# Role of serotonin brain circuit in the developmental emergence ofinnate fear

> **NIH NIH K01** · NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC · 2024 · $180,487

## Abstract

Fear is the human emotion that is elicited when danger or threat are perceived or recognized. Maladaptive fear
patterns are common in anxiety disorders. Fear responses are orchestrated by the activation of stimulus-specific
neural circuits that converge in the periaqueductal gray (PAG). Drugs targeting the serotonin (5-HT) system
decrease anxiety and increasing 5-HT levels attenuates fear responses in animals. Yet, how 5-HT exerts its
effects on fear behavior is not well understood. To study fear-like responses in mice I have developed a
behavioral assay, in which a predator odor is presented in a chamber that allows for fast on- and off-set of the
stimulus. I use deep learning algorithms to analyze behavior. Using projection-specific optogenetics, I already
found that 5-HT neurons projecting to the PAG ameliorate fear-like behavior. In Aim 1 and Aim 2 I will now
determine the role of endogenous 5-HT signaling in the PAG during normal behavioral response to threat. A risk
factor for adult anxiety-like behavior is increased 5-HT during early life that causes enduring changes in 5-HT
function. Yet, how specific circuits are affected is not understood. I found that chemogenetic or pharmacologic
increases in 5-HT signaling during postnatal (P) day 2 to 11 lead to exacerbated fear responses in the adult.
Functional imaging (fMRI) in this mouse model furthermore revealed robust PAG hyperactivity in response to
predator odor. These data suggest that developmentally elevated 5-HT signaling produces long-lasting changes
in adult 5-HT input into the dlPAG resulting in increased innate fear-like behaviors. I will test this hypothesis in
Aim 3. Aim 1 uses genetically encoded 5-HT and Ca2+ sensors to simultaneously monitor 5-HT input and
glutamatergic or GABAergic output in the dlPAG during behavior via fiber photometry. Aim 2 uses Cre-
dependent inhibitory Archaerhodopsin to optogenetically inhibit 5-HT input into the dlPAG. Aim 3 uses Ca2+ and
5-HT sensors to monitor 5-HT input and neuronal output in the dlPAG during fear behavior after developmentally
elevated 5-HTergic activity. Lastly, Aim 3 also uses my established DR(5-HT)-to-dlPAG pathway specific
optogenetic protocol to enhance 5-HT signaling in dlPAG in an attempt to rescue increased fear-like responses.
Together my Aims will uncover fundamental principles that govern the modulation of the PAG by 5-HT, which
will provide insight into pathophysiology and etiology of anxiety disorders.
Throughout my training I will work towards translational discoveries targeting developmentally disrupted neural
circuits such that maladaptive behaviors can be reversed, with the overall goal of developing new therapeutic
strategies. My career development plan capitalizes on my prior experience in molecular and developmental
neurophysiology and adds expertise in circuit and behavioral neuroscience. I have engaged a strong mentoring
team to guide my scientific efforts and my growth as an independent scientist. I believe ...

## Key facts

- **NIH application ID:** 10828400
- **Project number:** 5K01MH131895-02
- **Recipient organization:** NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
- **Principal Investigator:** Giulia Zanni
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $180,487
- **Award type:** 5
- **Project period:** 2023-04-13 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828400

## Citation

> US National Institutes of Health, RePORTER application 10828400, Role of serotonin brain circuit in the developmental emergence ofinnate fear (5K01MH131895-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10828400. Licensed CC0.

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