# Cellular and molecular analysis of startle modulation

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $535,370

## Abstract

Abstract
A remarkable feature of the nervous system is its ability to adjust stereotyped behavioral responses in a context
dependent manner. In vertebrates, sudden and intense acoustic stimuli evoke an evolutionarily conserved startle
response. While the execution of the acoustic startle response is extremely stereotyped, response probability is
modulated in a context-dependent manner. For example, repeated presentation of a startling stimulus
suppresses a behavioral response, representing a simple form of learning known as habituation. In humans,
modulation of startle behavior is impaired in several neuropsychiatric disorders, including in Attention Deficit-
Hyperactivity Disorder and autism spectrum disorders. Despite its importance, the molecular mechanisms
underlying startle modulation not well understood. Zebrafish show a remarkable behavioral plasticity, and we
have previously shown that larvae exhibit modulation of the acoustic startle response- including prepulse
inhibition and habituation- with behavioral and pharmacological characteristics similar to those in mammals. We
previously conducted the first forward genetic screen in vertebrates to isolate mutants defective in startle
modulation, and identified 14 mutants with defects in habituation behavior. None of these 14 mutants exhibit
morphological defects or overt defects in startle performance. Importantly, five of the six mutants we cloned so
far encode genes previously not implicated in vertebrate habituation. Here we propose to build on our success
in using a molecular genetics, phenotype based strategy to decipher the molecular and circuits mechanisms that
drive vertebrate habituation behavior. Specifically, rather than focusing on a single habituation gene, our strategy
is to continue to use whole genome sequencing to clone six additional mutants from our screen. Combined with
the six mutants we have already cloned, this provides an unparalleled toolbox critical to attain a comprehensive
model of the molecular-genetic and circuit mechanisms underlying habituation. Simultaneously, we focus on
select genes as entry points to further link genetic mutants to behavioral phenotypes and to decipher the
molecular and circuit mechanisms that regulate behavior. The experiments in this proposal will: (1) use a
molecular genetic approach including transgenic behavioral rescue to identify the neuronal populations in which
three genes critical for habituation function; (2) to use molecular and pharmacogenetic approaches in conjunction
with a behavioral assay to determine the signaling pathways through which the adaptor protein-2 sigma subunit
(AP2s1) critical for receptor endocytosis and the huntingtin interacting gene hip14 promote habituation; and 3)
to use an established whole genome sequencing/bioinformatics pipeline to identify the causative gene mutations
for six additional habituation mutants isolated from our genetic screen, generate CRISPR/Cas9 alleles to confirm
their identity and de...

## Key facts

- **NIH application ID:** 10071407
- **Project number:** 9R01NS118921-06
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Michael Granato
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $535,370
- **Award type:** 9
- **Project period:** 2021-02-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071407

## Citation

> US National Institutes of Health, RePORTER application 10071407, Cellular and molecular analysis of startle modulation (9R01NS118921-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10071407. Licensed CC0.

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