# Structure and Function of Striatal Neuromodulatory Dynamics

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $597,947

## Abstract

PROJECT SUMMARY
Although the neuromodulators dopamine (DA) and acetylcholine (ACh) are extensively implicated in the
pathogenesis and treatment of neuropsychiatric diseases, their effects on the activity of brain circuits are typically
studied separately, leaving their ability to dynamically cooperate in supporting brain function and dysfunction
incompletely understood. This is a significant limitation as (1) neuropsychiatric disorders typically involve
disturbances in multiple modulators, (2) existing therapies rarely target a single modulatory system, and (3) the
physiological actions of modulators are fundamentally inter-dependent, since many co-exist in individual brain
regions and converge on overlapping cells to stimulate receptors that complement, antagonize, or synergize with
one another. An influential hypothesis in the field of basal ganglia research is that ACh gates or modifies the
physiological actions of DA in the striatum – a subcortical forebrain region important for learning and motivating
goal-directed behaviors. However, we still lack a clear understanding of precisely when, how and over what time
course ACh interacts with DA to differentially affect striatal activity and behavior. We recently discovered that
ACh levels in the striatum of mice constantly undergo large, subsecond fluctuations that are temporally
coordinated with DA and modulated in amplitude depending on behavioral state. The main goal of this proposal
is therefore to build of this observation and to test the hypothesis that DA acts in concert with ACh, such that the
precise timing and amplitude of subsecond ACh transients relative to DA is key for deciphering the effects of DA
on striatal circuits and behavior. We will do so by first monitoring the dynamics of DA and ACh with subsecond
precision from the striatum of mice engaged in reward-based behaviors using dual-color photometry of red and
green DA and ACh sensors (Aim 1). Next, we will mechanistically dissect the functional impact of ACh on DA
release and on striatal activity using photometric imaging combined with genetic and pharmacological
manipulations (Aim 2). Lastly, we will establish that ACh transients can gate the effects of DA on motivation and
learning using calibrated optogenetic manipulations (Aim 3). Together, the proposed work will provide crucial
mechanistic insights into the structure and function of coordinated DA and ACh dynamics in the striatum of mice
and pave the way for future investigations into how the disruption or potentiation of such coordination in humans
contributes to the development or treatment of neuropsychiatric disorders.

## Key facts

- **NIH application ID:** 10882036
- **Project number:** 1R01MH133669-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Nicolas Xavier Tritsch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $597,947
- **Award type:** 1
- **Project period:** 2024-03-15 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882036

## Citation

> US National Institutes of Health, RePORTER application 10882036, Structure and Function of Striatal Neuromodulatory Dynamics (1R01MH133669-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10882036. Licensed CC0.

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