# Astrocyte-Neuron Circuits Underlying Cortical Mechanisms of Learned Behavior

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2024 · $415,416

## Abstract

Astrocytes are the major non-neuronal cell type in the cortex and are increasingly recognized as key contributors
to the development, plasticity and function of neuronal circuits. Yet, how they participate with neurons in learned
behavior and dynamically shape the underlying cortical circuits is poorly understood. The primary motor cortex
is required for learning and executing voluntary movements: the acquisition of a cued, stereotyped, movement
in mice is accompanied by synaptic remodeling of motor cortex neurons and the emergence of coordinated
movement-related ensemble neuronal activity. Here, we propose to examine functional astrocyte mechanisms
in motor cortex that mediate synaptic plasticity and neuronal dynamics during motor learning. Astrocytes have
highly ramified fine processes that contact nearly all synapses in the cortex, where they modulate synaptic
transmission and plasticity by mechanisms that include uptake of glutamate and GABA, primarily via the
transporters GLT1 and GAT3 respectively. Astrocytes also respond to, as well as modulate, synaptic activity with
spatiotemporally heterogeneous calcium transients in their processes, termed microdomains. We will examine
the role of astrocytes in shaping motor cortex circuits as mice learn a forelimb lever push movement, including
cued response onset and reliable movement trajectory, using a range of cutting-edge approaches: simultaneous
high-resolution imaging of astrocytes and neurons in vivo, computational encoding-decoding models of astrocyte
and neuronal activity, astrocyte-specific gene expression analyses, and novel astrocyte optogenetic and
CRISPR tools alongside established chemogenetic and viral knockdown methods. Building on our preliminary
data, which demonstrate parallel learning-related changes in astrocyte microdomain responses and neuronal
responses, along with gene expression changes in astrocyte GLT1 and GAT3, in Aim 1 we will determine
functional astrocyte calcium signatures in motor cortex during learning and their relationship to neuronal activity
and behavior. We hypothesize that astrocytes shape neuronal plasticity during task learning with corresponding
plasticity in their microdomain calcium responses, which we will specify computationally. In Aim 2, we will
determine the effect of astrocyte calcium signaling on motor learning and neuronal responses. We hypothesize
that disruption of calcium transients alters the emergence of neuronal ensembles and expert behavior, potentially
by altering astrocyte gene expression of transporter mechanisms. In Aim 3, we will determine the role of
astrocyte neurotransmitter transporter function in motor cortex circuits and learning. We hypothesize that
disrupting astrocytic modulation of excitatory transmission via GLT1, and inhibitory neurotransmission via GAT3,
disrupts astrocytic calcium responses together with neuronal circuit plasticity and behavior. Together, these
studies will provide a mechanistic, computational view of as...

## Key facts

- **NIH application ID:** 10908366
- **Project number:** 5R01NS130361-03
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** MRIGANKA SUR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $415,416
- **Award type:** 5
- **Project period:** 2022-09-22 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908366

## Citation

> US National Institutes of Health, RePORTER application 10908366, Astrocyte-Neuron Circuits Underlying Cortical Mechanisms of Learned Behavior (5R01NS130361-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10908366. Licensed CC0.

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