# Microglial-serotonin interactions in the developing brain.

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $475,823

## Abstract

Summary of Work
Decades of research have strongly linked disruptions in the serotonin (5HT) system to mental health disorders
such as depression, and social and communication difficulties. Despite this link a gap remains in understanding
the etiologies of many of these disorders. Beyond its role in neurotransmission, 5HT is a critical morphogenic
signal during neurodevelopment, with known roles in cell proliferation, migration and differentiation, and in
programmed cell death. We have recently determined that a maternal high saturated-fat diet (mHFD) throughout
pregnancy in mice causes bacterial endotoxin accumulation in fetal placenta and brain, driving a central immune
response and leading to sex-specific behavioral abnormalities in offspring. Measurement of 5HT levels in mHFD
offspring revealed a male-specific decrease in fetal brain that persisted into adulthood. Maternal dietary
intervention with tryptophan (the precursor to 5HT) rescued normal brain 5HT levels and behavior only in mHFD
males. Microglia colonize the developing dorsal raphe nucleus (DRN) where 5HT cell bodies are localized
starting as early as embryonic day (E)10 and thus are likely to shape this brain region as it develops. Strikingly,
in male offspring only, we found that mHFD increased microglial phagocytosis of 5HT neurons in the E14.5 DRN,
whereas either restoring normal 5HT levels via tryptophan supplementation of the dam's diet or conditional
knockout (cKO) of the innate immune receptor toll-like-receptor 4 (TLR4) in microglia prevents this overeating
response in male microglia and restores normal behavior. These data point to microglia as a critical effector cell
between maternal inflammatory signals and subsequent neural development. Our goal is to determine the
mechanisms by which microglia target 5HT cells for removal in males but not females in mHFD conditions, and
to determine if maternal diet alters specific DRN circuits in males vs females underlying the different behavioral
abnormalities.

## Key facts

- **NIH application ID:** 10941217
- **Project number:** 1R01MH137305-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Staci D Bilbo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $475,823
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10941217

## Citation

> US National Institutes of Health, RePORTER application 10941217, Microglial-serotonin interactions in the developing brain. (1R01MH137305-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10941217. Licensed CC0.

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