# Acetylcholine signaling allows cognitive processes in the brain to regulate physiological responses to the environment: the example of central control of opiate tolerance

> **NIH NIH DP1** · YALE UNIVERSITY · 2020 · $1,172,500

## Abstract

Abstract
A surprising, and lethal, observation is that addicts who are tolerant to high doses of opiates
in an environment where they use these drugs habitually, can overdose when they take the
drug in an unfamiliar environment. This phenomenon shows that a cognitive process,
encoding environmental cues, can regulate the function of peripheral organs in a manner that
could be the key to understanding a whole host of mind-body interactions that are important
for survival. I propose that acetylcholine (ACh), acting through its receptors (nicotinic or
nAChRs, and muscarinic or mAChRs) is uniquely placed to coordinate central cognitive
processes, for example context-dependent learning, with autonomic and physiological
processes we need for survival. More importantly, the big idea embedded in this proposal is
that if ACh coordinates homeostatic responses between the brain and the periphery, not only
does the brain control responses in the body, but changing the body can control cognition
and behavior. If this is the case, it suggests that we can intervene in the periphery to induce
opiate tolerance and prevent overdose, and maybe even treat opiate addiction.
Using new molecular genetic tools, we will trace direct connections between precise cell
types in the periphery and the brain, manipulate activity of peripheral and central neurons
alone and in combination, regulate opioid receptor signaling in organs, peripheral neurons,
central respiratory centers and brain areas involved in cognition, and determine the precise
mechanisms for context-dependent opioid tolerance for the first time. We will go beyond the
focus on specific neurons, one brain area, a single circuit or the brain in isolation, and begin
to address the constant and complex interaction between the body and the brain that is
essential for understanding how we are able to survive and adapt to a hostile environment. If
this program is successful, I will move from being a molecular and behavioral neuroscientist
to being an integrative physiologist, someone skilled in understanding the autonomic nervous
system and a respiratory biologist, and my lab will be able to tackle mechanistic questions
about brain-body interactions that were not approachable previously.

## Key facts

- **NIH application ID:** 9996677
- **Project number:** 5DP1DA050986-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Marina R Picciotto
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,172,500
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996677

## Citation

> US National Institutes of Health, RePORTER application 9996677, Acetylcholine signaling allows cognitive processes in the brain to regulate physiological responses to the environment: the example of central control of opiate tolerance (5DP1DA050986-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9996677. Licensed CC0.

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