# Role of Prokineticin 2 in Regulating Sleep in Zebrafish

> **NIH NIH R01** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2020 · $360,938

## Abstract

Light affects sleep indirectly by entraining the circadian clock, but also directly and rapidly via a phenomenon
known as the masking or direct effect of light on behavior. Masking refers to the observation that light exposure
at night induces sleep in nocturnal animals and suppresses sleep in diurnal animals, including humans,
whereas dark exposure during the day inhibits sleep in nocturnal animals. While masking is widespread in the
animal kingdom, the mechanisms that mediate masking are largely unknown. Understanding mechanisms that
regulate sleep is important because over 10% of Americans suffer from chronic sleep disorders that have poor
therapeutic options and cause an annual economic burden of $100 billion. Understanding how masking in
particular affects sleep is important because at least some of the sleep disruption observed in modern societies
results from masking due to widespread exposure to artificial light at night. Our preliminary experiments using
zebrafish suggest that the neuropeptide prokineticin 2 (Prok2) regulates masking. To our knowledge, this is the
first gene shown to regulate masking beyond the initial step of light detection by melanopsin in the retina, and
thus it provides a foothold to explore the genetic and neurological mechanisms through which light directly
affects sleep. Although a similar phenotype was observed in rodents, a role in masking was not explored, and
the developmental defects of prok2 mutant mice confound sleep studies. The zebrafish is a vertebrate model
that exhibits behavioral, anatomical, genetic and pharmacological conservation of mammalian sleep. While the
zebrafish has some limitations as a sleep model, its amenability to genetic, optogenetic and pharmacological
approaches, as well as its transparency and relatively simple yet conserved vertebrate brain, and the lack of
developmental defects in prok2 mutant animals, provide advantages for sleep studies that we exploit in this
proposal. The zebrafish is particularly appropriate for studying mechanisms that may underlie masking in
humans because it is a diurnal vertebrate. In Specific Aim 1 we use gain- and loss-of-function genetics, as well
as optogenetic and chemogenetic tools, to test the hypotheses that Prok2 and prok2-expressing neurons
regulate masking. We also test whether our findings for Prok2 apply to other peptides that have been proposed
to regulate behavior in a manner similar to Prok2. In Specific Aim 2, we explore potential mechanisms through
which Prok2 regulates masking, such as by regulating the activity of the noradrenergic locus coeruleus (Aim
2A), the expression of the sleep-promoting neuropeptide galanin in the hypothalamus (Aim 2B) or other sleep
regulatory pathways. These studies will for the first time identify genes and neurons in the brain that regulate
masking, and thus provide a basis to study the genetic and neurological mechanisms that underlie this
phenomenon. Because Prok2 acts via G-protein coupled receptors, wh...

## Key facts

- **NIH application ID:** 9825569
- **Project number:** 5R01NS095824-04
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** David Aaron Prober
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,938
- **Award type:** 5
- **Project period:** 2016-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9825569

## Citation

> US National Institutes of Health, RePORTER application 9825569, Role of Prokineticin 2 in Regulating Sleep in Zebrafish (5R01NS095824-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9825569. Licensed CC0.

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