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PSYCH 473 > Animal Models of Schizophrenia > Flashcards

Animal Models of Schizophrenia Flashcards

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1
Q

What are the animal endophenotypes of positive symptoms?

A

amphetamine-induced locomotion

sensory gating impairment

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2
Q

What are the animal endophenotypes of negative symptoms?

A

locomotion tests
social tests
sustained attention tasks
reward/pleasure tests
cognitive tests

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3
Q

What are the ongoing controversies in psychiatry?

A

validation crisis: only publishing positive outcomes

sensitivity to placebo effect: MDD

DSM-5 controversies

disorder heterogeneity: categorization used in diagnostics and research has hindered progress

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4
Q

What is research domain criteria (RDoC)?

A

developing initiative to provide a biologically-relevant framework for the understanding of mental disorders

proposed alternative to the DSM-V for both clinicians and researchers

proposes to modernize psychiatric illness by moving away from strictly symptom-based diagnostics

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5
Q

What are RDoC domains?

A

dimensional - ranges from normal to abnormal

inclusive of clinical symptoms

informed by genetic, cell, circuit, molecular, physiological, and system-level insights

“agnostic” to existing categories of illness

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6
Q

What are examples of RDoC domains?

A

negative valence: stress, fear, anxiety, loss

positive valence: motivation, reward learning, reward valuation

cognitive systems: attention, perception, working memory, cognitive control

social processing: attachment formation, social communication, perception of self, affiliation

arousal/modulatory: arousal, circadian rhythm, sleep and wakefulness

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7
Q

What is the negative valence domain in schizophrenia?

A

30-85% comorbidity with anxiety symptoms

30-41.5% comorbidity with anxiety disorder

comorbid stress/anxiety severity dependent on incidence of positive symptoms (hallucination, delusions)

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8
Q

What is the positive valence domain in schizophrenia?

A

motivational deficits: mediate abnormal cognition, social cognition

anhedonia

impaired reward representation, reward-learning, motivation for incentives: mesocorticolimbic and mesostriatal dopaminergic pathways

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9
Q

What is the cognitive valence domain in schizophrenia?

A

attentional deficits: impact on social function, anxiety, gating

working memory impairments: PFC and hippocampal circuits

impaired sensory gating mechanism: mesolimbic DA pathway

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10
Q

What is the social processing domain in schizophrenia?

A

decreased social drive: social withdrawal, decreased social interest

longitudinal studies show early social deficits: poor socialization before age 10 in 60% of individuals who later developed SCZ, early socialization deficits associated with increased risk of developing psychosis before 17

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11
Q

What is the pre-pulse inhibition test (PPI)?

A

test of sensory gating: proxy for positive symptoms

startle response recorded in response to auditory tone

low intensity (3-12 dB) pre-pulse (30-500 ms) results in inhibition of startle response (PPI)

SCZ patients (and unaffected relatives) have impaired PPI at 60 ms

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12
Q

What is PPI measurement in rodents?

A

PPI is readily reproduced in rodents

PPI deficits induced by: DA-receptor agonists, 5-HT2 receptor agonists

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13
Q

What is the CANTAB battery?

A

Cambridge neuropsychological test automated battery

developed at Cambridge in the 80’s

recently adapted for rodents

22 touch-screen based tests examining:
general memory and learning
working memory and executive function
visual memory
attention and reaction time
semantic/verbal memory
decision making and response control

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14
Q

What are amphetamine-induced locomotion tests?

A

amphetamines induce rapid DA release and cause locomotor hyperactivity: increased DA tone in the nigrostriatal pathway

antipsychotics acting at DA receptors can inhibit the locomotor effects

widely used for drug screening (biased towards DA receptor antagonists)

predictive validity, but lacking any face or construct validity

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15
Q

What is the psychedelic-induced head-twitch response?

A

hallucinogenic drugs (5HT2A receptor agonists, i.e., LSD) induce a head-twitch response in rodents

LSD was once considered to be a psychotomimetic drug in humans: hallucinations considered to be vastly different and lacking as model of psychosis

atypical antipsychotics having action at 5HT2A receptor will block the head-twitch response

some predictive validity for atypical antipsychotics

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16
Q

What are the models of schizophrenia in rodents?

A

genetic: DBA/2J mice, db/db mice, PSD-93/Dlg2 mice

environmental: maternal protein malnutrition, maternal immune activation

pharmacological: phencyclidine (PCP)

17
Q

What are DBA/2J mice?

