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psyc 318 > mental illness (schizophrenia) > Flashcards

mental illness (schizophrenia) Flashcards

1
Q

some characteristics of psychiatric illnesses like schizophrenia or autism (3)

A
  1. heritable (linked to genetics)
  2. common (4% frequency of severe mental disorders)
  3. harmful to reproductive success (decreases fertility rate)
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2
Q

schizophrenia is characterized by (4)

A
  1. social withdrawal
  2. disorganized thinking
  3. abnormal speech
  4. inability to understand reality (delusions of grandeur and persecution)
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3
Q

global prevalence of schizophrenia

A

1%

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4
Q

most common cause of schizophrenia

A

hundreds of relatively common gene variants that each individually confer small statistical increase in risk of developing schizophrenia (not single gene, not single brain region; more variant genes -> more risk)

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5
Q

mental disorders that have gene variant overlap with scz (5)

A
  1. BPD
  2. MDD
  3. autism
  4. OCD
  5. ADHD
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6
Q

are gene variants specific for one mental disorder and why

A

no; create vulnerability to mental illness in general because risks conferred aren’t specific to traditional diagnostic boundaries & considerable overlap of gene variants bw several mental illnesses; gene variants increase risk of developing mental illness, but are not causal

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7
Q

what is comorbidity

A

having more than 1 diagnosis at the same time

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8
Q

why do harmful gene variants persist in population when should be selected out (because of decreased reproductive success)

A

mutation-selection balance: susceptibility genes are continually selected out through evolution, but new mutations keep arising

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9
Q

what allows genetic variation to accumulate in population (even if mutations can disrupt brain function)

A

human genome evolved to buffer many insults; protects if individual mutations aren’t to severe

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10
Q

if a slightly bad mutation doesn’t cause disease, how can it increase probability of having a mental illness

A

it can collectively compromise evolved interactions of proteins within brain; reduces overall robustness of brain development and brain function; brain more vulnerable to other mutations and increased risk of developing mental illness

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11
Q

why is it difficult to study and treat neuropsychiatric disorders

A

limited understanding of circuit-level dysfunctions that underlie neuropsychiatric disorders

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12
Q

why are rare but penetrant genes getting more attention in fields of study

A

offer clear roadmap to identification of circuit-level disruptions; genetically well-defined

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13
Q

5% of scz (severe) cases are attributed to

A

rare gene copy number variations (duplicated or missing genes from chromosomal abnormalities)

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14
Q

why use mice models if their behavioral phenotypes don’t resemble human disorders

A

molecular, cellular and circuit phenotypes are likely to be informative

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15
Q

what chromosomal deletion in mice mimics 22Q11 deletion syndrome causing full-blow scz in human adults

A

chromosome 16 deletion

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16
Q

what is the authors’ hypothesis concerning what triggers scz

A

adverse bifurcation in late brain development in predisposed individuals

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17
Q

what interventions do the authors’ hypothesize could be prevent pathological process of developing scz

A

interventions aimed at promoting normal brain development during late adolescence

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18
Q

what is the mouse model for scz

A

LgDel+/- (missing 1 chromosome 16)

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19
Q

why is late adolescence more vulnerable for developing scz

A

unique transition when synchronized network activity is weaker than in adults and in early adolescence (dip in network activity)

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20
Q

which period of brain development is more susceptible to disruptions

A

late adolescence -> when coordinated activity is most important for brain maturation

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21
Q

which brain area is last to acquire adult-like features

A

PFC

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22
Q

important adult-like feature in PFC

A

coherent oscillatory activity of neuronal population in high-frequency gamma range

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23
Q

element specifically impaired in scz (2)

A
  1. gamma oscillations
  2. inhibitory interneurons that give rise to gamma oscillations
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24
Q

defining features of scz relate to

A

faulty PFC function

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25
Q

PFC-related scz features (2)

A
  1. deficits in working memory
  2. top-down control (impulse control and planning)
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26
Q

what is parvalbumin (PV)

A

calcium-binding protein highly expressed in certain populations of GABA interneurons

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27
Q

number of PV interneurons and PV expression in scz patients

A

PV interneurons present (normal number of PV interneurons), but decreased PV expression

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28
Q

underexpressed proteins in scz (2)

A
  1. PV
  2. GAD67
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29
Q

what is GAD67

A

enzyme that manufactures GABA from gluatamate

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30
Q

what do PV and GAD67 expression relate to

A

spiking activity of cell (dynamic expression)

