# Dissecting the role of medial versus lateral orbitofrontal circuit activity in perseverative behavior

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $180,537

## Abstract

PROJECT SUMMARY/ABSTRACT: Perseverative behaviors are prominent, disabling, and often treatment-
resistant symptoms of several neuropsychiatric disorders including Obsessive Compulsive Disorder (OCD).
Perseverative behavior refers to the repetition or continuation of a response that no longer results in a reward or
expected outcome. Human neuroimaging data has associated abnormal activity within orbitofronto-striatal
circuits with perseverative behavior in OCD patients. While early human neuroimaging studies identified
overactivation of the entire orbitofrontal cortex (OFC), more recent studies have linked overactivation of the
lateral OFC (lOFC) and hypoactivity of the medial OFC (mOFC) with OCD symptoms. Furthermore, preclinical
work in rodents suggests that activating mOFC-striatal projection neurons drives perseverative behavior, while
activating lOFC-striatal projection neurons suppresses perseverative behavior. Yet, a substantial gap in
knowledge remains regarding the mechanisms underlying the differential regulation of perseverative behavior
by the mOFC versus lOFC. This project will use chemogenetic and fiber photometry technologies in freely moving
mice to determine how neuronal activity within the mOFC versus lOFC regulate perseverative behaviors. We will
induce perseverative behavior in mice using acute challenge with a serotonin 1B receptor (5-HT1BR) agonist.
Pharmacological challenge with agonists for the 5-HT1BR, previously termed 5-HT1Dβ in humans, exacerbates
symptoms in OCD patients. Similarly, we found that treating mice acutely with a 5-HT1BR agonist induces
perseverative behaviors including a highly repetitive form of hyperlocomotion termed “route stereotypy”, and
perseverative responding in a delayed alternation task. These 5-HT1BR agonist-mediated effects can be
prevented by the only effective monotherapy for OCD, 4 weeks of chronic treatment with SRIs. Thus, acute 5-
HT1BR agonist treatment induces perseverative behaviors in mice with relevance to OCD. We will combine fiber
photometry and chemogenetics with our well-validated behavioral methods to identify the mechanisms
underlying the differential control over perseverative behavior by the mOFC versus lOFC. Previous work reported
that optogenetic stimulation of mOFC-ventromedial striatal projections induces perseverative grooming in mice,
while other work showed that optogenetic stimulation of lOFC-centromedial striatal projections suppresses
perseverative grooming. Here, we will assess the effects of chemogenetic inhibition of neuronal projections from
the mOFC versus lOFC to a large centromedial striatal region on 5-HT1BR agonist-induced perseverative
behavior. We will also determine whether perseverative behavior is associated with differential changes in
serotonin release into the mOFC versus lOFC using GRAB5-HT, and/or differential changes in the activity of
GABAergic interneurons or orbitostriatal projection neurons within the mOFC versus lOFC. Since dysfunction
with...

## Key facts

- **NIH application ID:** 10665272
- **Project number:** 1R21MH130819-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** STEPHANIE C DULAWA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $180,537
- **Award type:** 1
- **Project period:** 2023-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10665272

## Citation

> US National Institutes of Health, RePORTER application 10665272, Dissecting the role of medial versus lateral orbitofrontal circuit activity in perseverative behavior (1R21MH130819-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10665272. Licensed CC0.

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