Opposing Contributions of GABAergic and Glutamatergic Ventral Pallidal Neurons to Motivational Behaviors.
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ABSTRACT:
SUBMITTER: Stephenson-Jones M
PROVIDER: S-EPMC8573387 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Insomnia is often comorbid with depression, but the underlying neuronal circuit mechanism remains elusive. Recently, we reported that GABAergic ventral pallidum (VP) neurons control wakefulness associated with motivation. However, whether and how other subtypes of VP neurons regulate arousal and emotion are largely unknown. Here, we report glutamatergic VP (VPVglut2) neurons control wakefulness and depressive-like behaviors. Physiologically, the calcium activity of VPVglut2 neurons was increased during both NREM sleep-to-wake transitions and depressive/anxiety-like behaviors in mice. Functionally, activation of VPVglut2 neurons was sufficient to increase wakefulness and induce anxiety/depressive-like behaviors, whereas inhibition attenuated both. Dissection of the circuit revealed that separated projections of VPVglut2 neurons to the lateral hypothalamus and lateral habenula promote arousal and depressive-like behaviors, respectively. Our results demonstrate a subtype of VP neurons is responsible for wakefulness and emotion through separated projections, and may provide new lines for the intervention of insomnia and depression in patients.
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Project description:The ventral pallidum (VP) regulates motivation, drug addiction, and several behaviors that rely on heightened arousal. However, the role and underlying neural circuits of the VP in the control of wakefulness remain poorly understood. In the present study, we sought to elucidate the specific role of VP GABAergic neurons in controlling sleep-wake behaviors in mice. Fiber photometry revealed that the population activity of VP GABAergic neurons was increased during physiological transitions from non-rapid eye movement (non-REM, NREM) sleep to either wakefulness or REM sleep. Moreover, chemogenetic and optogenetic manipulations were leveraged to investigate a potential causal role of VP GABAergic neurons in initiating and/or maintaining arousal. In vivo optogenetic stimulation of VP GABAergic neurons innervating the ventral tegmental area (VTA) strongly promoted arousal via disinhibition of VTA dopaminergic neurons. Functional in vitro mapping revealed that VP GABAergic neurons, in principle, inhibited VTA GABAergic neurons but also inhibited VTA dopaminergic neurons. In addition, optogenetic stimulation of terminals of VP GABAergic neurons revealed that they promoted arousal by innervating the lateral hypothalamus, but not the mediodorsal thalamus or lateral habenula. The increased wakefulness chemogenetically evoked by VP GABAergic neuronal activation was completely abolished by pretreatment with dopaminergic D1 and D2/D3 receptor antagonists. Furthermore, activation of VP GABAergic neurons increased exploration time in both the open-field and light-dark box tests but did not modulate depression-like behaviors or food intake. Finally, chemogenetic inhibition of VP GABAergic neurons decreased arousal. Taken together, our findings indicate that VP GABAergic neurons are essential for arousal related to motivation.
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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.
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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.
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Project description:The bed nucleus of the stria terminalis (BNST) regulates defensive responses to threats and its anteroventral portion (BNST-AV) is involved. BNST-AV contains a minority of glutamatergic neurons scattered among a dominant population of GABAergic cells. There is evidence that these two cell types might exert opposite influences, the former promoting and the latter reducing anxiety. Although GABAergic cells greatly outnumber glutamatergic neurons in BNST-AV, in some circumstances the influence of glutamatergic cells appears to predominate. Related to this, BNST-AV receives a very strong noradrenaline (NA) input and negative emotional states are associated with a marked rise of NA concentration in BNST-AV. However, it is currently unclear whether NA differentially alters the excitability of glutamatergic and GABAergic BNST-AV neurons. Thus, to shed light on how BNST-AV regulates negative emotional states, the present study compared the physiological properties and NA responsiveness of glutamatergic and GABAergic BNST-AV neurons using whole-cell recordings in transgenic mice that express a fluorescent reporter in either cell group. We found that glutamatergic cells had a slightly more complex morphology than the GABAergic cells, a higher intrinsic excitability, and a different responsiveness to NA. Indeed, while NA inhibited EPSPs in both cell types through α1 and α2 adrenoreceptors, the EPSP reduction seen in glutamatergic cells had a lower amplitude and a shorter duration than in GABAergic cells. These differences were due to the presence of a β-receptor-mediated EPSP enhancement in the glutamatergic cells. Together, our results suggest that multiple properties contribute to the disproportionate influence of glutamatergic BNST-AV neurons.
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Project description:Pitx2, a paired-like homeodomain transcription factor, is expressed in post-mitotic neurons within highly restricted domains of the embryonic mouse brain. Previous reports identified critical roles for PITX2 in histogenesis of the hypothalamus and midbrain, but the cellular identities of PITX2-positive neurons in these regions were not fully explored. This study characterizes Pitx2 expression with respect to midbrain transcription factor and neurotransmitter phenotypes in mid-to-late mouse gestation. In the dorsal midbrain, we identified Pitx2-positive neurons in the stratum griseum intermedium (SGI) as GABAergic and observed a requirement for PITX2 in GABAergic differentiation. We also identified two Pitx2-positive neuronal populations in the ventral midbrain, the red nucleus, and a ventromedial population, both of which contain glutamatergic precursors. Our data suggest that PITX2 is present in regionally restricted subpopulations of midbrain neurons and may have unique functions that promote GABAergic and glutamatergic differentiation.
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