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Plasticity in ventral pallidal cholinergic neuron-derived circuits contributes to comorbid chronic pain-like and depression-like behaviour in male mice.

ABSTRACT: Nucleus- and cell-specific interrogation of individual basal forebrain (BF) cholinergic circuits is crucial for refining targets to treat comorbid chronic pain-like and depression-like behaviour. As the ventral pallidum (VP) in the BF regulates pain perception and emotions, we aim to address the role of VP-derived cholinergic circuits in hyperalgesia and depression-like behaviour in chronic pain mouse model. In male mice, VP cholinergic neurons innervate local non-cholinergic neurons and modulate downstream basolateral amygdala (BLA) neurons through nicotinic acetylcholine receptors. These cholinergic circuits are mobilized by pain-like stimuli and become hyperactive during persistent pain. Acute stimulation of VP cholinergic neurons and the VP-BLA cholinergic projection reduces pain threshold in naïve mice whereas inhibition of the circuits elevated pain threshold in pain-like states. Multi-day repetitive modulation of the VP-BLA cholinergic pathway regulates depression-like behaviour in persistent pain. Therefore, VP-derived cholinergic circuits are implicated in comorbid hyperalgesia and depression-like behaviour in chronic pain mouse model.

SUBMITTER: Ji YW

PROVIDER: S-EPMC10110548 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Plasticity in ventral pallidal cholinergic neuron-derived circuits contributes to comorbid chronic pain-like and depression-like behaviour in male mice.

Ji Ya-Wei YW Shen Zi-Lin ZL Zhang Xue X Zhang Kairan K Jia Tao T Xu Xiangying X Geng Huizhen H Han Yu Y Yin Cui C Yang Jian-Jun JJ Yang Jian-Jun JJ Cao Jun-Li JL Zhou Chunyi C Xiao Cheng C

Nature communications 20230417 1

Nucleus- and cell-specific interrogation of individual basal forebrain (BF) cholinergic circuits is crucial for refining targets to treat comorbid chronic pain-like and depression-like behaviour. As the ventral pallidum (VP) in the BF regulates pain perception and emotions, we aim to address the role of VP-derived cholinergic circuits in hyperalgesia and depression-like behaviour in chronic pain mouse model. In male mice, VP cholinergic neurons innervate local non-cholinergic neurons and modulat ...[more]

PMID: 37069246

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Project description:The ventral pallidum (VP) mediates motivated behaviors largely via the action of VP GABA and glutamatergic neurons. In addition to these neuronal subtypes, there is a population of cholinergic projection neurons in the VP, whose functional significance remains unclear. To understand the functional role of VP cholinergic neurons, we first examined behavioral responses to an appetitive (APP) odor that elicited approach, and an aversive (AV) odor that led to avoidance. To examine how VP cholinergic neurons were engaged in APP vs. AV responses, we used an immediate early gene marker and in-vivo fiber photometry, examining the activation profile of VP cholinergic neurons in response to each odor. Exposure to each odor led to an increase in the number of cFos counts and increased calcium signaling of VP cholinergic neurons. Activity and cre-dependent viral vectors were designed to label engaged VP cholinergic neurons in two distinct contexts: (1) exposure to the APP odor, (2) followed by subsequent exposure to the AV odor, and vice versa. These studies revealed two distinct, non-overlapping subpopulations of VP cholinergic neurons: one activated in response to the APP odor, and a second distinct population activated in response to the AV odor. These two subpopulations of VP cholinergic neurons are spatially intermingled within the VP, but show differences in electrophysiological properties, neuronal morphology, and projections to the basolateral amygdala. Although VP cholinergic neurons are engaged in behavioral responses to each odor, VP cholinergic signaling is only required for approach behavior. Indeed, inhibition of VP cholinergic neurons not only blocks approach to the APP odor, but reverses the behavior, leading to active avoidance. Our results highlight the functional heterogeneity of cholinergic projection neurons within the VP. These two subpopulations of VP cholinergic neurons differentially encode valence of olfactory stimuli and play unique roles in approach and avoidance behaviors.

