Restricted, repetitive behavior refers to multiple behavioral categories that include stereotyped movements, compulsions, and rituals. Repetitive behavior is diagnostic for autism spectrum disorders (ASD), highly prevalent in syndromic and non-syndromic intellectual and developmental disability (IDD), and common in certain neurological disorders (e.g. Tourette syndrome, fronto-temporal dementia). Despite its clinical importance, effective interventions for repetitive behavior are lacking owing, at least in part, to only a rudimentary understanding of the relevant neural circuitry mediating such behavior. Identifying discrete neural pathways controlling repetitive behaviors is key to determining neurobiological mechanisms and developing effective treatments. Our prior work, using two mouse models of repetitive behavior, has identified cortico- basal ganglia circuitry dysregulation, specifically decreased neuronal activation in brain areas associated with the indirect basal ganglia pathway. What is lacking, however, is direct evidence of discrete basal ganglia projections that control the expression of repetitive behavior. Thus, the overall goal of this project is to determine specific cortical basal ganglia pathways that control repetitive behavior. We will test two hypotheses: activation of the indirect basal ganglia pathway via disinhibition of the subthalamic nucleus (STN) will significantly and rapidly reduce repetitive behavior and inhibition of the hyperdirect pathway will exacerbate repetitive behavior. To test these hypotheses, we will employ in vivo optogenetics to manipulate, with the requisite temporal and spatial resolution, the critical functional circuitry hypothesized to mediate the expression of repetitive behavior. Using this approach, we propose to test directly the importance of the indirect and the hyperdirect basal ganglia pathways in mediating repetitive behavior. This will be done using an inbred mouse strain (C58) that exhibits a well-characterized, robust repetitive behavior phenotype. Dissecting the basal ganglia circuitry controlling the expression of repetitive behavior will be innovative and impactful and guide the development of novel treatments in disorders involving aberrant repetitive behavior.

Public Health Relevance

Repetitive behaviors are diagnostic for autism and a common feature of other neurodevelopmental disorders. We will use an animal model to determine the specific neural pathways that control the expression of repetitive behavior. This information will be useful in developing new treatments for restricted repetitive behavior in individuals with neurodevelopmental disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH110911-01
Application #
9168489
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Simmons, Janine M
Project Start
2016-06-01
Project End
2018-02-28
Budget Start
2016-06-01
Budget End
2017-02-28
Support Year
1
Fiscal Year
2016
Total Cost
$225,000
Indirect Cost
$75,000
Name
University of Florida
Department
Psychiatry
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611