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

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.

SUBMITTER: Chen W

PROVIDER: S-EPMC11103501 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Distinct eLPBChAT projections for methamphetamine withdrawal anxiety and primed reinstatement of conditioned place preference.

Chen Wenwen W Guo Hao H Zhou Ning N Mai Yuning Y Hu Tao T Xu Xing X He Teng T Wen Jun J Qin Shan S Liu Chengyong C Wu Wenzhong W Kim Hee Young HY Fan Yu Y Ge Feifei F Guan Xiaowei X

Theranostics 20240429 7

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 (eLPBChAT), which modulates METH primed-reinstatement of conditioned place preference (CPP). Here, the anatomical structures and func ...[more]

PMID: 38773977

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Project description:Abstract Drug relapse is a big clinical challenge in the treatment of addiction, but its neural circuit mechanism is far from being fully understood. Here, we identified a novel cholinergic pathway from choline acetyltransferase-positive neurons in the external lateral parabrachial nucleus (eLPBChAT) to the GABAergic neurons in the central nucleus of the amygdala (CeAGABA) and explored its role in methamphetamine priming-induced reinstatement of conditioned place preference. The anatomical structure and functional innervation of the eLPBChAT–CeAGABA pathway were investigated by various methods such as fluorescent micro-optical sectioning tomography, virus-based neural tracing, fibre photometry, patch-clamp and designer receptor exclusively activated by a designer drug. The role of the eLPBChAT–CeAGABA pathway in methamphetamine relapse was assessed using methamphetamine priming-induced reinstatement of conditioned place preference behaviours in male mice. We found that the eLPBChAT neurons mainly projected to the central nucleus of the amygdala. A chemogenetic activation of the eLPBChAT neurons in vitro or in vivo triggered the excitabilities of the CeAGABA neurons, which is at least in part mediated via the cholinergic receptor system. Most importantly, the chemogenetic activation of either the eLPBChAT neurons or the eLPBChAT neurons that project onto the central nucleus of the amygdala decreased the methamphetamine priming-induced reinstatement of conditioned place preference in mice. Our findings revealed a previously undiscovered cholinergic pathway of the eLPBChAT–CeAGABA and showed that the activation of this pathway decreased the methamphetamine priming-induced reinstatement of conditioned place preference. He et al. identified a novel cholinergic projection from choline acetyltransferase-positive neurons in the external lateral parabrachial nucleus (eLPBChAT) to the GABAergic neurons in the central nucleus of the amygdala (CeAGABA), which is involved in methamphetamine relapse. The chemogenetic activation of either the LPBChAT neurons or the eLPBChAT–CeAGABA pathway attenuated the methamphetamine-primed reinstatement of conditioned place preference. Graphical Abstract Graphical abstract

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

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Distinct eLPB<sup>ChAT</sup> projections for methamphetamine withdrawal anxiety and primed reinstatement of conditioned place preference.

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Distinct eLPBChAT projections for methamphetamine withdrawal anxiety and primed reinstatement of conditioned place preference.

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Distinct eLPB&lt;sup&gt;ChAT&lt;/sup&gt; projections for methamphetamine withdrawal anxiety and primed reinstatement of conditioned place preference.

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

Distinct eLPB<sup>ChAT</sup> projections for methamphetamine withdrawal anxiety and primed reinstatement of conditioned place preference.