# Androgen receptors and sex differences in the biological clock

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $451,219

## Abstract

Abstract
Time of day is a strong determinant of our experience: waking, sleeping, meals, and working occur in
predictable patterns. Endogenous clocks in the brain and peripheral tissues control the appropriate timing of
physiology and behavior. But people are not all synchronized in the same way—some have an early
chronotype (larks) and some have a late chronotype (owls). As with more severe disruptions of the clock,
delayed chronotype is a predictor of sleep disorders, metabolic disease, and neurological disorders.
Importantly, chronotype also differs between sexes, so differences in biological clock function may explain
some of the sex biases in these pathologies. We have previously shown that (1) circadian clock function is
strongly influenced by steroid hormones in males but not in females, (2) this is due to a change in the
sensitivity of the clock to light, and (3) this is traceable to the effects of androgens on light-responsive neurons
that express androgen receptors (AR) in the suprachiasmatic nucleus—the location of the brain’s circadian
clock. Though lacking AR, the same neuronal population exists in females. The circadian clock is therefore an
excellent system to determine the structural and functional pathways by which biological sex and androgen
signaling control a circadian clock function (free-running period of the clock) and an output behavior
(chronotype) that have relevance for health. We hypothesize that androgens reduce the clock’s photosensitivity
to compensate for underlying organizational differences and thereby ensure similar behavior patterns between
males and females. We will first investigate how androgens affect the excitability of identified AR-expressing
neurons (Aim 1) and how this alters the spatiotemporal network of the brain’s clock (Aim 2). Next, we test how
the presence of the receptor affects rhythmic behavior and light sensitivity (Aim 3). Finally, we will
pharmacogenetically manipulate AR neurons for the first time in any neuronal system to determine the role that
these neurons play in organizing clock function and controlling its response to light (Aim 4). These Aims are
enabled by two important mouse models: one in which the AR can be knocked out conditionally, and one in
which AR neurons express CRE recombinase. Using the latter, SCN neurons expressing AR can be identified
and manipulated by pharmacogenetics.

## Key facts

- **NIH application ID:** 10111577
- **Project number:** 5R01NS102962-04
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Matthew P Butler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $451,219
- **Award type:** 5
- **Project period:** 2018-05-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10111577

## Citation

> US National Institutes of Health, RePORTER application 10111577, Androgen receptors and sex differences in the biological clock (5R01NS102962-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10111577. Licensed CC0.

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