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Ventral pallidum neurons dynamically signal relative threat.

ABSTRACT: The ventral pallidum (VP) is anatomically poised to contribute to threat behavior. Recent studies report a VP population that scales firing increases to reward but decreases firing to aversive cues. Here, we tested whether firing decreases in VP neurons serve as a neural signal for relative threat. Single-unit activity was recorded while male rats discriminated cues predicting unique foot shock probabilities. Rats' behavior and VP single-unit firing discriminated danger, uncertainty, and safety cues. Two populations of VP neurons dynamically signaled relative threat, decreasing firing according to foot shock probability during early cue presentation, but disproportionately decreasing firing to uncertain threat as foot shock drew near. One relative threat population increased firing to reward, consistent with a bi-directional signal for general value. The second population was unresponsive to reward, revealing a specific signal for relative threat. The results reinforce anatomy to reveal the VP as a neural source of a dynamic, relative threat signal.

SUBMITTER: Moaddab M

PROVIDER: S-EPMC7794503 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Ventral pallidum neurons dynamically signal relative threat.

Moaddab Mahsa M Ray Madelyn H MH McDannald Michael A MA

Communications biology 20210108 1

The ventral pallidum (VP) is anatomically poised to contribute to threat behavior. Recent studies report a VP population that scales firing increases to reward but decreases firing to aversive cues. Here, we tested whether firing decreases in VP neurons serve as a neural signal for relative threat. Single-unit activity was recorded while male rats discriminated cues predicting unique foot shock probabilities. Rats' behavior and VP single-unit firing discriminated danger, uncertainty, and safety ...[more]

PMID: 33420332

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Project description:Altered activity of the ventral pallidum (VP) underlies disrupted motivation in stress and drug exposure. The VP is a very heterogeneous structure composed of many neuron types with distinct physiological properties and projections. Neuronal PAS 1-positive (Npas1+) VP neurons are thought to send projections to brain regions critical for motivational behavior. While Npas1+ neurons have been characterized in the globus pallidus external, there is limited information on these neurons in the VP. To address this limitation, we evaluated the projection targets of the VP Npas1+ neurons and performed RNA-sequencing on ribosome-associated mRNA from VP Npas1+ neurons to determine their molecular identity. Finally, we used a chemogenetic approach to manipulate VP Npas1+ neurons during social defeat stress (SDS) and behavioral tasks related to anxiety and motivation in Npas1-Cre mice. We used a similar approach in females using the chronic witness defeat stress (CWDS). We identified VP Npas1+ projections to the nucleus accumbens, ventral tegmental area, medial and lateral habenula, lateral hypothalamus, thalamus, medial and lateral septum, and periaqueductal gray area. VP Npas1+ neurons displayed distinct translatome representing distinct biological processes. Chemogenetic activation of hM3D(Gq) receptors in VP Npas1+ neurons increased susceptibility to a subthreshold SDS and anxiety-like behavior in the elevated plus maze and open field while the activation of hM4D(Gi) receptors in VP Npas1+ neurons enhanced resilience to chronic SDS and CWDS. Thus, the activity of VP Npas1+ neurons modulates susceptibility to social stressors and anxiety-like behavior. Our studies provide new information on VP Npas1+ neuron circuitry, molecular identity, and their role in stress response.SIGNIFICANCE STATEMENT The ventral pallidum (VP) is a structure connected to both reward-related and aversive brain centers. It is a key brain area that signals the hedonic value of natural rewards. Disruption in the VP underlies altered motivation in stress and substance use disorder. However, VP is a very heterogeneous area with multiple neuron subtypes. This study characterized the projection pattern and molecular signatures of VP Neuronal PAS 1-positive (Npas1+) neurons. We further used tools to alter receptor signaling in VP Npas1+ neurons in stress to demonstrate a role for these neurons in stress behavioral outcomes. Our studies have implications for understanding brain cell type identities and their role in brain disorders, such as depression, a serious disorder that is precipitated by stressful events.

Project description:Opioid addiction is a chronic, relapsing disorder. Whether addicted individuals are forced to abstain or they decide themselves to quit using drugs, relapse rates are high-especially upon encountering contexts and stimuli associated with prior opioid use. Rodents similarly show context- and cue-induced reinstatement of drug seeking following abstinence, and intriguingly, the neural circuits underlying these relapse-like behaviors differ when abstinence is involuntarily imposed, responding is extinguished, or animals decide themselves to cease taking drug. Here, we employ two complementary rat behavioral models of relapse-like behavior for the highly reinforcing opioid drug remifentanil, and asked whether GABAergic neurons in the ventral pallidum (VPGABA) control opioid seeking under these behavioral conditions. Specifically, we asked how chemogenetically stimulating VPGABA neurons with clozapine-N-oxide (CNO) influences the ability of contextual or discrete remifentanil-paired cues to reinstate drug seeking following either voluntary abstinence (punishment-induced; GroupPunish), or extinction training (GroupExt). In GroupPunish rats, we also chemogenetically inhibited VPGABA neurons, and examined spontaneous VP activity (Fos) during cued reinstatement. In both GroupPunish and GroupExt rats, stimulating Gq-signaling in VPGABA neurons augmented remifentanil reinstatement in a cue- and context-dependent manner. Conversely, engaging inhibitory Gi-signaling in VPGABA neurons in GroupPunish suppressed cue-induced reinstatement, and cue-triggered seeking was correlated with Fos expression in rostral, but not caudal VP. Neither stimulating nor inhibiting VPGABA neurons influenced unpunished remifentanil self-administration. We conclude that VPGABA neurons bidirectionally control opioid seeking regardless of the specific relapse model employed, highlighting their fundamental role in opioid relapse-like behavior across behavioral models, and potentially across species.

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Ventral pallidum neurons dynamically signal relative threat.

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Ventral pallidum neurons dynamically signal relative threat.

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