# Role of Dopamine receptor-expressing cortical projection circuits in cognitive flexibility

> **NIH NIH R21** · UNIVERSITY OF FLORIDA · 2022 · $190,625

## Abstract

Role of Dopamine receptor-expressing cortical projection circuits in cognitive flexibility
Abstract
Dopamine is a crucial neuromodulator of cognitive flexibility, which is essential for daily activities,
and achieving goals efficiently. Dopamine dysfunction leads to disruption in flexibility, which is
implicated in many CNS disorders such as schizophrenia, OCD, and drug addiction. Prefrontal
cortex (PFC) pyramidal neurons and their projections to the striatum are critical in regulating
cognitive flexibility. Dopamine and dopamine receptors on PFC neurons also play a critical role in
regulating cognitive flexibility. Our recent findings show a previously unappreciated topographical
organization of dopamine receptor expressing PFC pyramidal neurons and circuits. However, the
effects of these PFC dopamine receptor circuits on cognitive flexibility is not known. Our goal is
to dissect the functional role of these distinct dopamine receptor cortico-striatal circuits. In this
proposal, we will use an interdisciplinary approach (pharmacology, neuron tracing, behavior and fiber
photometry) to test the central hypothesis that distinct topographically-organized D2R+ or
D1R+ PFC subcircuits differentially regulate cognitive flexibility and striatal dopamine. In
Aim 1, using intersectional chemogenetic approaches, we will manipulate D1R+ sub-circuits that
project to distinct subcortical targets, and test their effects on behavioral flexibility and striatal
dopamine. In Aim 2, using intersectional chemogenetic approaches, we will manipulate D2R+ sub-
circuits that project to distinct subcortical targets, and test their effects on behavioral flexibility and
striatal dopamine. Our studies will significantly advance our understanding of the local and global
circuit effects of cortical dopamine and dopamine receptors, and understand their role in normal
and pathological regulation of cognitive flexibility. Our studies will also provide a strong rationale
for future studies to better target cortico-striatal circuits in the treatment of cognitive inflexibility.

## Key facts

- **NIH application ID:** 10451272
- **Project number:** 1R21MH127377-01A1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Nikhil Urs
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $190,625
- **Award type:** 1
- **Project period:** 2022-02-10 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10451272

## Citation

> US National Institutes of Health, RePORTER application 10451272, Role of Dopamine receptor-expressing cortical projection circuits in cognitive flexibility (1R21MH127377-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10451272. Licensed CC0.

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