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31
Q

relationship bw learning and PV & GAD67 (2)

A

learning associated with (1) changes in PV and GAD67 expression in PV interneurons and (2) changes in amount of excitatory input these cells receive

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32
Q

effect of decreased PV expression in scz patients compared to ‘wt’ on synchrony

A

calcium determines how fast neuron fires and how quickly it hyperpolarizes: more PV, neuron fires faster (good at buffering calcium)
scz -> PV interneurons don’t fire as fast (less PV) so synchrony is disrupted

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33
Q

elements looked at to test if LgDel+/- mouse is a good scz model of scz patients (4)

A
  1. is there reduced oscillatory activity in PFC?
  2. is there reduced PV expression in cortical PV interneurons?
  3. is there reduced excitatory input onto cortical PV interneurons?
  4. do they exhibit learning and memory deficits associated with scz?
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34
Q

what do tasks that depend on PFC and hippocampus function involve

A

contextual information or memory generalization

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35
Q

function of which brain areas are disrupted in scz mice models (2)

A

PFC and hippocampus

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36
Q

gamma oscillations correlate with

A

firing of inhibitory neurons

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37
Q

when are gamma oscillations more prominent

A

during alert, attentive wakefulness

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38
Q

how did the authors examine gamma oscillations in LgDeL+/- mice

A
  1. put metal wires in PFC
  2. electrical activity recorded was put through fast fourier transform
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39
Q

mPFC oscillatory activity (free exploration) in LgDel+/- mice compared to WT

A
  1. low gamma oscillations comparable
  2. LgDel+/- mice have decreased high gamma oscillations than WT
40
Q

what is fast fourier transform

A

takes a complex waveform and deconstructs it into individual sine waves (frequency of sine waves most prevalent in original signal)

41
Q

how did the authors measure level of PV and GAD67 protein in LgDel+/- mice

A
  1. cross Cre-tdTomato and PV-Cre mice to ID PV interneurons (PV interneurons tagged in red)
  2. IHC used to compare PV and GAD67 protein expression levels in Cre+ cells (PV interneurons) -> overlap
42
Q

PV and GAD67 expression in LgDel+/- mice

A

reduced

43
Q

correlation bw PV and GAD67 in PV interneurons in WT and LgDel+/- mice

A

highly correlated; most cells have both; only difference is LgDel+/- mice have low intensity of PV and GA67 (but still correlated)

44
Q

low PV expression is associated with (2)

A

reduced spiking activity and reduced neural plasticity

45
Q

number of PV interneurons and PV expression in LgDel+/- mice & win which brain areas

A

number of PV interneurons normal; reduced PV expression; PV altered everywhere in brain

46
Q

in which neurons is PV expression most dynamic

A

early born PV neurons (not late born)

47
Q

what is BrdU and what is it used for

A

synthetic nucleoside that can get incorporated into DNA during cell division (replacing thymidine); used for tracking cell development (permanent label)

48
Q

how did the authors compare PV expression in early vs late born PV neurons

A
  1. injected BrdU at different points in embryonic development (E11.5 and E13.5)
  2. analyze brain sections in adulthood
49
Q

results of BrdU injection at E11.5 and E13.5 (PV expression) in LgDel+/- compared to WT in mPFC and dCA3 & conclusion

A

E11.5 (early born): WT -> spread out in mPFC and dCA3; LgDel -> decreased intensity in mPFC and dCA3
E13.5 (late born): WT -> decreased intensity in mPFC and dCA3 (normal); LgDel -> comparable to WT in mPFC and dCA3
conclusion: early born (not late born) PV neurons in LgDel mice have reduced PC expression

50
Q

what is bassoon

A

protein found in glutamatergic axon terminals (used as marke)

51
Q

what is gephyrin

A

protein that attaches to GABA receptors (used as marker)

52
Q

what are bassoon and gephyrin used for

A

bassoon -> label excitatory synapses
gephyrin -> label inhibitory synapses

53
Q

how did the authors examine the possibility that low PV expression is linked to reduced excitatory synaptic input + results + conclusion

