Novelty exploration-activated ensemble in the lateral hypothalamus confers analgesic and anxiolytic effects PMID: 42156381

ADC Targets in Oncology

2026-04-10

Novelty exploration-activated ensemble in the lateral hypothalamus confers analgesic and anxiolytic effects

Nat Commun. 2026 May 19;17(1):4418. doi: 10.1038/s41467-026-73205-x.

Tao Jia ^# ¹ ² ³ ⁴ , Yi-Ting Peng ^# ¹ ² ³ , Yi-Ling Sun ^# ¹ ² ³ , Cui Yin ¹ ² ³ , Xizhi Gu ¹ ² ³ , Liqun Yang ⁴ , Song Zhang ⁵ , Jun-Li Cao ⁶ ⁷ ⁸ ⁹ , Cheng Xiao ¹⁰ ¹¹ ¹² , Chunyi Zhou ¹³ ¹⁴ ¹⁵

Affiliations

1. School of Anesthesiology, Xuzhou Medical University, Xuzhou, China.
2. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China.
3. Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, Xuzhou Medical University, Xuzhou, China.
4. Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
5. Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
6. School of Anesthesiology, Xuzhou Medical University, Xuzhou, China. [email protected].
7. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China. [email protected].
8. Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, Xuzhou Medical University, Xuzhou, China. [email protected].
9. Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. [email protected].
10. School of Anesthesiology, Xuzhou Medical University, Xuzhou, China. [email protected].
11. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China. [email protected].
12. Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, Xuzhou Medical University, Xuzhou, China. [email protected].
13. School of Anesthesiology, Xuzhou Medical University, Xuzhou, China. [email protected].
14. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China. [email protected].
15. Jiangsu Province Key Laboratory of Anesthesiology and Brain Science, Xuzhou Medical University, Xuzhou, China. [email protected].
# Contributed equally.

Abstract

While attention distraction alleviates pain and negative affect, the underlying neural circuits remain unclear. Here, we show that novelty exposure, a means to attract attention, significantly alleviates acute and chronic pain in mice. Using a Fos-driven viral strategy, we identified a lateral hypothalamus (LH) neuronal ensemble activated during novelty exploration. This novelty ensemble also responds to pain- and anxiety-like stimuli. Activation of this ensemble produces analgesic and anxiolytic effects, whereas its inhibition exacerbates pain and anxiety-like behavior in mouse pain models. The LH ensemble comprises both GABAergic and glutamatergic subpopulations, both contributing to pain and anxiety modulation. However, activating their specific projections to the lateral preoptic area, lateral habenula, ventral tegmental area, and lateral periaqueductal gray regulates pain and anxiety in distinct patterns. Together, we define an LH novelty-activated neuronal subpopulation mediating the analgesic and anxiolytic benefits of novelty exposure, revealing circuit-specific targets for relieving pain and anxiety.