# Dissecting the role of striatal cell types in abnormal repetitive behaviors and treatment response

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $471,436

## Abstract

PROJECT SUMMARY/ABSTRACT
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...

## Key facts

- **NIH application ID:** 10334446
- **Project number:** 5R01MH119837-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Susanne Elizabeth Ahmari
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $471,436
- **Award type:** 5
- **Project period:** 2019-04-11 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10334446

## Citation

> US National Institutes of Health, RePORTER application 10334446, Dissecting the role of striatal cell types in abnormal repetitive behaviors and treatment response (5R01MH119837-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10334446. Licensed CC0.

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