Despite the fact that abnormal repetitive behaviors are prominent, disabling, and notoriously-treatment resistant symptoms of many severe childhood onset neuropsychiatric disorders such as Obsessive Compulsive Disorder (OCD), Tourette Syndrome (TS), and autism, we still have a quite limited understanding of how they are encoded in the brain. Convergent clinical studies have highlighted the importance of cortico- striatal circuits in the development of abnormal repetitive behaviors, with functional neuroimaging studies consistently demonstrating 1) symptom-associated striatal hyperactivity that is 2) resolved by effective treatment. However, it is unknown how the two major opposing cell-types of the striatum, D1 and D2-spiny projection neurons (SPNs), contribute to striatal hyperactivity during these aberrant behaviors, and how activity in these two cell types is impacted by pharmacologic treatments. Although a prevailing theory suggests that intrinsically-generated abnormal repeated motor patterns might result from either excessive activation of the D1-associated direct pathway or decreased activation of the D2-associated indirect pathway, there is little direct evidence to support this idea. To begin to dissect the contributions of D1 and D2-SPNs to striatal hyperactivity and these maladaptive behaviors, we used an animal model system that displays both hyperactivity in central striatum (CS) and perseverative actions including compulsive grooming and abnormal reversal learning (Manning et al, in prep): SAPAP3-KO mice. Using in vivo microscopy in freely moving animals, we demonstrated that SAPAP3-KOs have increased grooming-associated striatal firing rates, consistent with published work. Surprisingly, when we selectively examined D1-SPNs, contrary to expectations we saw decreased activity compared to WT at initiation of compulsive grooming events, suggesting decreased responsiveness of D1-SPNs to cortical inputs in vivo. This activity pattern was normalized by effective fluoxetine treatment. These data suggest a novel model in which decreased activity in D1-SPNs and excessive activity in D2-SPNs promotes initiation of abnormal repetitive behaviors. In this project we will use state- dependent optogenetics, in vivo microscopy, and in vivo electrophysiology to both directly test this model and determine the impact of effective fluoxetine treatment on striatal D1, D2, and FSI (fast-spiking interneuron) activity patterns.
In Aim 1, we will identify D2-activity patterns during abnormal repetitive behaviors using in vivo microscopy and electrophysiology in freely-moving mice.
In Aim 2, we will use in vivo microscopy to identify D1- and D2-SPN activity patterns associated with successful fluoxetine treatment, and determine whether silencing D2-SPN activity can recapitulate this normalization.
In Aim 3, we will explore the relationship between FSI activity and the fluoxetine treatment response. The ultimate goal of these studies is to help refine neurostimulation-based treatment strategies for disabling perseverative and compulsive behaviors.

Public Health Relevance

PUBLIC HEALTH RELEVANCE: Abnormal repetitive thoughts and behaviors are prominent, disabling, and notoriously-treatment resistant symptoms of many severe and highly comorbid childhood onset neuropsychiatric disorders such as Obsessive Compulsive Disorder (OCD), Tourette Syndrome (TS), and autism. However, we still have a quite limited understanding of how these maladaptive behaviors are encoded in the brain. Defining the contribution of supplementary motor cortex to the generation and execution of perseverative thought patterns and repetitive actions may help develop new strategies for prevention and optimize existing neurostimulation protocols for these symptoms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH119837-01
Application #
9709695
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Rossi, Andrew
Project Start
2019-04-11
Project End
2023-01-31
Budget Start
2019-04-11
Budget End
2020-01-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15260