nav1.7 (spontaneous pain)

central sensitization (amplification): excitation, disinhibition

75
Q

two forms of itch

A

chemical itch: activated by pruritogens, can be histamine dependent or independent, high threshold nociceptors (pruriceptor)

mechanical itch: activated by innocuous mechanical stimuli, histamine independent, low threshold mechanoreceptor

76
Q

spinal circuits processing chemical itch vs chemical itch

A

chemical itch: there are parallel pathways transmitting chemical itch

3 subsets of itch neurons in the DRG

mechanical itch: pathway is distinct from chemical itch

77
Q

population coding hypothesis: pain vs itch

A
  • there are itch specific and pain specific circuits
    • itch stimuli activate GRPR+ neurons in spinal cord
  • itch sensing neurons can respond to painful stimuli
    • itch neurons express TRPV1 like pain neurons
  • pain suppresses itch
    • activation of pain pathway can cause inhibition of itch path
78
Q

reflex arc steps

A
  1. Activation of mechanical receptors
  2. Activation of sensory neurons in DRG
  3. Info processing in spinal cord
  4. Activation of motor neurons
  5. Response by effectors
79
Q

hierarchical organization of movement control

A

motor cortex → brainstem nuclei → local circuit nuerons → motor neurons → skeletal muscles

80
Q

spinal cord organization: which receptors go where

A

nocioceptors and mechanoreceptors project from dorsal root ganglion to specific laminae in dorsal horn (spinal cord)

proprioceptors project to ventrally located motor neurons in spinal cord, which connect back to muscle to drive movement

81
Q

muscle pairs

A

extensor contraction: extends joint

flexor contraction: decreases joint angle

82
Q

motor pools and motor units

A

each muscle fiber innervated by single motor neuron

single motor neuron innervates multple muscle fibers (motor unit)

motor pool: motor neurons that innervate same muscle

83
Q

size principle of motor neurons

A

neurons w/ smaller motor units (small axon diameters and cell bodies) fire before neurons w/ large motor unit size

this difference used for fine motor control

84
Q

motor columns

A

motor neurons are organized in motor columns in ventral spinal cord along rostral-caudal axis

medial: trunk muscles

lateral: limb muscles

rostral: forelimb

caudal: hindlimb

85
Q

different spinal cord sections

A

cervical spinal cord: controls arms

lumbar spinal cord: controls legs

86
Q

stretch in muscle fibers

A

Aα mechanoreceptors are activated by stretch of muscle spindles, info is sent to sensory neurons

87
Q

stretch reflex

A

Proprioceptors detect stretch, trigger motor response to counteract stretch (negative feedback loop)

88
Q

reciprocal inhibition

A

contraction of one muscle set is accompanied by relaxation of antagonistic muscle

89
Q

most inputs to motor neurons are mediated by

A

spinal interneurons

90
Q

interneurons and rabies virus

A

transsynaptic retrograde labeling:

inject into motor neuron, crosses synapse, and labels premotor interneurons

does NOT label proprioceptor projection to spinal cord (bc retrograde only)

91
Q

excitatory premotor interneurons + example

A

amplify signaling, excitatory input

example: flexor withdrawal reflex (withdraw limb from aversive stimuli)

92
Q

inhibitory premotor interneurons examples

A

stretch reflex: reciprocal inhibition

crossed extensor reflex: activation of extensor muscles and inhibiton of flexor muscles on opposite side of the body

93
Q

central pattern generators (CPG)

A

circuit that is capable of producing rhythmic output w/o sensory feedback

94
Q

cat experiment about central pattern generators

A
  • disconnect cortex/thalamus from brainstem/spinal cord
    • cat can’t control its motion
  • electrically stimulate brainstem motor center to initiate movement
    • result: recordings show similar walking pattern (rhythmic/coordinated muscle contraction in absence of sensory feedbacjk)
95
Q

how do central pattern generators work

A

flexor and extensor motor neurons are excited by excitatory premotor neurons

excitatory premotor neurons inhibit each other and the other motor neuron

96
Q

right left alteration in central pattern generators

A

excitatory premotor neurons are required for left-right alternation (inhibits the opposite side)

