# Striatal Regulation of Cortical Acetylcholine Release

> **NIH NIH R21** · NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC · 2022 · $202,686

## Abstract

The basal ganglia regulate cortical function via cortico-striatal-thalamo-cortical loops. Two functionally
opposing pathways the direct and indirect pathway either activate or inhibit thalamo-cortical circuits via the
basal ganglia output nuclei, the globus pallidus and the substantia nigra. Recent slice physiology experiments,
however, suggest an additional more direct link by which the striatum regulates cortical activity. In slices both
direct and indirect pathway neurons of the dorsal striatum inhibit cholinergic neurons that project to frontal
cortical areas. One area that receives inputs from striatal-inhibited cholinergic neurons is the orbitofrontal
cortex (OFC). The OFC supports reversal learning a measure of behavioral flexibility that is affected in several
mental disorders including obsessive-compulsive disorder, schizophrenia and drug addiction. Strikingly, not
much is known about the regulation of the OFC by cholinergic neurons, whether cholinergic projections to the
OFC modulate reversal learning and whether cholinergic projections to the OFC are regulated by the striatum
during behavior. This explorative R21 application is a first step to address these gaps in knowledge. We will
use the mouse and the modern circuit dissection tools available to the mouse to test the overarching
hypothesis that direct and indirect pathways regulate reversal learning via inhibition of OFC-projecting
cholinergic neurons. To address this hypothesis we propose the following two aims:
Aim 1: To determine whether cholinergic neurons projecting to the OFC support reversal learning
In aim 1.1 we will use Ca2+ imaging to measure the activity of OFC-projecting cholinergic neurons. In aim 1.2
we will inhibit OFC-projecting cholinergic neurons and determine how this affects cortical acetylcholine release
and reversal learning.
Aim 2: To determine whether the striatum regulates reversal learning via the cholinergic system
In aim 1.2 and aim 1.2 we will inhibit indirect or direct pathway neurons during reversal learning to determine
how this affects cortical acetylcholine release and reversal learning.
Understanding the role of the basal ganglia in regulating OFC function and reversal learning will have
important implications for brain disorders with abnormalities in cortico-striatal circuitry and impaired reversal
learning including schizophrenia, obsessive-compulsive disorder and drug addiction.

## Key facts

- **NIH application ID:** 10372475
- **Project number:** 1R21MH126380-01A1
- **Recipient organization:** NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
- **Principal Investigator:** Christoph Kellendonk
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $202,686
- **Award type:** 1
- **Project period:** 2022-01-12 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372475

## Citation

> US National Institutes of Health, RePORTER application 10372475, Striatal Regulation of Cortical Acetylcholine Release (1R21MH126380-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10372475. Licensed CC0.

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