# Mechanisms underlying sleep homeostasis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $302,250

## Abstract

Abstract
 Despite the extraordinary conservation of sleep across evolution and the established
importance of sleep to human health, the needs fulfilled by sleep remain one of the biggest
mysteries in neuroscience. In fact, no consensus has emerged about either the
neuroanatomical origins or the molecular basis by which sleep need is sensed and discharged.
It is a vexing but understandable problem. Screens for candidate genes are too time-consuming
and expensive to be practical in vertebrates. And among cheaper, more genetically tractable
model organisms, most assays are designed only to identify mutations that constitutively disturb
daily sleep, not genes that regulate the mysterious homeostatic process that senses and
responds to sleep need. To address this major deficiency, my lab has developed a simple,
robust, high-throughput thermogenetic assay for measuring sleep need in Drosophila. Using this
assay we have demonstrated that arousal-promoting neurons surprisingly only rarely drive sleep
homeostasis. In this proposal we identify these rare neurons as cells that express the gene ppk,
describe their likely sensory role, and highlight experiments to determine the types of
information that these neurons transduce to drive sleep need. Furthermore, by suppressing the
activity of various neurons in the brain, we have also identified postsynaptic effectors of ppk
neurons. Using a genetically encoded Ca2+ sensor we will confirm the functional connectivity
between these different cellular regulators of sleep need. Using a combination of forward
genetic screening and mass spectrometry, we have also identified molecules that appear to be
required to mediate sleep homeostasis. We will confirm the functions of these molecules in
regulating sleep need and identify the subset of proteomic changes that occur during sleep
homeostasis due to these functions. Lastly, we have shown that sleep homeostasis is required
following sleep deprivation in order for subsequent memory formation to occur. Thus, we will
determine whether mechanisms underlying the two processes are likely to be shared.
Specifically, we will reduce the activity of newly discovered neurons and molecules we have
implicated in sleep homeostasis to determine if they are also required for associative memory
formation. Defining mechanisms underlying sleep homeostasis and their relation to cognition, as
proposed in this grant, would represent major breakthroughs in neuroscience and may facilitate
the development of novel pharmacotherapies to intervene in sleep-related disorders.

## Key facts

- **NIH application ID:** 9929020
- **Project number:** 5R01GM125080-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** William J Joiner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $302,250
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929020

## Citation

> US National Institutes of Health, RePORTER application 9929020, Mechanisms underlying sleep homeostasis (5R01GM125080-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9929020. Licensed CC0.

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