Research Models of Autism Flashcards
What are the phenotypes of ASD?
social deficits
social communication: language deficits
intellectual disability
restricted, repetitive behaviors
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
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)
What are the genetic models of autism?
FMR1 KO mice
OTR KO mice
OT KO mice
CD38 KO mice
What are the environmental models of autism?
prenatal valproic acid
neonatal borna disease virus infection
maternal immune activation (MIA)
What are the phenotype models of autism?
BTBRT+TF/J mice
BALB/C mice
microtine rodents
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 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
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
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
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
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 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
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
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
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
