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Opposing Contributions of GABAergic and Glutamatergic Ventral Pallidal Neurons to Motivational Behaviors.

ABSTRACT: The ventral pallidum (VP) is critical for invigorating reward seeking and is also involved in punishment avoidance, but how it contributes to such opposing behavioral actions remains unclear. Here, we show that GABAergic and glutamatergic VP neurons selectively control behavior in opposing motivational contexts. In vivo recording combined with optogenetics in mice revealed that these two populations oppositely encode positive and negative motivational value, are differentially modulated by animal's internal state, and determine the behavioral response during motivational conflict. Furthermore, GABAergic VP neurons are essential for movements toward reward in a positive motivational context but suppress movements in an aversive context. In contrast, glutamatergic VP neurons are essential for movements to avoid a threat but suppress movements in an appetitive context. Our results indicate that GABAergic and glutamatergic VP neurons encode the drive for approach and avoidance, respectively, with the balance between their activities determining the type of motivational behavior.

SUBMITTER: Stephenson-Jones M

PROVIDER: S-EPMC8573387 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Opposing Contributions of GABAergic and Glutamatergic Ventral Pallidal Neurons to Motivational Behaviors.

Stephenson-Jones Marcus M Bravo-Rivera Christian C Ahrens Sandra S Furlan Alessandro A Xiao Xiong X Fernandes-Henriques Carolina C Li Bo B

Neuron 20200113 5

The ventral pallidum (VP) is critical for invigorating reward seeking and is also involved in punishment avoidance, but how it contributes to such opposing behavioral actions remains unclear. Here, we show that GABAergic and glutamatergic VP neurons selectively control behavior in opposing motivational contexts. In vivo recording combined with optogenetics in mice revealed that these two populations oppositely encode positive and negative motivational value, are differentially modulated by anima ...[more]

PMID: 31948733

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Project description:BACKGROUND:The ability to appropriately integrate and respond to rewarding and aversive stimuli is essential for survival. The ventral pallidum (VP) plays a critical role in processing both rewarding and aversive stimuli. However, the VP is a heterogeneous structure, and how VP subpopulations integrate into larger reward networks to ultimately modulate these behaviors is not known. We identify a noncanonical population of glutamatergic VP neurons that play a unique role in responding to aversive stimuli and constraining inappropriate reward seeking. METHODS:Using neurochemical, genetic, and electrophysiological approaches, we characterized glutamatergic VP neurons (n = 4-8 mice/group). We performed patch clamp and in vivo electrophysiology recordings in the lateral habenula, rostromedial tegmental nucleus, and ventral tegmental area to determine the effect of glutamatergic VP neuron activation in these target regions (n = 6-10 mice/group). Finally, we selectively optogenetically stimulated glutamatergic VP neurons in a real-time place preference task and ablated these neurons using a virally expressed caspase to determine their necessity for reward seeking. RESULTS:Glutamatergic VP neurons exhibit little overlap with cholinergic or gamma-aminobutyric acidergic markers, the canonical VP subtypes, and exhibit distinct membrane properties. Glutamatergic VP neurons innervate and increase firing activity of the lateral habenula, rostromedial tegmental nucleus, and gamma-aminobutyric acidergic ventral tegmental area neurons. While nonselective optogenetic stimulation of the VP induced a robust place preference, selective activation of glutamatergic VP neurons induced a place avoidance. Viral ablation of glutamatergic VP neurons increased reward responding and abolished taste aversion to sucrose. CONCLUSIONS:Glutamatergic VP neurons constitute a noncanonical subpopulation of VP neurons. These glutamatergic VP neurons increase activity of the lateral habenula, rostromedial tegmental nucleus, and gamma-aminobutyric acidergic ventral tegmental area neurons and adaptively constrain reward seeking.

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:The ventral pallidum (VP) has emerged as a critical node in the mesolimbic reward system. Modulating the VP can impact the subjective valuation of rewards, reward motivation, and reward seeking under conflict, making it an attractive target for clinical neuromodulation therapies that manage substance use disorders. To understand how to rationally modulate the VP, we need a better understanding of the electrophysiological properties of VP neurons and the molecular and biophysical determinants of these properties. Here, we used patch-clamp electrophysiology to characterize the intrinsic properties of glutamatergic VP (VPGlu) neurons and observed two distinct electrophysiological profiles: VPGlu neurons that undergo depolarization block in response to progressively increasing current injection amplitudes and those that were resistant to depolarization block. To explore the mechanisms that could contribute to these distinct profiles, we used targeted ribosome affinity purification to identify ion channel subunits and regulatory proteins by isolating actively transcribed mRNA selectively from VPGlu neurons. We then used this transcriptomic information to implement a Markov Chain Monte Carlo method to parameterize a large population of biophysically distinct multicompartment models of VPGlu neurons conforming to either subpopulation. Based on prior literature suggesting parvalbumin (PV) is expressed in a subset of VPGlu neurons, and that PV expression governs the firing properties of those neurons, we tested the hypothesis that PV expression accounted for differences in subgroups, by increasing the maximal firing frequency and conferring resistance to depolarization block. In contrast, our model determined that PV expression at physiological levels had no effect on maximum firing rate. However, supraphysiological expression levels of PV appeared to induce a depolarization block in previously depolarization block-resistant neuron models, suggesting that other intracellular calcium-binding proteins could play a role in determining the firing phenotype of VPGlu neurons. We corroborated this result with single-cell patch-clamp RT-PCR, which confirmed that PV expression did not distinguish the two electrophysiologically distinct subpopulations. Together, these findings establish that VPGlu neurons are composed of biophysically distinct subpopulations that have not been appreciated in prior studies interrogating the function of this population. With the advent of novel tools for cell-type specific pharmacology and targeted neurostimulation, this understanding will be critical for developing strategies to rationally modulate VPGlu cells to treat disorders characterized by maladaptive reward seeking.

Dataset Information

Opposing Contributions of GABAergic and Glutamatergic Ventral Pallidal Neurons to Motivational Behaviors.

Publications

Opposing Contributions of GABAergic and Glutamatergic Ventral Pallidal Neurons to Motivational Behaviors.

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