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Theranostics 2024; 14(7):2881-2896. doi:10.7150/thno.95383 This issue Cite

Research Paper

Distinct eLPB^ChAT projections for methamphetamine withdrawal anxiety and primed reinstatement of conditioned place preference

Wenwen Chen^1,*, Hao Guo^1,*, Ning Zhou^1,*, Yuning Mai¹, Tao Hu¹, Xing Xu¹, Teng He¹, Jun Wen¹, Shan Qin², Chengyong Liu², Wenzhong Wu², Hee Young Kim³, Yu Fan^1,✉, Feifei Ge^1,✉, Xiaowei Guan^1,✉

1. Department of Human Anatomy and Histoembryology, Nanjing University of Chinese Medicine, Nanjing, China.
2. Department of Acupuncture-Moxibustion and Rehabilitation, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
3. Department of Physiology, Yonsei University College of Medicine, Seoul, South Korea.
* These authors equally contributed to this work.

✉ Corresponding authors: guanxw918edu.cn (XG), yfanedu.cn (YF), ffgeedu.cn (FG).

Abstract

Methamphetamine (METH) withdrawal anxiety symptom and relapse have been significant challenges for clinical practice, however, the underlying neuronal basis remains unclear. Our recent research has identified a specific subpopulation of choline acetyltransferase (ChAT⁺) neurons localized in the external lateral portion of parabrachial nucleus (eLPB^ChAT), which modulates METH primed-reinstatement of conditioned place preference (CPP). Here, the anatomical structures and functional roles of eLPB^ChAT projections in METH withdrawal anxiety and primed reinstatement were further explored.

Methods: In the present study, a multifaceted approach was employed to dissect the LPB^ChAT+ projections in male mice, including anterograde and retrograde tracing, acetylcholine (Ach) indicator combined with fiber photometry recording, photogenetic and chemogenetic regulation, as well as electrophysiological recording. METH withdrawal anxiety-like behaviors and METH-primed reinstatement of conditioned place preference (CPP) were assessed in male mice.

Results: We identified that eLPB^ChAT send projections to PKCδ-positive (PKCδ⁺) neurons in lateral portion of central nucleus of amygdala (lCeA^PKCδ) and oval portion of bed nucleus of the stria terminalis (ovBNST^PKCδ), forming eLPB^ChAT-lCeA^PKCδ and eLPB^ChAT-ovBNST^PKCδ pathways. At least in part, the eLPB^ChAT neurons positively innervate lCeA^PKCδ neurons and ovBNST^PKCδ neurons through regulating synaptic elements of presynaptic Ach release and postsynaptic nicotinic acetylcholine receptors (nAChRs). METH withdrawal anxiety and METH-primed reinstatement of CPP respectively recruit eLPB^ChAT-lCeA^PKCδ pathway and eLPB^ChAT-ovBNST^PKCδ pathway in male mice.

Conclusion: Our findings put new insights into the complex neural networks, especially focusing on the eLPB^ChAT projections. The eLPB^ChAT is a critical node in the neural networks governing METH withdrawal anxiety and primed-reinstatement of CPP through its projections to the lCeA^PKCδ and ovBNST^PKCδ, respectively.

Keywords: eLPB^ChAT-lCeA^PKCδ, eLPB^ChAT-ovBNST^PKCδ, methamphetamine, anxiety, conditioned place preference

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