Two parallel lateral hypothalamic GABAergic projections differentially modulate pain and anxiety in mice
- 1Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China
- 2Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, Xuzhou Medical University, Xuzhou, Jiangsu, China
- 3Department of Anesthesiology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
Abstract
The lateral hypothalamus (LH) is fundamentally involved in motivated behaviors, yet the precise functional segregation of its GABAergic projections in modulating pain and its affective dimensions remains poorly understood. Here, using male and female mice, we revealed that LH GABAergic neurons sent parallel projections to two pivotal pain and affect processing centers: the lateral parabrachial nucleus (LPB) and the paraventricular nucleus of the thalamus (PVT). In vivo fiber photometry revealed that LH GABAergic terminals in both the PVT and LPB are robustly activated by noxious, aversive, and rewarding stimuli, indicating their roles in encoding salient and affective information. Critically, we uncovered a remarkable functional segregation of these LH GABAergic pathways. Optogenetic activation of the LH-PVT projection exerted anxiogenic effects without altering pain sensitivity in both naïve and neuropathic pain mice; whereas optogenetic inhibition of this pathway exerted significant analgesic and anxiolytic effects specifically in neuropathic pain, highlighting a context-dependent modulation of pain and affect. In contrast, optogenetic activation of the LH-LPB projection induced contralateral pronociception without impacting affective behaviors, conversely, inhibition of this pathway significantly elevated contralateral pain thresholds in both physiological and neuropathic pain conditions. We also demonstrated that stimulation of the LH-LPB projection acted via a disinhibitory mechanism involving local LPB GABAergic interneurons to enhance activity of LPB glutamatergic neurons. Collectively, our findings delineate two parallel and functionally segregated LH GABAergic output pathways that differentially control distinct aspects of pain experience, thereby offering novel circuit-specific targets for the treatment of chronic pain and its debilitating emotional comorbidities.
Pain is intimately linked with emotional processing, but the neuronal circuitry delineating this relationship is incompletely understood. This study characterizes two parallel GABAergic outputs from the lateral hypothalamus that control these distinct aspects of pain experience.
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BibTeX
@article{sun2026parallel,
title = {{Two parallel lateral hypothalamic GABAergic projections differentially modulate pain and anxiety in mice}},
author = {Yi-Ling Sun and Yi-Ting Peng and Xue Zhang and Cui Yin and Cheng Xiao and Junping Chen and Chunyi Zhou},
journal = {PLOS Biology},
year = {2026},
month = nov,
doi = {10.1371/journal.pbio.3004096},
url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004096},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Two parallel lateral hypothalamic GABAergic projections differentially modulate pain and anxiety in mice
AU - Yi-Ling Sun
AU - Yi-Ting Peng
AU - Xue Zhang
AU - Cui Yin
AU - Cheng Xiao
AU - Junping Chen
AU - Chunyi Zhou
PY - 2026
DA - 2026/11/05
JO - PLOS Biology
DO - 10.1371/journal.pbio.3004096
UR - https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004096
AB - The lateral hypothalamus (LH) is fundamentally involved in motivated behaviors, yet the precise functional segregation of its GABAergic projections in modulating pain and its affective dimensions remains poorly understood. Here, using male and female mice, we revealed that LH GABAergic neurons sent parallel projections to two pivotal pain and affect processing centers: the lateral parabrachial nucleus (LPB) and the paraventricular nucleus of the thalamus (PVT). In vivo fiber photometry revealed that LH GABAergic terminals in both the PVT and LPB are robustly activated by noxious, aversive, and rewarding stimuli, indicating their roles in encoding salient and affective information. Critically, we uncovered a remarkable functional segregation of these LH GABAergic pathways. Optogenetic activation of the LH-PVT projection exerted anxiogenic effects without altering pain sensitivity in both naïve and neuropathic pain mice; whereas optogenetic inhibition of this pathway exerted significant analgesic and anxiolytic effects specifically in neuropathic pain, highlighting a context-dependent modulation of pain and affect. In contrast, optogenetic activation of the LH-LPB projection induced contralateral pronociception without impacting affective behaviors, conversely, inhibition of this pathway significantly elevated contralateral pain thresholds in both physiological and neuropathic pain conditions. We also demonstrated that stimulation of the LH-LPB projection acted via a disinhibitory mechanism involving local LPB GABAergic interneurons to enhance activity of LPB glutamatergic neurons. Collectively, our findings delineate two parallel and functionally segregated LH GABAergic output pathways that differentially control distinct aspects of pain experience, thereby offering novel circuit-specific targets for the treatment of chronic pain and its debilitating emotional comorbidities. Pain is intimately linked with emotional processing, but the neuronal circuitry delineating this relationship is incompletely understood. This study characterizes two parallel GABAergic outputs from the lateral hypothalamus that control these distinct aspects of pain experience.
SN - 1545-7885
ER -