# Serotonin and the Modulation of Brain Behavior

> **NIH NIH R01** · NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC · 2020 · $540,419

## Abstract

Project Summary. Most neuropsychiatric disorders have developmental origins. Such vulnerability is often
restricted to sensitive periods, but affected behaviors, modulating factors, and underlying mechanisms are
scarcely understood. We have identified an early postnatal 5-HT-sensitive period in mice that affects adult
anxiety/depression-related behaviors and cognitive function. Altered adult behaviors are associated with reduced
anatomical connectivity between the raphe, the basolateral amygdala (BLA) and the medial prefrontal cortex
(mPFC) in this mouse model, but it remains unknown what the consequences are on physiological connectivity
and how alterations causally impact behavior. In wildtype mice, it is well established that raphe-mPFC-BLA
circuitry regulates anxiety and depression-related behaviors and cognitive function. But also here, mechanistic
insight especially at the level of 5-HTergic circuitry remains superficial. Hence, in the context of understanding
normal brain function as well as developmental vulnerability, we view it as critical to elucidate the role of 5-HT
input into postsynaptic circuits and its relationship with behavior. We furthermore believe that such insight into
circuit function is needed to improve diagnosis and treatment strategies for neuropsychiatric disorders. Our
proposal focuses on studying the raphe-mPFC-BLA circuit because of its central role in mediating and
modulating emotional behaviors. Through optogenetics, we will directly investigate reciprocal circuit nodes at the
physiological and behavioral level in WT mice and after developmental 5-HT interference. Furthermore, our
developmental mouse models demonstrate that pharmacologic and genetic interventions to serotonin
transporter or MAOA function produce comparable effects on behavior. Here we investigate the critical question
if this vulnerability extends to 5-HTergic neuronal activity, using a pharmacogenetic approach.
 Our research will impact the understanding of the pathophysiology in depression/anxiety and cognitive
impairment. Our research will likewise impact our understanding of how to treat these same conditions. We find
that increased 5-HT signaling during development leads to functionally blunted 5-HTergic and mPFC pathways
in adulthood, which in turn cause deficits in stress adaptation and fear extinction, and increase amygdala
reactivity and fear conditioned learning. Conversely, 5-HT terminal activity in the BLA selectively reduces fear
conditioning learning. These findings already indicate that terminal 5-HT activity in the BLA might be a promising
biological target for the treatment of fear-related symptomatology. 5-HT receptors within the amygdala that relay
the 5-HTergic signal to the postsynaptic circuitry might be interesting molecular targets for drug development.
Furthermore, altered activity patterns identified here, might become measurable through non-invasive methods
in humans to aid diagnosis. While more research is needed to in...

## Key facts

- **NIH application ID:** 9878916
- **Project number:** 5R01MH080116-11
- **Recipient organization:** NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
- **Principal Investigator:** JAY A GINGRICH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $540,419
- **Award type:** 5
- **Project period:** 2008-02-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878916

## Citation

> US National Institutes of Health, RePORTER application 9878916, Serotonin and the Modulation of Brain Behavior (5R01MH080116-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9878916. Licensed CC0.

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