# How does neuromodulation shape the fluidity of spatial working memory?

> **NIH NIH DP2** · UNIVERSITY OF CALIFORNIA BERKELEY · 2022 · $1,305,654

## Abstract

ABSTRACT / PROJECT SUMMARY
Spatial navigation requires working memory for the ability to flexibly update an internal representation of position
as one moves through the world, yet also stably hold “in mind” one’s position during periods of rest. Despite the
critical importance of working memory for a wide range of cognitive processes, we currently lack basic
understanding of how working memory circuits balance the fundamental tension between flexibility and stability.
This gap is due to three major challenges: (1) defining a complete network that holds internal representations
during working memory; (2) the ability to causally test how fluidly networks can transition between distinct
representations; and (3) a conceptual framework for how transition probabilities are modulated at a biophysical
level. This proposal will overcome these challenges by investigating how dopamine modulates the stability of
internal spatial representations in a tractable experimental system: the central complex of the fruit fly, Drosophila.
We have developed methods to measure how dopaminergic modulation shapes synaptic, cellular, and network
dynamics of genetically identified neurons that code for spatial orientation. First, we will measure when dopamine
modulates navigational circuits using whole-cell electrophysiology from the brains of flies walking in virtual reality.
Then we will define how dopamine levels shape network dynamics by using optogenetics to explore how
dopamine alters the ease of overwriting spatial representations. Finally, we will use cell-type specific
perturbations of dopamine receptors with in vivo electrophysiology and calcium imaging to define how changes
to synaptic and intrinsic properties shape network fluidity. The ultimate goal is a biophysical-level description of
how neuromodulation shapes working memory processing online. Due to the difficulty of interpreting and
perturbing population activity that is distributed across large mammalian brains, these experiments have been
previously out of reach. By using Drosophila, we can focus on a compact navigational circuit comprised of only
a few hundred neurons with known connectivity and unmatched genetic access. Although there are clear
differences between flies and mammals, dopamine signaling and spatial coding properties (head direction
networks) are strikingly conserved across species. These similarities argue that the principles we discover in the
fruit fly will be relevant to cognitive processing in other animals. A mechanistic understanding of working memory
fluidity is essential for the top-down design of therapeutic strategies to treat cognitive disorders.

## Key facts

- **NIH application ID:** 10472347
- **Project number:** 1DP2NS132373-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Yvette E Fisher
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,305,654
- **Award type:** 1
- **Project period:** 2022-09-20 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10472347

## Citation

> US National Institutes of Health, RePORTER application 10472347, How does neuromodulation shape the fluidity of spatial working memory? (1DP2NS132373-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10472347. Licensed CC0.

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