# Rapid Estrogen Signaling in Brain Circuits that Guide Complex Behavior

> **NIH NIH R01** · UNIVERSITY OF MASSACHUSETTS AMHERST · 2021 · $337,162

## Abstract

PROJECT SUMMARY
Anyone who starts learning a new foreign language can attest: sensory stimuli like speech and
song are near-continuous streams of complex sounds. With practice, listeners can learn to parse
the meaning in streams of Mandarin or Stravinsky. Communication sounds that vary over the
course of milliseconds (e.g., songs and speech) are optimally encoded by high-precision, low-
jitter neuronal activity. The neurons that process and respond to complex, dense sound streams
therefore exhibit fast and precise timing of action potentials. The spike timing of sensory neurons
is also shaped by the current context, such as shifts in attention and changes in external or internal
states. Mechanisms that account for this dynamic richness in our sensory and cognitive
experience are becoming clearer. In the cortex, fast-spiking inhibitory interneurons are essential
for coding and learning about sensory stimuli. The activity of fast-spiking interneurons is shaped
by the moment-by-moment actions of neuromodulators like oxytocin, dopamine, serotonin, and
catecholamines. These mechanisms can help explain how organisms assign different values of
valence and salience to sensory stimuli depending on contexts like parenting, aggression, mating,
and stress. A recently-discovered neuromodulatory system - the synthesis and action of
‘neuroestrogens’ within the brain - now holds a great deal of promise for deeper understanding of
sensory processing and cognition. Estrogen treatments can ameliorate a variety of neurological
disorders, including Parkinson’s disease, Alzheimer’s disease, and epilepsy. Yet because the
neuromodulatory perspective of brain estrogen synthesis is relatively new, the therapeutic
potential of neuroestrogen signaling itself is currently untapped. The research program in this
proposal will unpack the specific contribution of ultraprecise, fast inhibitory interneurons to the
modulatory actions of neuroestrogens in the cortex. We will test the hypothesis that
neuroestrogens directly modulate fast spiking interneurons in the cortex to regulate spike timing
precision and behavioral discrimination learning. The proposed projects will take advantage of
recent molecular and technological advances to genetically target fast-spiking inhibitory
interneurons. This work will therefore address a fundamental gap in our understanding of how
estrogen production within the brain guides complex behavior, and could ultimately inform the
development of highly-targeted estrogen therapies for cognitive and neurological disorders.

## Key facts

- **NIH application ID:** 10124440
- **Project number:** 5R01NS082179-08
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS AMHERST
- **Principal Investigator:** LUKE R REMAGE-HEALEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $337,162
- **Award type:** 5
- **Project period:** 2014-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124440

## Citation

> US National Institutes of Health, RePORTER application 10124440, Rapid Estrogen Signaling in Brain Circuits that Guide Complex Behavior (5R01NS082179-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10124440. Licensed CC0.

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