97
Q

MdV neurons

A

MdV premotor neurons are presynaptic to only specific subset of forelimb motor neurons

receive inputs from multiple brain regions (motor cortex, superior colliculus, cerebellum)

important for reaching and grasping (skilled motor learning)

98
Q

what does ablating purkinje cells in cerebellum do

A

disorganized walking

99
Q

organization of the cerebellar circuit

A

mossy fibers → granule cells and climbing fibers → purkinje cells (output of cerebellum)

basket cells and stellate cells are inhibitory interneurons

100
Q

motor functions of cerebellum

A

skilled motor learning

forward modeling: combines sensory and motor info to predict where an object will be in the future

101
Q

nonmotor functions of cerebellum

A

cerebellum sends projections to the frontal lobe and influences cognition, emotion, motivation, judgement

damage impairs language perception, cognition

102
Q

basal ganglia

A

projects to area involved in motor control ,cognition, judgement

initiate and maintain activity in the cortex

103
Q

organization of the basal ganglia

A

striatum receives input from cortex and thalamus

sends inputs to dopaminergic neurons in SNc and VTA (send modulatory output back to striatum)

also output to superior colliculus and brainstem

104
Q

basal ganglia: two major GABAergic outputs

A

Direct (D1+): excitatory, enhances movement

Indirect (D2+): inhibitory, suppresses movement

105
Q

motor cortex is where?

premotor regions include?

A

M1 is in frontal lobe

premotor regions include premotor cortex, supplementary motor area, supplementary eye field, presupplementary motor area

106
Q

upper motor neurons of M1 project to:

A

lower motor neurons via corticospinal tracts

also connect to interneurons of spinal cord to influence reflexes and CPGs

107
Q

M1 seems to use ____ to encode direction of movement

A

population coding (combination of neurons signal direction of movement)

108
Q

movement coding in M1: firing rate of neuron determines:

A

direction of movement

109
Q

what is neurodegeneration

A

progressive loss of structure or function of neurons, including death of neurons

110
Q

physical changes of alzheimer’s disease

A

brain shrinks (nerve cell death and tissue loss)

plaques (clumps of beta amyloid protein)

tangles (twisted strands of another protein

111
Q

treatments of alzheimer’s

A

early stages: acetylcholinesterase inhibitors

severe stages: NMDA receptor antagonist

112
Q

amyloid plaques made up of

A

beta amyloid protein

113
Q

what are neurofibrillary tangles made fo

A

microtubule associated tau protein (taupathy)

114
Q

amyloid hypothesis

A

amyloid beta protein disrupts communication b/w cells and activate immune cells, which trigger inflmamation

small soluble aggregates of it are more toxic than large accumulations

115
Q

production of amyloid beta

A

Aβ is part of transmembrane protein called amyloid precursor protein (APP), cleaved by α-secretase or β-secretase to form APP-α or APP-β

γ-secretase then produces Aβ (Aβ42 most likely to form aggregates)

116
Q

what evidence implicates Aβ

A

mice w/ mutation in 3 genes for Aβ production develop amyloid plaques

down syndrome people w/ 3 fcopies of chromosome carrying APP gene develop amyloid plaques

116
Q

mutations in APP gene causes

A

familial Alzheimer’s disease (FAD)

117
Q

mutation in _____ and ____ increase Aβ production

A

App gene and presenilin (PS1 and PS2)

118
Q

presenilins (PS) and catalytic activity

A

catalytic components of γ-secretase complexes

complexes contain PEN2 and APH1 also

aspartyl residues in transmembrane domains 6 and 7 required for catalytic activity

119
Q

toxic Aβ effects

A

impaired synaptic plasticity

neuron death

LTD (learning/memory affected)

spine loss

120
Q

3 phases of AD

A
  • First phase (preclinical AD): Aβ accumulates w/o symptoms
  • Second phase (mild cognitive impairment MCI): taupathy and neurodegeneration, predementia
  • Third phase (AD): neurodegeneration eliminates neurons irreversibly, serious dementia
121
Q

mouse models to study pathogenesis of AD:

