Autism spectrum disorders (ASDs) are characterized by a suite of cognitive and social deficits, as well as by a range of somatic abnormalities, including mitochondrial, metabolic, and thermoregulatory deficits. The metabolic features of ASDs have received little attention from researchers investigating ASD-related phenotypes in mouse models. In addition, few researchers have taken a developmental approach to modeling ASD-related social deficits, despite the ASDs being understood as developmental disorders. Recent evidence indicates that several mouse models of social dysfunction (e.g., oxytocin and oxytocin receptor knockouts) have striking metabolic and thermoregulatory deficits that have gone unnoticed in previous studies of ASD-related phenotypes. A framework for relating social and metabolic deficits is lacking, and it is unclear to what extent the social deficits displayed b these models may relate to disrupted metabolic (e.g., thermal) homeostasis. We will test a framework in which social and metabolic phenotypes are seen as intimately related across developmental timescale, and in which animals with compromised metabolic and/or thermoregulatory homeostasis are predicted to exhibit deficits in basic aspects of social functioning. We will employ a suite of developmental, genetic, and pharmacological methods to elucidate these relations, and will focus on brown adipose tissue (BAT) thermogenesis as a model system for relating social and metabolic phenotypes in mouse models. First, we will track individual developmental trajectories in mice from high- and low-social strains, employing a battery of metabolic and social/emotional measures during development, with the aim of exploring the impact of naturally occurring variation in metabolic phenotypes on variation in social and emotional phenotypes. Next, we will characterize social and metabolic functioning in a number of mouse lines and genetically-engineered gene 'knockout' constructs selected for having deficits in either social or metabolic functioning, with the aim of testing our hypothesis that metabolic and social phenotypes manifest co-variations within and across mouse strains and constructs. We will also test the contribution of thermal conditions during animal rearing and testing to performance on commonly used tests of social and emotional functioning in several mouse models of ASD-related phenotypes already known to possess significant thermoregulatory deficits. This experiment will clarify the role that thermoregulatory deficits pla in the social and emotional deficits displayed by these mice. Lastly, we will examine the hypothesis that metabolic heat generated by BAT plays a significant role in mediating the prosocial effects of oxytocin in mouse models using pharmacological manipulation of BAT and oxytocin functioning. These experiments will greatly add to our knowledge of the development and expression ASD- related phenotypes in mouse models, and will have high translational value, given the presence of poorly understood metabolic deficits in ASD.

Public Health Relevance

Autism spectrum disorders (ASDs) are complex and serious developmental disorders frequently characterized by poorly understood metabolic (e.g., mitochondrial) dysfunction. Recent evidence has made it clear that several mouse models of ASD-like social dysfunction similarly display severely compromised metabolic homeostasis. This project investigates the role of such metabolic deficits in contributing to social dysfunction in mouse models, while building a framework for relating metabolic and social deficits that may suggest new routes for treatment of ASD.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD082203-02
Application #
9053504
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Kau, Alice S
Project Start
2015-04-13
Project End
2018-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Indiana University Bloomington
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401