A
  1. IHC in postmortem brains
  2. used bassoon (excitatory) and gephyrin (inhibitory) to label synapses
  3. results: lower bassoon in LgDel (decreased excitatory synapses on PV interneurons) & no difference to WT of gephyrin
  4. conclusion: LgDel+/- mice have reduced density of excitatory synapses onto mPFC PV neurons
54
Q

what is the PSAM-PSEM chemogenetic technique

A

similar to DREADD system: PSAM receptor = pharmacologically selective actuator module & PSEM ligand = pharmacologically selective effector module

55
Q

what are PSAM-5HT3 and PSAM-GlyR chimeric proteins

A

PSAM-5HT3 -> sodium ion channel (excitatory)
PSAM-GlyR -> chloride ion channel (inhibitory)

56
Q

what activates PSAM-5HT3 and PSAM-GlyR

A

agonist PSEM^308

57
Q

how did the authors test if reduced PV expression is a consequence of reduced PV neuron activity

A
  1. PSAM-PSEM chemogenetic technique
  2. normal PV-Cre mice express PSAM-GlyR receptor in mPFC PV+ neurons
  3. chemogenetic inhibition of PV neurons
58
Q

effect of chemogenetic inhibition of WT PV+ neurons on PV expression and gamma oscillations

A

PV expression -> reduced to LgDel typical levels
gamma oscillations -> reduced to LgDel typical levels

59
Q

how is reduced PV expression related to reduced gamma oscillations

A

PV neuron activity is decreased/silenced -> PV protein stops being produced -> neuron firing is decreased -> decreased in gamma oscillations

60
Q

what does reduced gamma network activity in adult LgDel+/- mice reflect

A

low PV neuron activity and expression

61
Q

difference bw brain areas involved in cFC and FC

A

cFC involves hippocampus, FC does not

62
Q

relationship bw fear conditioning and PV levels and activity

A

fear conditioning shows increase in PV levels and spiking in early born PV neurons

63
Q

what is contextual fear conditioning compared to fear conditioning

A

cFC pairs electrical shocks with particular context; FC pairs electrical shock with sensory stimulus

64
Q

behavior of LgDel mice in contextual fear memory (cFC) compared to WT: (a) memory retrieval (freezing); (b) PV plasticity, mPFC; (c) gamma power

A

(a) decreased freezing to context than WT after cFC (decreased fear, decreased learning)
(b) no increased PV expression after cFC (WT have increased PV expression because learning)
(c) no change in brain oscillations after cFC

65
Q

what is trace conditioning and what brain area does it require

A

learning tasks where CS and US presentations are separated in time (gap in time = trace period); hippocampus

66
Q

why do authors test both contextual fear memory and trace fear memory when both involve hippocampus

A

contextual fear memory -> no exact moment in time when can record neural activity
trace fear memory -> exact moment in time when can record neural activity (trace period)

67
Q

describe the trace auditory fear conditioning task the authors put LgDeI mice through (9 steps)

A

acquisition phase:
1. context exposure
2. exposure to CS (tone)
3. 30s trace when neural activity dissipates
4. exposure to US
5. inter-trial interval
6. repeat steps 2-5 6x
retrieval phase
7. novel context
8. exposure to CS
9. measure freezing

68
Q

result of trace auditory fear conditioning task LgDel mice vs WT and why

A

LgDel mice had reduced freezing to tone (CS) because they aren’t learning well (non-functional hippocampus doesn’t retain info during trace period in acquisition phase)

69
Q

PFC PV activity during trace conditioning WT vs LgDel

A

WT: some PV neurons increase firing rate at CS onset, some decrease firing rate at CS onset
LgDel: same pattern as WT, but less PV neurons inhibited and les PV neurons excited

70
Q

what aspects of PV neurons are altered in LgDel mice (3)

A
  1. reduced expression
  2. reduced excitability
  3. reduced response to learning
71
Q

during which period of life do gamma oscillations differ bw WT and LgDel mice in the mPFC

A

adulthood: WT have higher gamma oscillations than LgDel

72
Q

lesion to PFC: what are mice able to do and what do they have deficits with

A

still able to learn task, but when something changes, deficits are observed

73
Q

4 tasks to test mPFC-dependent cognitive deficits in LgDel mice

A
  1. simple discrimination (learn to dig at specific odor)
  2. complex discrimination (distracting dimension, like floor texture, is introduced, but isn’t important)
  3. intra-dimensional shift (new odors and textures, but reward still associated with odor: changes, but conclusion is the same)
  4. reverse of intra-dimensional shift (reward associated with opposite odor)
74
Q

performance of adolescent LgDel mice in intra-/extra-dimensional set shifting task

