# Mechanisms that regulate microglial dynamics in the context of plasticity

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $392,295

## Abstract

Remodeling of cortical networks by visual experience during development relies on rapid changes in synaptic
structure and function. The exquisite specificity of these activity-driven synaptic changes begs the question of
how they are implemented. Surprisingly we have recently shown that microglia, the brain’s immune cells, are
critical in this process. However, only a handful of the microglial mechanisms that contribute to plasticity have
been described. These pathways were initially studied for their roles in neuroinflammatory responses and it is
becoming clear that such mechanisms are also used in microglial function in the healthy brain. Norepinephrine
signaling through microglial adrenergic receptors is known to affect microglial function in pathological settings
but microglial contributions to norepinephrine’s effects on plasticity are as yet unstudied. Adrenergic signaling is
a particularly intriguing candidate as it directly opposes the purinergic signaling pathway in microglia that we
showed to be critical for plasticity, suggesting that adrenergic signaling in microglia could also impact synaptic
remodeling. Additionally, adrenergic signaling modulates global state changes between sleep and wakefulness,
and we have recently discovered that arousal changes microglial dynamics, which are critical to microglia-
synapse interactions. Therefore, in this proposal we will test the hypothesis that norepinpehrine acting through
microglial adrenergic receptors alters microglial function thereby affecting plasticity. To rigorously
investigate how norepinephrine affects physiological microglia, we will first examine how adrenergic signaling
affects microglial dynamics, surveillance and injury response in vivo (Aim1). We will then examine how
adrenergic signaling in microglia affects activity-dependent plasticity in the visual cortex (Aim 2) and the
associated functions of microglia during plasticity (Aim 3). We will use pharmacological approaches to alter
adrenergic signaling while monitoring microglia and visual responses, and we will determine whether effects are
specific to adrenergic signaling in microglia using conditional microglia-specific knock-out of the beta 2
adrenergic receptor (β2 AR) which is expressed at high levels within microglia. These studies will provide
important insight into the molecular mechanisms used by microglia when interacting with synapses which is
critical for understanding how microglia contribute to synaptic plasticity. Because synaptic plasticity is affected
in a large number of neurodevelopmental and neurological disorders, many of which are also associated with
aberrant adrenergic signaling, our work will provide potential targets for intervention to reinstate appropriate
plastic changes and ameliorate symptoms in these diseases.

## Key facts

- **NIH application ID:** 9874041
- **Project number:** 1R01NS114480-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Anna K Majewska
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $392,295
- **Award type:** 1
- **Project period:** 2020-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9874041

## Citation

> US National Institutes of Health, RePORTER application 9874041, Mechanisms that regulate microglial dynamics in the context of plasticity (1R01NS114480-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9874041. Licensed CC0.

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