Anterior cingulate cortex projections to the dorsal medial striatum underlie insomnia associated with chronic pain

Ya-Dong Li; Yan-Jia Luo; Wei-Kun Su; Jing Ge; Andrew Crowther; Ze-Ka Chen; Lu Wang; Michael Lazarus; Zi-Long Liu; Wei-Min Qu; Zhi-Li Huang

doi:10.1016/j.neuron.2024.01.014

Anterior cingulate cortex projections to the dorsal medial striatum underlie insomnia associated with chronic pain

Neuron. 2024 Apr 17;112(8):1328-1341.e4. doi: 10.1016/j.neuron.2024.01.014. Epub 2024 Feb 13.

Authors

Ya-Dong Li¹, Yan-Jia Luo², Wei-Kun Su³, Jing Ge⁴, Andrew Crowther⁵, Ze-Ka Chen⁴, Lu Wang⁴, Michael Lazarus⁶, Zi-Long Liu⁷, Wei-Min Qu⁸, Zhi-Li Huang⁹

Affiliations

¹ Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Joint International Research Laboratory of Sleep, and Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Songjiang Research Institute, Songjiang Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Emotions and Affective Disorders (LEAD), Shanghai 201699, China. Electronic address: [email protected].
² Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Joint International Research Laboratory of Sleep, and Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
³ Songjiang Research Institute, Songjiang Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Emotions and Affective Disorders (LEAD), Shanghai 201699, China.
⁴ Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Joint International Research Laboratory of Sleep, and Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
⁵ Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158, USA.
⁶ International Institute for Integrative Sleep Medicine (WPI-IIIS) and Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
⁷ Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Joint International Research Laboratory of Sleep, and Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
⁸ Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Joint International Research Laboratory of Sleep, and Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
⁹ Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Joint International Research Laboratory of Sleep, and Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: [email protected].

PMID: 38354737
DOI: 10.1016/j.neuron.2024.01.014

Abstract

Chronic pain often leads to the development of sleep disturbances. However, the precise neural circuit mechanisms responsible for sleep disorders in chronic pain have remained largely unknown. Here, we present compelling evidence that hyperactivity of pyramidal neurons (PNs) in the anterior cingulate cortex (ACC) drives insomnia in a mouse model of nerve-injury-induced chronic pain. After nerve injury, ACC PNs displayed spontaneous hyperactivity selectively in periods of insomnia. We then show that ACC PNs were both necessary for developing chronic-pain-induced insomnia and sufficient to mimic sleep loss in naive mice. Importantly, combining optogenetics and electrophysiological recordings, we found that the ACC projection to the dorsal medial striatum (DMS) underlies chronic-pain-induced insomnia through enhanced activity and plasticity of ACC-DMS dopamine D1R neuron synapses. Our findings shed light on the pivotal role of ACC PNs in developing chronic-pain-induced sleep disorders.

Keywords: anterior cingulate cortex; calcium imaging; chronic pain; dopamine; dopamine D1 receptor; dopamine D2 receptor; insomnia; pyramidal neurons; sleep; striatum.

MeSH terms

Animals
Chronic Pain*
Gyrus Cinguli / physiology
Mice
Pyramidal Cells
Sleep Initiation and Maintenance Disorders*