Autism spectrum disorders (ASD) are defined solely in terms of behavior. Their diagnostic symptoms: Impairment in social interaction;in communication;and restricted, repetitive, and stereotyped patterns of behavior;have presented a challenge in terms of the mouse models that facilitate research on the biology of these disorders. This laboratory, with its focus on behavioral analysis, will work with 3 outstanding behavioral geneticists, Drs. Jacki Crawley, Valerie Bolivar, and W. Scott Young, to integrate novel behavioral approaches with the use of candidate genes for involvement in the control of behaviors potentially related to ASD. Our preliminary studies using ethological and experimental approaches to mouse sociality have identified two interactive amicable or eusocial (i.e. not based on aggressive or sexual motivations) behaviors in C57BL/6J mice (huddling and frontal approach), and one mouse communication behavior, scent marking, that may provide parallels to these diagnostic symptoms of ASD. The project will utilize mice with mutations/targeted deletions of each of six genes: Engrailed 2;Reelin;Fragile X;Methyl-CpG-binding protein 2;Oxytocin, and arginine vasopressin 1b receptor, that have previously shown associations with deficient social behaviors, or enhanced representation in ASD or related conditions. The BTBR T+ tf/J mouse strain that has shown striking social deficiencies in previous work, will be used as a [low-social strain]. It will be compared to the C57BL/6J mice that are the background strain for many of these mutations. These mice will be evaluated in three tests: 1) The seminatural Visible Burrow System, in which interactive amicable or eusocial behaviors have been characterized and stereotypicalbehaviors can be detected. 2) Scent marking, using a protocol that measures both social olfactory communication in mice, and, the ability of the subject to form a relatively long-duration social memory differentiating between familiar and an unfamiliar conspecifics. Third, a well-established three-compartment test that measures both sociability to conspecifics vs. nonsocial stimuli, and preference for novel vs familiar conspecifics. These tests will also provide nearly 25 hours of videorecordings of each mouse in seminatural and structured situations, enabling a fine-grained analysis of repetitive or stereotyped behaviors, an additional focus of this laboratory. Mice showing significant changes in these behaviors will be evaluated for neurological/locomotor deficits, to assess specificity of changes and subjected to a breeding algorithm to determine if their behavior changes are due to mutant or ablated genes, or to flanking regions on the chromosome. This program will integrate a much finer and more detailed evaluation of behaviors potentially related to ASD with analysis of the effects of mutations in genes that may be related to these disorders.

Public Health Relevance

Autism spectrum disorder (ASD) is an increasingly common neurodevelopmental disorder defined by interactive social deficits, communication deficits, and the presence of ritualistic, repetitive behaviors. Although considerable information is available on genetic conditions that may be associated with ASD, experimental animal research to characterize and verify these gene-symptom relationships has been hampered by the lack of a broad-based and detailed analysis of relevant behaviors in mice. This proposal begins with broad-based and detailed ethological and experimental analyses of mouse social behavior (preliminary studies), and with this laboratory's history of identifying and evaluating repetitive or stereotyped behaviors in rodents, and proposes to work in collaboration with leading behavior geneticists in analyzing these behaviors in mice with mutations in a number of candidate genes for ASD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH081845-04
Application #
8225387
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Simmons, Janine M
Project Start
2009-04-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$342,540
Indirect Cost
$95,040
Name
University of Hawaii
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822
Meyza, Ksenia Z; Defensor, Erwin B; Jensen, Ashley L et al. (2013) The BTBR T+ tf/J mouse model for autism spectrum disorders-in search of biomarkers. Behav Brain Res 251:25-34
Blanchard, D Caroline; Summers, Cliff H; Blanchard, Robert J (2013) The role of behavior in translational models for psychopathology: functionality and dysfunctional behaviors. Neurosci Biobehav Rev 37:1567-77
Pearson, Brandon L; Corley, Michael J; Vasconcellos, Amy et al. (2013) Heparan sulfate deficiency in autistic postmortem brain tissue from the subventricular zone of the lateral ventricles. Behav Brain Res 243:138-45
Blanchard, D Caroline; Defensor, Erwin B; Meyza, Ksenia Z et al. (2012) BTBR T+tf/J mice: autism-relevant behaviors and reduced fractone-associated heparan sulfate. Neurosci Biobehav Rev 36:285-96
Meyza, Ksenia Z; Blanchard, D Caroline; Pearson, Brandon L et al. (2012) Fractone-associated N-sulfated heparan sulfate shows reduced quantity in BTBR T+tf/J mice: a strong model of autism. Behav Brain Res 228:247-53
Pearson, B L; Defensor, E B; Pobbe, R L H et al. (2012) Mecp2 truncation in male mice promotes affiliative social behavior. Behav Genet 42:299-312
Corley, Michael J; Meyza, Ksenia Z; Blanchard, D Caroline et al. (2012) Reduced sulfate plasma concentrations in the BTBR T+tf/J mouse model of autism. Physiol Behav :
Pobbe, Roger L H; Pearson, Brandon L; Defensor, Erwin B et al. (2012) Oxytocin receptor knockout mice display deficits in the expression of autism-related behaviors. Horm Behav 61:436-44
Sugawara, Atsushi; Pearson, Brandon L; Blanchard, D Caroline et al. (2012) Mouse females devoid of exposure to males during fetal development exhibit increased maternal behavior. Psychoneuroendocrinology 37:383-95
Defensor, Erwin B; Pearson, Brandon L; Pobbe, Roger L H et al. (2011) A novel social proximity test suggests patterns of social avoidance and gaze aversion-like behavior in BTBR T+ tf/J mice. Behav Brain Res 217:302-8

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