A
  1. SD: same as WT
  2. CD: learning takes longer because easily distracted
  3. IDS: same as WT
  4. IDSRe: same as WT
75
Q

performance of adult LgDel mice in intra-/extra-dimensional set shifting (4)

A
  1. SD: same as WT
  2. CD: learning takes longer because easily distracted
  3. IDS: takes longer because hard for adults to switch
  4. IDSRe: takes longer
76
Q

conclusion of the intra-/extra-dimensional set shifting task

A

adult LgDel mice have trouble learning new odor during IDS compared to adolescent LgDel mice

77
Q

what does the social recognition task (SRT) test

A

hippocampus function: do the mice recognize the mouse in the cage in the 2nd trial or not

78
Q

adolescent vs adult LgDel mice in the SRT task

A

adolescent: recognizes familiar mouse in 2nd trial
adult: doesn’t recognize the same mouse in the 2nd trial (think it’s new mouse)

79
Q

what does the SRT task suggest and how it relates to scz patients

A

failure to suppress inappropriate actions in adult LgDel mice which might reflect ineffective top-down control on behavior (executive functions) in scz patients

80
Q

effect of D2 receptor antagonist haloperidol on adult LgDel mice

A

(1) normalization of gamma activity, (2) PV expression and (3) restores behavior deficits in PFC and hippocampus (cFC, SRT), but only up to 6h later, not 48h later (effect doesn’t last)

81
Q

which antipsychotic treatment normalizes aberrant functions in LgDel mice

A

D2 receptor antagonists

82
Q

brain areas where PV neuron abnormalities were observed in adult and young LgDel mice

A

adult - everywhere
young - 2 hippocampal areas: CA1 and subiculum

83
Q

what do the authors propose could increase the duration of the effects of the medication

A

if given at the time when PV deficits first emerge, maybe effects of D2R antagonists would be more enduring

84
Q

what produced a long-lasting and brain-wide rescue of PV expression in LgDel mice

A

local injections in ventral hippocampus of D2R antagonist every 2 days from P60-P70 (adolescent-adulthood transition, when PV deficits start occurring)

85
Q

local injections to ventral hippocampus of D2R antagonist every 2 days from P60-P70 rescued… (6)

A
  1. early-born PV neuron plasticity (PV expression)
  2. excitatory synapses
  3. PFC gamma oscillations
  4. fear conditioning memory (cFC and trace)
  5. social recognition memory (SRT)
  6. performance on intra-/extra-dimensional set shifting task (mPFC)
86
Q

when are D2R antagonist treatments ineffective (long-lasting effects)

A

10 day treatments before P55 (too young) or after P75 (too old)

87
Q

how many days of D2R antagonist treatment in young mice is effective and how many days is ineffective (long-lasting effects)

A

6 days (P60-P66) is effective and 4 days (P60-P64) is ineffective

88
Q

what is the sensitive time window for repeated D2R antagonist treatment to produce long-lasting, system-wide rescue

A

between P60 and P75

89
Q

which brain areas must be targeted by D2R antagonist treatment to produce long-lasting, brain-wide effects and targeting which brain areas have no effect

A

mPFC and vH; other prefrontal areas or dH

90
Q

efficacy of systemic injection of D2R antagonists within P60-P70 time frame

A

as effective as local treatment in the vH

91
Q

efficacy of chemogenetic activation of PV neurons in vH or mPFC

A

as effective as D2R antagonist in rescuing PV expression, network activity and cognitive function

92
Q

how does chemogenetic activation lead to long-lasting, brain-wide rescue

A

opening of ion channel -> more spiking -> change in gene expression -> change in neuron activity -> change in brain network

93
Q

how does long-lasting rescue of elements prevent scz phenotype even with predisposing genetic background

A

might suppress some network dysfunction during critical period of brain maturation, allowing healthy transition to adult brain function

94
Q

how does elevated low gamma power in adolescent LgDel mice relate to vH-mPFC connectivity

A

elevated low gamma power might reflect abnormally high CA3-CA1 activity, which might interfere with proper maturation of vH-mPC connectivity at the transition to adulthood

95
Q

what is the best treatment option for long-lasting rescue of PV neuron function, network function and cognition

A

10-day D2R antagonist treatment during well-defined period in adolescence (or chemogenetic activation of PV neurons in vH or mPFC)

psyc 318 (6 decks)

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