# Direct lateral habenula projection to a critical pain transmission circuit

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $643,262

## Abstract

SUMMARY
Untreated and inadequately treated pain has substantially increased as a problem in the US over at least the
last 20 years. Increasing fears around prescribing opioids have also contributed to inadequate analgesic
treatment. Importantly, often chronic pain and major depressive disorder (MDD) are comorbid. Therefore,
discoveries of previously unknown neural circuits that can be targeted to address not only nociceptive discomfort
but also the affective component of chronic pain and its interactions with depression remains an important area
of focus for research. We recently showed that the lateral habenula (LHb) is a brain region that contributes to
both acute nociception and the aversiveness of chronic pain. The LHb also plays a role in behavioral models of
depression in rodents and has been targeted for deep brain stimulation to treat MDD in humans. LHb neurons
generally fire more in response to noxious stimuli and aversive behavioral states. We recently found that a
glutamatergic input from the lateral preoptic area of the hypothalamus (LPO) to the LHb is activated by noxious
stimuli, and inhibiting LPO → LHb neurons relieves the mechanical hypersensitivity induced by a neuropathic
pain model (spared nerve injury, SNI) in male rats. Inhibiting LPO → LHb also generated a conditioned place
preference in male and female animals with SNI, but not the control animals. This suggests that targeting this
circuit should have less abuse liability compared to agents that act on neural circuits that produce reward in
control animals. Here we propose to investigate the projections out of the LHb that transmit the pain signal
compared to the projections that modulate depression-model-related changes in behavior. While many have
studied the direct and indirect projections from the LHb to the dopaminergic systems and dopamine systems
contribute to pain and relief signaling, the LHb also sends a direct excitatory projection to the parabrachial
nucleus (PBN), an important component of the pain processing circuitry. The PBN receives nociceptive inputs
from the dorsal horn of the spinal cord and transmits pain signals to the central nucleus of the amygdala.
Therefore an LHb input to the PBN is a direct route for the LHb to have a strong impact on both sensory and
affective components of pain. The LHb also projects to the dorsal raphe nucleus (DRN), which is strongly
implicated in MDD in humans and depression models in rodents. Our preliminary findings show that the
projections to the PBN and DRN are from mostly non-overlapping sets of LHb neurons, making interactions
possible but not necessary. Here we propose to systematically investigate the contributions of the LHb → PBN
and LHb → DRN to nociception and motivated behaviors at the anatomical, neurophysiological, and behavioral
levels. We will make these measurements in control animals, animals with SNI, and animals treated with
repeated aversive restraint stress (a model for inducing depression-related be...

## Key facts

- **NIH application ID:** 10978098
- **Project number:** 1R01NS134981-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Elyssa Margolis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $643,262
- **Award type:** 1
- **Project period:** 2024-06-06 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978098

## Citation

> US National Institutes of Health, RePORTER application 10978098, Direct lateral habenula projection to a critical pain transmission circuit (1R01NS134981-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10978098. Licensed CC0.

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