# The role of glutamate receptors in compulsive and perseverative behavior

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $518,480

## Abstract

The dorsolateral striatum integrates convergent cortical and thalamic input to control action initiation and termination
Multiple disorders including obsessive compulsive disorder (OCD), autism spectrum disorders (ASDs),
and Tourette syndrome have altered function or maladaptive rearrangements of triatal circuits, resulting
in aberrant perseverative and repetitive behaviors. The spiny projection neurons (SPNs) make up approximately
90% of all the neurons in the striatum and are strictly divided by their incorporation and contribution
to the direct pathway (important for action initiation) and the indirect pathway (involved in action termination
In particular, two glutamate receptor types, Group 1 metabotropic glutamate receptors (mGluRs) and
kainate receptors (KARs) are important in regulating activity of both the direct pathway SPNs (dSPNs) and indirect
pathway neurons (iSPNs). Each of these receptors have multiple overlapping cellular functions, yet it remains
unclear how each receptor type contributes precisely to establishing and modulating synapses, and affecting
excitability of SPNs in the dorsolateral striatum. We have developed novel mice in which each of these
receptors are ablated conditionally in either dSPN or iSPNs. These mice demonstrate interesting behavioral
phenotypes that suggest divergent and dichotomous roles for each glutamate receptor type in the striatum.
In this proposal we will take a comprehensive approach to map the cellular to circuit function of mGluRs
and KARs, and determine how each of them has distinct roles in regulating striatal output. The goal is to
determine how each of the receptor types regulates synaptic and intrinsic properties of the SPNs, and how
contribute to the balanced output of this circuit that is vital to appropriate behavioral actions. Thus, in the first
aim we will determine the cellular roles of mGluRs and KARs in each of the SPN types. In the second aim we
will determine how each of the glutamate receptor types contributes to the balanced activity of the striatal circuit.
Finally, in the third aim we will use in vivo imaging of SPN activity during the initiation of motor and habitual
actions to determine whether imbalanced SPN function is evident during aberrant and maladaptive behaviors
when glutamate receptors are ablated in SPNs. Together these studies will take a comprehensive and
integrative approach to determine the cellular and circuit roles played by glutamate receptors in regulating striatal
circuits, and will inform us about how these receptors contribute to disorders with maladaptive and compulsive
behaviors.

## Key facts

- **NIH application ID:** 10343699
- **Project number:** 5R01MH099114-10
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Anis Contractor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $518,480
- **Award type:** 5
- **Project period:** 2012-09-17 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10343699

## Citation

> US National Institutes of Health, RePORTER application 10343699, The role of glutamate receptors in compulsive and perseverative behavior (5R01MH099114-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10343699. Licensed CC0.

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