A

the oldest inbred mouse strain: mouse inbreeding uses sibling-sibling crosses to reach effective genetic homogeneity

compares with C57BL/6J in popularity and variability of use

spontaneously develops SCZ-like symptoms

18
Q

What is negative valence in DBA/2J mice?

A

increased stress and anxiety-like behaviors

avoidance of open-field

decreased exploration of elevated plus maze

increased latency, fewer entries in light/dark box

lack of preference for novel objects

immobility in FST

19
Q

What is positive valence in DBA/2J mice?

A

impaired sucrose preference

insensitivity to ethanol, nicotine, amphetamine, morphine

measurable differences in mesolimbic dopamine system

20
Q

What is the cognitive domain in DBA/2J mice?

A

impaired auditory PPI: PPI restored with typical or atypical antipsychotic treatment

complete absence of tactile PPI

lack of contextual blocking in fear conditioning

poor performance in learning and memory tasks

hippocampal and amygdala structural alterations

21
Q

What is the social processing domain in DBA/2J mice?

A

no differences from C57BL/6J

22
Q

What is the arousal domain in DBA/2J mice?

A

poor studied

23
Q

What are db/db mice?

A

leptin receptor-deficient mouse strain

leptin is an adipose-derived hormone controlling satiety

spontaneous mutant on the C57BL/6 line

common model for obesity and diabetes

24
Q

What is the negative domain in db/db mice?

A

increased anxiety

susceptible to learned helplessness

increased immobility in FST

25
Q

What is the positive domain in db/db mice?

A

poorly studied

decreased preference for voluntary ethanol consumption

26
Q

What is the cognitive domain in db/db mice?

A

age-dependent decreased PPI emerging after puberty

impaired spatial learning

normal object recognition

impaired LTP/LTD in hippocampal CA1

27
Q

What are the phenotypes of db/db mice?

A

arousal domain changes

no social deficits

obesity confounds locomotor tasks

predictive validity not established

28
Q

What are PSD-93/Dlg2 mice?

A

PSD93 is a membrane associated guanylate kinase

analog of PSD95

formation of NMDAR-associated signaling complexes in the post-synaptic density

polymorphisms identified in human SCZ patients

increased transcript, decreased protein expression reported in PFC and ACC in post-mortem SCZ tissues

29
Q

What is the limited behavioral characterization in PSD-93/Dlg2 mice?

A

negative domain, positive domain, arousal domain, social domain

one of the first demonstration of deficits induced by an identified SCZ polymorphisms

30
Q

What is the cognitive domain in PSD-93/Dlg2 mice?

A

impaired visual discrimination

impaired cognitive flexibility

impaired visuo-spatial learning and memory

correlations between CANTAB test battery (SCZ humans) and CANTAB-based touchscreen operant behavioral assay (mice)

31
Q

What is the maternal protein malnutrition model?

A

models adverse early environmental events seen as risk in SCZ

prenatal protein malnutrition leads to increased anxiety-like behaviors

coupled with elevated corticosterone response

32
Q

What are the positive domains of the maternal protein malnutrition model?

A

decreased motivation to earn reward

decreased sucrose preference

33
Q

What are the cognitive domains of the maternal protein malnutrition model?

A

age-dependent decreased PPI

increased striatal NMDAR binding

impaired memory acquisition in operant conditioning

impaired hippocampal DG LTP

34
Q

What is phencyclidine (PCP)?

A

NMDAR antagonist

inhibits hippocampal and cerebellar activity

cortical hyperactivity

dissociative and hallucinogenic

35
Q

What are the effects of PCP in humans?

A

induces both positive and negative symptoms

psychosis, hallucinations, paranoia

emotional withdrawal, motor retardation

formal thought disorder and neuropsychological deficits

36
Q

What are the negative domains of PCP phenotypes?

A

hyperlocomotion - (anxiety?)

inconsistent changes in anxiety tasks

learned helplessness in FST

37
Q

What are the positive domains of PCP phenotypes?

A

decreased sucrose preference

decreased conditioned food-reward

possibly confounded by attention deficits

38
Q

What are the cognitive domains of PCP phenotypes?

A

impairments: attentional set shifting, cognitive flexibility, processing speed, novel-object recognition, spatial learning, episodic memory, sensorimotor gating (PPI)

PFC and hippocampal deficits implicated

increased startle response

39
Q

What are the social domains of PCP phenotypes?

A

attenuated social interaction

PSYCH 473 (14 decks)

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