Research Models of Autism Flashcards by Mona Fazakas

What are the phenotypes of ASD?

social deficits

social communication: language deficits

intellectual disability

restricted, repetitive behaviors

How well did you know this?

Not at all

Perfectly

What are the animal endophenotypes of ASD?

social behavior: social recognition, reciprocal social interactions, social interactions, social approach, social preference

vocalization alteration: atypical ultrasonic vocalizations

cognition: cognitive flexibility

repetitive behavior: hyperactivity, stereotypies

How well did you know this?

Not at all

Perfectly

What are the animal models of autism?

genetic models involve genes proposed to contribute to ASD (causal models, construct validity) or in systems associated with ASD (associative models, face validity)

environmental models involve known causal risks for ASD (construct validity)

phenotype models reproduce phenotypes of ASD (face validity)

How well did you know this?

Not at all

Perfectly

What are the genetic models of autism?

FMR1 KO mice

OTR KO mice

OT KO mice

CD38 KO mice

How well did you know this?

Not at all

Perfectly

What are the environmental models of autism?

prenatal valproic acid

neonatal borna disease virus infection

maternal immune activation (MIA)

How well did you know this?

Not at all

Perfectly

What are the phenotype models of autism?

BTBRT+TF/J mice

BALB/C mice

microtine rodents

How well did you know this?

Not at all

Perfectly

Why is predictive validity difficult to establish in ASD models?

no current pharmacology treats core symptoms of ASD

antidepressants (depression, anxiety), psychostimulants (attention deficits, impulsivity), and antipsychotics (aggressive, repetitive, and self-injurious behaviors) are used to treat comorbidities and difficult behaviors

anticonvulsants used to treat comorbid seizures

How well did you know this?

Not at all

Perfectly

How can behavioral therapy be translated to animal models?

individuals with autism are responsive to speech, language, and occupational therapy, predictable environmental enrichment, adherence to routine, and multi-sensory stimulation

animal models are amenable to such manipulations (especially predictable enrichment and multi-modal sensory stimulation paradigms) but are rarely tested

How well did you know this?

Not at all

Perfectly

What is the social recognition tests for social behavior in rodents?

measure of social memory

rodent introduced to familiar and novel conspecifics and time spent in olfactory investigation measured

decreased time investigating familiar is indicative of memory

How well did you know this?

Not at all

Perfectly

What is the social preference test for social behavior in rodents?

degree of preference for novel vs. familiar individual

measured by time spent in proximity to novel or familiar rodent in adjacent chambers

preference for social novelty indicative of social motivation

How well did you know this?

Not at all

Perfectly

What is the partner preference test for social behavior in rodents?

measures bonding between rodents

preference for bonded conspecific measured by time spent in huddle with novel vs. familiar

How well did you know this?

Not at all

Perfectly

What is the ultrasonic vocalizations test for communication deficits in rodents?

ultrasonic vocalizations are a normal response to acute isolation in pups

indicative of social anxiety

decreased vocalizations is proposed to parallel social communication deficits in ASD

How well did you know this?

Not at all

Perfectly

How is oxytocin (OXT) involved in autism?

hypophyseal peptide hormone released into the posterior pituitary

normal roles in reproduction, labor, and lactation

recent work recognizes role for oxytocin in pro-social behavior

OXT is a putative pharmacotherapeutic for social deficits in ASD

How well did you know this?

Not at all

Perfectly

What are putative OXT therapeutics?

as a peptide hormone, OXT administration is challenging due to rapid catabolism and low BBB permeability (half-life of 3 minutes in blood)

intranasal OXT: allows rapid access and moderate permeability across BBB, multiple ongoing trials

non-peptide agonists: BBB permeable agonists for the OXT receptor

OXT releasers: agonists to stimulate OXT releasing neurons

P-LAP inhibitors: antagonists of placental leucine aminopeptidase, the enzyme responsible for degradation of OXT

How well did you know this?

Not at all

Perfectly

What are BTBR T+TF/J and BALB/C mice?

inbred mouse strains screened for variations in social behavior

BALB/C and BTBR mice showed reduced social behaviors

decreased vocalizations

decreased scent marking

BTBR show altered OTR system

but BTBR pups show increased isolation-induced vocalization

variation in inbred strains arose through independent selection: low construct validity, but high face validity

How well did you know this?

Not at all

Perfectly

What are microtine rodents?

voles of the genus Microtus show interesting patterns of social behavior

prairie voles (Microtus ochrogaster) lives in colonies and form life-long monogamous bonds

share huddles, grooming, nesting, and pup-rearing responsibilities

the closely related meadow or montane voles inhabit solitary burrows and lacks any of these bonding characteristics

What is the difference between montane and prairie voles?

prairie vole and the related montane vole show high variability in social behavior

prairie vole is highly affiliative and socially monogamous

montane and meadow voles are asocial and non-monogamous

differences in developmental and neurological bases of social behavior have been applied to ASD

general model for social behavior

no construct validity for ASD

What are the limitations of Microtine rodents?

no construct validity

limited predictive validity

limited face validity

useful model for studying general neurological correlates of social behavior

How do early life social interactions impact oxytocin?

maternal care is associated with increased oxytocin (OXT) function/release

maternal separation decreases the expression of OXT, particularly in female offspring

in humans early childhood neglect correlates with decreased OXT levels in urine, and adult women exposed to abuse as a child have decreased OXT in CSF

human infants with high parent-infant synchrony (i.e. enhanced capacity to respond to infant’s socio-affective signals) have increased OXT levels in saliva compared with low parent-infant synchrony

effects seem to be cross-generational

human parents with high parent-infant synchrony also shown increased salivary OXT

How do early life social interactions affect adult social behaviors?

early social deprivation induces changes in social behaviors that persist into adulthood in animal models: impaired maternal care, increased/decreased aggression (species-specific), impaired social recognition

female offspring of low-licking/grooming dams (rats) show earlier sexual receptivity

male offspring of low-licking/grooming dams show increased dominant play-fighting behaviors

early social deprivation and enhancement lead to correlations in OXT system function and social behaviors: current studies are investigating causality in animal models

What are the three common OXT KO mice models?

