# Astrocyte control of neural circuits and behavior

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $431,336

## Abstract

Project Summary
Astrocytes are important regulators of neural circuit activity. Intracellular astrocyte Ca2+ signaling often correlates with
local synaptic activity and behavioral state. Astrocytes express a range of neurotransmitters (NTs) receptors, in many
contexts respond to NTs with increases in cellular Ca2+, and disruption of astrocyte calcium signaling can meaningfully
impact neurophysiology and animal behavior. However, the mechanisms by which astrocytes sense neurotransmission,
signal intracellularly and ultimately modulate circuit function remain poorly defined. Our goal is to identify and
functionally characterize endogenous signaling molecules that allow astrocytes to regulate neural circuits.
 We use Drosophila as a model to study astrocyte biology. Flies astrocytes are similar to their mammalian
counterparts by morphological, developmental, molecular and functional criteria, and this system offers a powerful array
of tools for characterizing gene function in vivo. In the previous cycle, we identified a simple circuit where
octopamine/tyramine (the fly orthologs of norepinephrine, NE) signal directly to astrocytes thought the Octopamine-
Tyramine Receptor (Oct-TyrR) GPCR, this activates the TRP channel Water Witch (Wtrw), which stimulates intracellular
astrocyte Ca2+ signaling and modifies downstream neuronal activity and behavior. This work (1) established a fly circuit
to study how astrocytes respond to neuromodulatory input and modulate circuits, and (2) demonstrated NE/Oct/Tyr-
dependent modulation of astrocyte Ca2+ signaling is an evolutionarily conserved astrocytic signaling mechanism.
 In preliminary work we found bath application of many NTs (i.e. glutamate, acetylcholine, GABA and dopamine)
failed to elicit Ca2+ signaling events in astrocytes. However, a brief pre-exposure of astrocytes to Oct/Tyr resulted in
potent astrocytic Ca2+ signaling events in response to these NTs within seconds, which depended on Oct-TyrR. This
suggests an arousal stimulus (i.e. norepinephrine/Oct/Tyr) gates the ability of astrocytes to sense the NTs Glu, Ach,
GABA and DA, and dramatically changes astrocyte function in vivo. In Aim 1 we will determine how PLC and
DAG/IP3 signaling downstream of Oct-TyrR regulate astrocyte sensitivity to Glu, GABA and Ach. In Aim 2 we will
characterize the role of adenylate cyclase, cAMP and PKA in gating astrocyte sensitivity to dopamine after Oct/Tyr
exposure. We will identify the source(s) of Ca2+ signaling activated by these NTs (e.g. is it Wtrw?), and explore how these
Oct/Tyr-gated events affect animal behavior. Finally, we will explore how astrocyte Ca2+ signaling events regulate neural
activity and behavior—among the most important unsolved questions in our field. In preliminary work we performed a
forward genetic screen for genes that when knocked down selectively in astrocytes, suppressed the ability of TRP
channel-mediated astrocyte Ca2+ entry to induce seizure behavior. We identified many genes, most o...

## Key facts

- **NIH application ID:** 10852985
- **Project number:** 5R01NS053538-20
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Marc R Freeman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $431,336
- **Award type:** 5
- **Project period:** 2006-01-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852985

## Citation

> US National Institutes of Health, RePORTER application 10852985, Astrocyte control of neural circuits and behavior (5R01NS053538-20). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10852985. Licensed CC0.

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