# Cholinergic Mechanisms of Associative Learning in Cortical Circuits

> **NIH NIH R21** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $460,855

## Abstract

Project Summary
Numerous observations both in humans and in experimental animals support the notion that acetylcholine (ACh)
is important for learning and memory. However, the cellular and circuit mechanisms through which ACh’s
biochemical control over the excitability of cortical cells reorganizes cortical dynamics and mediate learning and
learning related plasticity, or other cognitive functions, remain poorly understood. This application takes
advantage of technological advances in the last decade that facilitate exploring how cortical neurons are
modulated under physiological circumstances of ACh release, as well as determine the contribution of these
modulations to the physiology of cortical neurons and networks during behavior. We have implemented a simple
associative learning task that has been shown to depend on changes in cortical circuitry in the whisker
representation area of the primary somatosensory cortex (wS1) and is well suited to investigating the cellular
and circuit mechanisms by which ACh promotes associative learning. We have obtained preliminary evidence
that acquisition of the association of the conditioned stimulus and a reward requires ACh release in wS1. The
goal of this exploratory R21 grant is to demonstrate feasibility of several experimental strategies to study the
cellular and circuit mechanisms by which ACh promotes learning in the task we have implemented and to begin
testing hypotheses about cholinergic mechanisms responsible for the behavior. For these goals, we propose two
Aims. In Aim 1, we investigate the requirement of ACh during different phases of the associative learning task.
In Aim 1A, we use 2-photon microscopy with a genetically-encoded fluorescent ACh sensor to investigate the
magnitude and time course of ACh release in wS1 during the acquisition and consolidation of the associative
learning and during performance of the task after the association has been learned. In Aim 1B we develop a
chemogenetics strategy for the transient suppression of cholinergic activity in wS1 during specific phases of the
associative learning. In Aim 2 we begin to develop a pharmaco-genetic strategy using cell-specific genetic
ablation of specific cholinergic receptors in different types of excitatory neurons and inhibitory interneurons to
begin to discover cholinergic actions that are important for associative learning in our task. These experiments
will help develop a framework for understanding how dysfunction in ACh signaling results in neurocognitive
disorders associated with the cholinergic system, and provide insights into potential cell-type specific
interventions.

## Key facts

- **NIH application ID:** 10951778
- **Project number:** 1R21MH137452-01
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Bernardo Rudy
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $460,855
- **Award type:** 1
- **Project period:** 2024-09-06 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10951778

## Citation

> US National Institutes of Health, RePORTER application 10951778, Cholinergic Mechanisms of Associative Learning in Cortical Circuits (1R21MH137452-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10951778. Licensed CC0.

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