OXT KO: prevents release of OT

OTR receptor KO: prevents activity of OT

CD38 KO: inducer of OT release

What are oxytocin KO mice?

OXT, OTR, and Cd38 KO all block recognition of familiar conspecifics in social recognition tests

normal sensory and non-social learning and memory

normal habituation to non-social odors

What are the specific findings of OTR KO mice?

forebrain-specific OTR KO mice show deficits in social recognition selective to strain background

failure to recognize familiarity of same strain of mice but can discriminate mice of a difficult background

suggestive of OXT involvement in “fine” social discrimination

how do OXT and OXT receptor KO mice produce social deficits?

decreased social memory: failure to recognize conspecifics in social recognition tests, normal sensory/olfactory function and non-social learning and memory

decreased isolation anxiety: decreased ultrasonic vocalizations after maternal separation of pups

What are OXT system KO mice?

OXT, OTR, CD38 KO mice show decreased vocalizations after isolation from dam and other pups decreased isolation anxiety and locomotion (attempts to reunite with dam across barrier) pups show a general increase in locomotion and exploration: thought to reflect decreased anxiety children with high-function ASD show reduced social stress in Trier social stress test BUT OXT is anxiolytic and proposed to act in ASD by reducing social anxiety

What is predictive validity of KO models?

OXT, OTR, and CD38 KO mice recover social deficits by a single intracerebroventricular injection of OXT deficits recover if OXT delivered before, but not after initial social exposure suggests OXT involvement in encoding but not recall of social information possible role in enhancing saliency of social information

How does intranasal OXT affect human social behaviors?

in-OXT improves social function in autism and schizophrenia: increases gaze-fixing on faces, improves social recognition and cognition, improves affective recognition and retention of affective speech, some studies show decreases in repetitive behavior but limited evidence for role of OXT in heritable cases of autism: deletion of OTR gene in some families, evidence for methylation differences in OTR (epigenetics)

How does intranasal OXT alters behavior in healthy controls?

OXT is now being investigated experimentally in a number of human studies looking at specific behaviors IN-OXT increases social cognition in healthy controls: increased gaze-fixation, increased socio-affective processing IN-OXT decreases emotional processing: in fMRI studies, OXT groups show decreased activation of the amygdala while viewing frightful faces or threatening scenes

What are the limitations of OXT models?

limited evidence of OXT system dysfunction in ASD: low construct validity OXT enhances social capability in "normal" rodents and humans possible compensatory mechanism to OXT action rather than direct rescue of ASD deficits unknown if OXT has impact on other phenotypes of ASD outside social domain

What are the environmental models of ASD?

prenatal exposure to valproic acid (anti-convulsant) is a known risk for development of ASD prenatal exposure in rodents produces behaviors consistent with ASD decreased social interactions decreased sensitivity to pain: increased sensitivity to non-painful stimuli repetitive/stereotypic-like activity increased anxiety long-lasting fear memories - difficult to extinguish altered isolation-induced vocalization

What is the VPA model of autism?

decreased spine density and increased dendrite length: suggestive of hypo- and hyper-connectivity phenotypes behavioral interventions reverse VPA phenotypes: environmental enrichment, multi-sensory stimulation environmental enrichment and multi-sensorimotor stimulation shown to ameliorate some symptoms in autistic children

How is maternal infection related to autism?

maternal infection is associated with an increased risk of developing autism evidence of inflammation in ASD children that persists into adulthood elevated cytokines and pathology of microgliosis and astrogliosis in post-mortem ASD brain elevated cytokines in CSF of ASD children (3-10) dysregulation of immune genes in autistic brain in microarray studies

How is neonatal borna disease virus infection associated with autism?

major human risk for ASD (rubella) is a human-specific infection BDV is a persistent neurotropic virus capable of infecting humans, rodents, horses, sheep, cattle, and birds causes persistent, non-lethal infection of neural cells analogous to in utero rubella infection first rodent model used to investigate prenatal risk of ASD

What is the BDV model of ASD?

rats infected at birth - neonatal period neuroanatomical deficits: cerebellum, limbic behavioral deficits: hyperreactivity, circadian rhythm disturbance, social-play deficits, cognitive deficits, chronic anxiety

What are the limits of the BDV model of ASD?

persistent infection - not seen in ASD timing of insult - neonatal (3rd trimester) does not match risk of viral infection in ASD may reflect the specific neurotoxic effects of infection rather than the maternal immune activation largely supplanted by MIA models for ASD: POLYI:C model is the preferred system

What is maternal immune activation?

POLYI:C effects are moderated indirectly through placental transmission of inflammation key role for IL-6 in placental transmission of inflammation