Project description:The interconnected nuclei of the ventral basal ganglia have long been identified as key regulators of motivated behavior, and dysfunction of this circuit is strongly implicated in mood and substance use disorders. The ventral pallidum (VP) is a central node of the ventral basal ganglia, and recent studies have revealed complex VP cellular heterogeneity and cell- and circuit-specific regulation of reward, aversion, motivation, and drug-seeking behaviors. Although the VP is canonically considered a relay and output structure for this circuit, emerging data indicate that the VP is a central hub in an extensive network for reward processing and the regulation of motivation that extends beyond classically defined basal ganglia borders. VP neurons respond temporally faster and show more advanced reward coding and prediction error processing than neurons in the upstream nucleus accumbens, and regulate the activity of the ventral mesencephalon dopamine system. This review will summarize recent findings in the literature and provide an update on the complex cellular heterogeneity and cell- and circuit-specific regulation of motivated behaviors and reinforcement by the VP with a specific focus on mood and substance use disorders. In addition, we will discuss mechanisms by which stress and drug exposure alter the functioning of the VP and produce susceptibility to neuropsychiatric disorders. Lastly, we will outline unanswered questions and identify future directions for studies necessary to further clarify the central role of VP neurons in the regulation of motivated behaviors. Significance: Research in the last decade has revealed a complex cell- and circuit-specific role for the VP in reward processing and the regulation of motivated behaviors. Novel insights obtained using cell- and circuit-specific interrogation strategies have led to a major shift in our understanding of this region. Here, we provide a comprehensive review of the VP in which we integrate novel findings with the existing literature and highlight the emerging role of the VP as a linchpin of the neural systems that regulate motivation, reward, and aversion. In addition, we discuss the dysfunction of the VP in animal models of neuropsychiatric disorders.

Project description:BackgroundChronic postsurgical pain (CPP) markedly impairs patients' quality of life. Research has shown that chronic stress may extend incisional nociception in male mice. Dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) are integral to stress-related mental disorders (including major depressive disorder, anxiety disorders, and PTSD) and pain. However, the impact of chronic social defeat stress (CSDS) on mesolimbic dopamine (DA) transmission in the development of CPP is yet to be established. It remains uncertain whether the dopamine signals in the rostral anterior cingulate cortex (rACC), which regulate pain, derive from the VTA. This study aims to explore the role of VTA-rACC dopaminergic circuits in a mouse model of CPP induced by CSDS.MethodsWe conducted CSDS on C57BL/6 J wild-type male mice (n = 12-16 mice/group) and DAT-cre male mice (n = 10-12 mice/group). After 10 days of CSDS, a left posterior plantar incision was made to establish a mouse model of CPP. Paw withdrawal thresholds (PWTs) were evaluated using Von-Frey fibre stimulation. The open field test (OFT) and elevated plus maze test (EPM) were used to assess pain-related negative emotions. We used immunofluorescence staining and Western Blot to analyse D1, D2, c-Fos, and TH expression. DAergic fibre projections in the VTA-rACC neural pathway were traced using retrograde tracing and immunofluorescence staining. Optogenetics and Chemogenetics were employed to manipulate DAergic neurons in the VTA and their axons in the rACC.ResultsThe ipsilateral PWTs in male C57BL/6 J mice significantly decreased after surgery, returning to baseline after seven days. Conversely, in CSDS mice, ipsilateral PWTs remained reduced for at least 30 days post-incision. A significant reduction in TH-positive neurons expressing c-Fos in the VTA of CPP mice was observed 15 days post-incision. Activating DAergic neurons significantly improved ipsilateral PWTs and locomotor performance in the OFT and EPM in CPP mice post-incision. Additionally, D1 expression in the rACC was found to decrease in CPP mice, and this reduction counteracted the increase in PWTs caused by activating DAergic neuron axon terminals in the rACC.ConclusionCSDS results in chronicity of postsurgical nociception and anxiety-like negative emotions, with alterations in DA transmission playing a role in CPP. Specific activation of DAergic neurons mitigates nociceptive responses and anxiety-like bahaviors, possibly mediated by D1 receptors in the rACC.

Dataset Information

Plasticity in ventral pallidal cholinergic neuron-derived circuits contributes to comorbid chronic pain-like and depression-like behaviour in male mice.

Publications

Plasticity in ventral pallidal cholinergic neuron-derived circuits contributes to comorbid chronic pain-like and depression-like behaviour in male mice.

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