# Cholinergic Contribution to Circuits Underlying Depression

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $418,750

## Abstract

Abstract
The primary pharmacologic treatment for depression over the past several decades has been drugs that inhibit
synaptic reuptake of monoamine neurotransmitters. Although the importance of monoamine neurotransmission
in antidepressant efficacy cannot be discounted, other neurotransmitter systems are known to contribute to the
mechanism of action of antidepressants. Furthermore, the existence of a large group of non-responding
patients necessitates development of novel compounds to treat depression. A growing body of data suggests
that cholinergic systems may be potential targets for development of novel antidepressant compounds, and
that excessive cholinergic signaling may contribute to the pathophysiology of depression. Depression can be
conceptualized as a maladaptive response in which the ensemble of stress-related behaviors does not switch
back to the collection of behaviors that allow exploration of the environment and pursuit of natural rewards.
Neuromodulators are well placed to coordinate these ensembles of behavior and to mediate the switch
between coordinated behavioral states. ACh facilitates stress-related learning and hypervigilance through
actions in the amygdala and promotes stress-related avoidance mediated through the hippocampus. The
effects in each of these brain areas are distinct and mediated through different receptor subtypes, and we
propose that these can be bound into an ensemble of stress-related behaviors by release of ACh. We
therefore hypothesize that increasing ACh signaling in amygdala and hippocampus facilitates the transition to
this stress-related behavioral ensemble and consequently, blocking cholinergic receptors of different kinds
promotes an adaptive, antidepressant response. In these studies we will identify neuronal mechanisms in
amygdala underlying cholinergic regulation of stress-related behaviors, test the hypothesis that phasic
increases in ACh signaling in hippocampus, as occurs in response to stress, induces behaviors related to
depression, and determine whether distinct populations of ACh neurons projecting to amygdala and
hippocampus are responsible for the effects of cholinergic signaling on stress-induced behaviors.

## Key facts

- **NIH application ID:** 9932477
- **Project number:** 5R01MH077681-14
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Marina R Picciotto
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2006-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932477

## Citation

> US National Institutes of Health, RePORTER application 9932477, Cholinergic Contribution to Circuits Underlying Depression (5R01MH077681-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9932477. Licensed CC0.

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