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Glutamatergic and GABAergic anteroventral BNST projections to PVN CRH neurons regulate maternal separation-induced visceral pain

Neuropsychopharmacology volume 48, pages 1778–1788 (2023)Cite this article

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Abstract

Early-life stress (ELS) is thought to cause the development of visceral pain disorders. While some individuals are vulnerable to visceral pain, others are resilient, but the intrinsic circuit and molecular mechanisms involved remain largely unclear. Herein, we demonstrate that inbred mice subjected to maternal separation (MS) could be separated into susceptible and resilient subpopulations by visceral hypersensitivity evaluation. Through a combination of chemogenetics, optogenetics, fiber photometry, molecular and electrophysiological approaches, we discovered that susceptible mice presented activation of glutamatergic projections or inhibition of GABAergic projections from the anteroventral bed nucleus of the stria terminalis (avBNST) to paraventricular nucleus (PVN) corticotropin-releasing hormone (CRH) neurons. However, resilience develops as a behavioral adaptation partially due to restoration of PVN SK2 channel expression and function. Our findings suggest that PVN CRH neurons are dually regulated by functionally opposing avBNST neurons and that this circuit may be the basis for neurobiological vulnerability to visceral pain.

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Fig. 1: Separation of mice exposed to MS into susceptible and unsusceptible populations.
Fig. 2: Activation of CRH neurons within the PVN mediates susceptibility.
Fig. 3: Mapping of the connections between glutamatergic and GABAergic avBNST neurons and PVN CRH neurons.
Fig. 4: Identification of the functional connections in the GABAergic/glutamatergic avBNST-PVN CRH neuron pathway and the effect of optogenetic modulation of this pathway on behavior.
Fig. 5: Restoring SK2 expression and function in resilient mice rescues visceral hypersensitivity.

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Funding

Funding

The present study was supported by STI2030-Major Projects (2021ZD0203100), the National Natural Science Foundation of China (Grant Numbers 82271257, 82071228), and Startup Funds from Xuzhou Medical University (RC20552252).

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  1. These authors contributed equally: Si-Ting Huang, Ke Wu.

Authors and Affiliations

  1. NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China

    Si-Ting Huang, Ke Wu, Miao-Miao Guo, Shuai Shao, Rong Hua & Yong-Mei Zhang

  2. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China

    Si-Ting Huang, Ke Wu, Miao-Miao Guo, Shuai Shao, Rong Hua & Yong-Mei Zhang

  3. Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China

    Si-Ting Huang, Ke Wu, Miao-Miao Guo, Shuai Shao, Rong Hua & Yong-Mei Zhang

  4. Emergency Department, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221116, Jiangsu, China

    Rong Hua

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Contributions

Conceptualization: STH, YMZ. Methodology and Investigation: STH, KW, MMG, SS. Supervision: RH, YMZ. Funding acquisition: STH, YMZ. Writing-original draft: STH, YMZ. Writing-revies & editing: STH, KW, MMG, SS, RH, YMZ.

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Correspondence to Yong-Mei Zhang.

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Huang, ST., Wu, K., Guo, MM. et al. Glutamatergic and GABAergic anteroventral BNST projections to PVN CRH neurons regulate maternal separation-induced visceral pain. Neuropsychopharmacol. 48, 1778–1788 (2023). https://doi.org/10.1038/s41386-023-01678-1

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