App knock in and APP overexpressing mice

A

exhibit extensive Aβ pathology w/o taupathy and neurodegeneration

(mutation of tau protein are not cause of AD)

122
Q

ApoE hypothesis

A

ε4 allele of ApoE is major risk factor for AD

123
Q

parkinsons disease is the most common

A

neurodegenerative movement disorder

second most common progressive neurodegenerative disorder (after alzheimers disorder)

124
Q

two symptoms of PD

A

bradykinesia (slow movement)

tremors

125
Q

direct pathway

A

D1+ GABAergic striatum neurons project to GPi and SNr in basal ganglia

promote movement

126
Q

indirect pathway

A

D2+ GABAergic striatum neurons project GPe

inhibits movement

127
Q

SNc and VTA

A

SNc: movement

VTA: motivation, reward prediction

128
Q

cellular mechanism of PD

A

loss of SNc dopaminergic neurons

D1+ neuron activation reduces (hyperactivation of GPi and SNr inhibitory projection neurons)

129
Q

protein problem w/ PD

A

misfolded α-synuclein

regulates DA storage (reduced number of vesicles available for storage, DA in cytoplasm increase, oxidative stress)

130
Q

what does α-synuclein do normally

A

lots at presynaptic terminal, participates in vesicle recycling

degraded by the UPS and by lysosomes

interacts strongly w/ membranes (plasma, mitochondrial)

131
Q

PINK1 and parkin

A

normally, PINK1 degraded in mitochondria

mitochondrial damage: PINK1 and Parkin accumulate in outer membrane of mitochondria; PINK1 causes ubiquitination of Parkin, causing mitophagy

oxidized and aggregated α-synuclein inhibits mitophagy, inducing cell apoptosis (bad)

132
Q

PINK1 KO and parkin

A

PINK1 KO: no mitophagy (Parkin not ubiquitinated, enlarged mitochondria)

PINK1 KO + overexpressed Parkin: mitophagy, like WT

133
Q

PD treatment

A

L-dopa (tyrosine is precursor)

deep brain stimulation

cell replacement therapy (induced pluripotent stemp cell)

134
Q

electron microscopy

A

uses electrons to image

high resolution images

can image very small tings (1-20nm)

135
Q

brainbow

A

ratio of RGB expression allows for unique cell type identification (express RGB construct in tandem to get different colors)

can make each cell type a different color

relies upon Cre-LoxP system

default color is red

136
Q

Rett syndrome is what kind of genetic disorder

A

X-linked disorder

patients usually are girls because males tend to die early since they only have one copy on the X chromosome

137
Q

Rett syndrome caused by mutations in what gene

A

Mecp2 gene, which encodes methyl-CpG-binding protein 2

located on X chromosome

involved in chromatin remodeling and transcriptional regulation

138
Q

Mecp2 domains

A

methyl-CpG-binding domain (MBD)

transcriptional repression domain (TRD)

139
Q

what Mecp2 do

A

recruits transcriptional corepressor complex containing Sin3A and histone deacetylase (HDAC) to methylated CpG islands

results in target gene transcription inhibition

140
Q

what else Mecp2 do

A

is also able to activate gene transcription by recruiting CREB and other transcriptional factors to non-CG methylated DNA regions

141
Q

how does Mecp2 cause neurological deficits: summary

A

MeCP2 binds to methylated DNA and regulates gene expression

can cause splicing, missense, nonsense, deletion, insertion (any of these can cause loss of function)

142
Q

Mecp2 KO mice

A

mimic symptoms of Rett:

  • slow development of brain
  • mobility problems, breathing problems
  • rescue: overexpressing MeCP2 in the KO mice allows them to have normal brain weight
143
Q

MeCP2 conditional KO mice

A

KO gene in adults

  • Gad67-Cre: targets GABAergic neurons
  • Cross w/ Mecp2f/f
    • KO Mecp2 only in GABAergic neurons
    • overgrooming, skin lesions
    • Mecp2 regulates GABA synthesis

Bio 222 Cell/Molec Neuroscience (7 decks)

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