# Determining optimal parameters for dynamic cholinergic modulation of associative learning

> **NIH NIH K08** · MASSACHUSETTS EYE AND EAR INFIRMARY · 2020 · $197,100

## Abstract

Project Summary / Abstract
Acetylcholine is an important modulator of brain function and cognition, and cholinergic deficiency is implicated
in several neuropsychiatric diseases, including delirium. Cholinergic stimulation would appear to be a
promising cognitive therapy, however, cholinesterase inhibitors that broadly augment the action of
acetylcholine have had limited clinical success and significant side effects. Therefore, there is a critical need to
understand cholinergic circuits better to develop therapies that can precisely maximize their function. To
address this need, we must address a knowledge gap regarding whether cholinergic function changes as
subjects learn associations between cues, responses, and reinforcers. With a combination of cutting-edge
circuit dissection tools, we can now selectively target one of the densest cholinergic projections to a cognitive
circuit: the cholinergic projection from the basal forebrain to the basolateral amygdala. Work in this research
proposal will identify if the activity and effects of this cholinergic projection are strongest when subjects are
uncertain about the associations between cues and reinforcers, as is hypothesized based on preliminary data.
The proposed project seeks to determine how the function of basal forebrain cholinergic neurons changes with
associative learning, using the framework of a continuous performance task sensitive to cholinergic blockade
and analogous to those used in delirium evaluations. A successful outcome of this proposal will be the
determination of how spatially and temporally targeted stimulation can significantly benefit cognitive control and
associative learning.
The additional goals of this Mentored Clinical Scientist Research Career Development Award (K08) for the
applicant are to 1. Develop expertise in circuit dissection techniques to investigate how specific circuit functions
change with behavioral demands; 2. Develop expertise in targeted neuromodulation in order to maximize
circuit function for cognitive benefit; 3. Develop professional skills, including sharing scientific knowledge
through papers and presentations, successfully obtaining funding including independent grants, and mentoring
and leadership skills to run an interdisciplinary research program. This career development award will extend
the applicant's prior training in behavioral electrophysiology and clinical focus on delirium and alterations in
mental status in order to connect physiologic and behavioral findings into specific circuits and networks that
could be potential therapeutic targets. This award will be a crucial stepping-stone towards the overall goal of
developing into an independent clinician-scientist, moving from bedside to bench to research the acute
cognitive disorders that are common and yet poorly understood in clinical practice, in particular delirium.

## Key facts

- **NIH application ID:** 9855076
- **Project number:** 5K08MH116135-04
- **Recipient organization:** MASSACHUSETTS EYE AND EAR INFIRMARY
- **Principal Investigator:** Eyal Yaacov Kimchi
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $197,100
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9855076

## Citation

> US National Institutes of Health, RePORTER application 9855076, Determining optimal parameters for dynamic cholinergic modulation of associative learning (5K08MH116135-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9855076. Licensed CC0.

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