# Serotonergic modulation of the circuits and cell-types of the lateral habenula

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $561,579

## Abstract

Project Summary
Serotonin (5-HT)-releasing neurons in the mammalian mid/hindbrain are critical for fundamental behaviors and
cognitive processes, including emotional control, arousal, and motor control. Selective serotonin reuptake
inhibitors (SSRIs) increase brain 5-HT levels and are the most commonly prescribed treatment for major-
depression in humans. However, our understanding of the mechanisms by which 5-HT influences synapses,
cells, and circuits is limited, prohibiting improvement of depression therapeutics. A major target of 5-HT
neurons is the lateral habenula (LHb), a subcortical structure principally implicated in evaluating the outcome
(positive or negative) of an action. The LHb is the only brain region that shows consistent hyperactivity several
rodent models of chronic stress and additional studies have recently refined this observation indicating “burst-
firing” in LHb is causally related several behavioral phenotypes (including anhedonia) following chronic stress.
Recently, using single-cell transcriptome wide sequencing, we genetically defined the neuronal subclasses
within the LHb for the first time revealing cell-type specific expression of both 5-HT receptors and genes
related to burst-firing. Our central hypothesis is that 5-HT release dynamically modulates the habenula circuit
though neuron-type specific expression of 5-HT receptors and that burst-firing in specific, genetically defined
LHb neuron-types is required for anhedonia following chronic stress. This proposal seeks to 1) identify the
neuron-type(s) in the LHb that exhibit burst-firing in vitro and in vivo, 2) determine how 5-HT modulates
neuron-types and local connectivity within the LHb and 3) define the neuron-types in the LHb required for
chronic stress induced anhedonia. By revealing how 5-HT modulates habenular circuits, the proposed work
will provide a comprehensive understanding of the cellular and circuit targets of this important neuromodulator.
These findings will form the foundation for understanding the principal mechanisms by which SSRIs impact
synapses and circuits of the LHb, uncovering new avenues for therapeutic intervention in major depressive
disorder and other neurological disorders treated by these drugs.

## Key facts

- **NIH application ID:** 10873842
- **Project number:** 5R01MH133608-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Michael L Wallace
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $561,579
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873842

## Citation

> US National Institutes of Health, RePORTER application 10873842, Serotonergic modulation of the circuits and cell-types of the lateral habenula (5R01MH133608-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10873842. Licensed CC0.

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