# MECHANISMS OF CIRCADIAN CLOCK OUTPUT

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $307,284

## Abstract

In this proposal, I outline a set of three related yet independent studies of circadian neural
output. Recent advances in imaging and data analysis capture information regarding network
phenomena with increasing spatial and temporal precision. The circadian pacemaker system
we study is advantageous in that it produces physiological activity both spontaneously and
rhythmically. In the previous cycle, we used planar illumination methods to perform 24 hr in vivo
brain-wide scans of the circadian neural circuit. That work introduced a new concept to
theories of how the circadian network encodes time: we showed that the molecularly
synchronous pacemaker network displays sequential activation by different identified
pacemaker groups across the day. Further we found pacemaker cell interactions, in the form
of neuropeptide-mediated delay, represents a key mechanism to effect sequential pacemaker
activation. The scientific premise for this project rests on the need to extend those
observations on circadian pacemaker neuronal plasticity and to understand how these activity
patterns are transmitted to downstream centers. Here I propose work that continues real-time
in vivo studies of neuronal activity patterns for the core Drosophila circadian pacemaker
neurons. It also continues the focused analysis of neuropeptide modulatory mechanisms that
critically regulate the specific timing of pacemaker activity.
To extend the scope of our initial studies, and to provide a better understanding of neuronal
properties of pacemakers and pacemaking networks, this program will pursue three Aims. Aim
1 will better define daily Ca2+ dynamics in pacemakers by (i) performing in-depth, high
frequency sampling, and (ii) by determining the sub-cellular mechanisms underlying these
fluctuations. Aim 2 will pursue a Structure-Function analysis of the PDF receptor (PDFR),
especially its C-terminus, to understand the regulatory mechanisms that control the quantitative
extent of daily PDF signaling. It also seeks to identify key PDFR regulatory proteins. Aim 3
seeks to extend the scope of our work beyond the circadian pacemaker network to identify
downstream circuit elements: we will focus on subsets of neurons in the Central Complex for
which preliminary evidence suggests an involvement in daily rhythmic physiology associated
with locomotion.
Jet-lag, shift-work and disturbances in sleep-activity cycles all contribute to degrade mental and
physical well-being. Two major causes of death (stroke and cardiac arrest) display clear time-
of-day variation, yet, we have little understanding of the causal links between circadian clock
functions and disease mechanisms. This research program is dedicated to a better
understanding of fundamental circadian output mechanisms.

## Key facts

- **NIH application ID:** 9836895
- **Project number:** 5R01NS108393-18
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Paul H Taghert
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $307,284
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836895

## Citation

> US National Institutes of Health, RePORTER application 9836895, MECHANISMS OF CIRCADIAN CLOCK OUTPUT (5R01NS108393-18). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9836895. Licensed CC0.

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