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The reinforcement of drug-seeking motivation following drug withdrawal is recognized as a significant factor contributing to relapse. The ventral pallidum (VP) plays a crucial role in encoding and translating motivational aspects of reward. However, current research lacks a clear understanding of how the VP mediates drug-seeking motivation and the feedback modulation between the VP and the nucleus accumbens (NAc) following drug withdrawal. Therefore, utilizing a rat model of cocaine self-administration, we investigated the circuitry mechanisms underlying drug-seeking behavior post-drug withdrawal involving the NAc-VP pathway. Initially, we observed a significant enhancement in drug-seeking behavior 14 days after cocaine withdrawal. Subsequently, we identified the feedback mechanism through which the NAc-VP regulates this behavior. Immunofluorescence results indicated an increase in c-Fos expression levels in the ventral pallidum ventromedial (VPvm) and ventrolateral ventral pallidum (VPvl) following drug withdrawal. Calcium fiber photometry further elucidated that during the expression of high motivational drug-seeking behavior, there was a specific enhancement in VPvm neuronal activity, and retrograde tracing techniques suggested a weakened transmission function in the NAc-VPm pathway. Additionally, chemical genetic techniques demonstrated that inhibiting the activity of the NAc-VP pathway could increase the motivational level of drug-seeking behavior. These findings indicate that the reduced inhibitory function of the NAc-VP pathway following prolonged cocaine withdrawal forms the basis for heightened reactivity in VPvm neurons, thus regulating the expression of high motivational behavior triggered by drug-related cues. Our study results suggest that maintaining normal NAc-VP pathway functionality may decrease drug-seeking motivation post long-term drug withdrawal, offering new insights for interventions targeting relapse. [ABSTRACT FROM AUTHOR]

Pramipexole, a D2/D3 dopamine receptor agonist, is used to treat the motor symptoms of Parkinson's disease, caused by degeneration of the dopaminergic nigrostriatal pathway. There are three paradoxes associated with its mode of action. Firstly, stimulation of D2/D3 receptors leads to neuronal inhibition, although pramipexole does not inhibit but promotes some dopamine-modulated functions, such as locomotion and reinforcement. Secondly, another dopamine-modulated function, arousal, is not promoted but inhibited by pramipexole, leading to sedation. Thirdly, pramipexole-evoked sedation is associated with an increase in pupil diameter, although sedation is expected to cause pupil constriction. To resolve these paradoxes, the path from stimulation of D2/D3 receptors to the modification of dopamine-modulated functions has been tracked. The functions considered are modulated by midbrain dopaminergic nuclei: locomotion – substantia nigra pars compacta (SNc), reinforcement/motivation – ventral tegmental area (VTA), sympathetic activity (as reflected in pupil function) – VTA; arousal – ventral periaqueductal grey (vPAG), with contributions from VTA and SNc. The application of genetics-based molecular techniques (optogenetics and chemogenetics) has enabled tracing the chains of neurones from the dopaminergic nuclei to their final targets executing the functions. The functional neuronal circuits linked to the D2/D3 receptors in the dorsal and ventral striata, stimulated by inputs from SNc and VTA, respectively, may explain how neuronal inhibition induced by pramipexole is translated into the promotion of locomotion, reinforcement/motivation and sympathetic activity. As the vPAG may increase arousal mainly by stimulating cortical D1 dopamine receptors, pramipexole would stimulate only presynaptic D2/D3 receptors on vPAG neurones, curtailing their activity and leading to sedation. [ABSTRACT FROM AUTHOR]

Cues paired with alcohol can be potent drivers of craving, alcohol-seeking, consumption, and relapse. While the ventral pallidum is implicated in appetitive and consummatory responses across several reward classes and types of behaviors, its role in behavioral responses to Pavlovian alcohol cues has not previously been established. Here, we tested the impact of optogenetic inhibition of ventral pallidum on Pavlovian-conditioned alcohol-seeking in male Long Evans rats. Rats underwent Pavlovian conditioning with an auditory cue predicting alcohol delivery to a reward port and a control cue predicting no alcohol delivery, until they consistently entered the reward port more during the alcohol cue than the control cue. We then tested the within-session effects of optogenetic inhibition during 50 % of cue presentations. We found that optogenetic inhibition of ventral pallidum during the alcohol cue reduced port entry likelihood and time spent in the port, and increased port entry latency. Overall, these results suggest that normal ventral pallidum activity is necessary for Pavlovian alcohol-seeking.

The ways in which sensory stimuli acquire motivational valence through association with other stimuli is one of the simplest forms of learning. Although we have identified many brain nuclei that play various roles in reward processing, a significant gap remains in understanding how valence encoding transforms through the layers of sensory processing. To address this gap, we carried out a comparative investigation of the mouse anteromedial olfactory tubercle (OT), and the ventral pallidum (VP) - 2 connected nuclei of the basal ganglia which have both been implicated in reward processing. First, using anterograde and retrograde tracing, we show that both D1 and D2 neurons of the anteromedial OT project primarily to the VP and minimally elsewhere. Using two-photon calcium imaging, we then investigated how the identity of the odor and reward contingency of the odor are differently encoded by neurons in either structure during a classical conditioning paradigm. We find that VP neurons robustly encode reward contingency, but not identity, in low-dimensional space. In contrast, the OT neurons primarily encode odor identity in high-dimensional space. Although D1 OT neurons showed larger responses to rewarded odors than other odors, consistent with prior findings, we interpret this as identity encoding with enhanced contrast. Finally, using a novel conditioning paradigm that decouples reward contingency and licking vigor, we show that both features are encoded by non-overlapping VP neurons. These results provide a novel framework for the striatopallidal circuit in which a high-dimensional encoding of stimulus identity is collapsed onto a low-dimensional encoding of motivational valence.

Abstract Dysfunction of subcortical D2-like dopamine receptors (D2Rs) can lead to positive symptoms of schizophrenia, and their analog, the increased locomotor activity in schizophrenia model MAM-E17 rats. The ventral pallidum (VP) is a limbic structure containing D2Rs. The D2R antagonist sulpiride is a widespread antipsychotic drug, which can alleviate positive symptoms in human patients. However, it is still not known how sulpiride can influence positive symptoms via VP D2Rs. We hypothesize that the microinjection of sulpiride into the VP can normalize hyperactivity in MAM-E17 rats. In addition, recently, we showed that the microinjection of sulpirid into the VP induces place preference in neurotypical rats. Thus, we aimed to test whether intra-VP sulpiride can also have a rewarding effect in MAM-E17 rats. Therefore, open field-based conditioned place preference (CPP) test was applied in neurotypical (SAL-E17) and MAM-E17 schizophrenia model rats to test locomotor activity and the potential locomotor-reducing and rewarding effects of sulpiride. Sulpiride was microinjected bilaterally in three different doses into the VP, and the controls received only vehicle. The results of the present study demonstrated that the increased locomotor activity of the MAM-E17 rats was caused by habituation disturbance. Accordingly, larger doses of sulpiride in the VP reduce the positive symptom-analog habituation disturbance of the MAM-E17 animals. Furthermore, we showed that the largest dose of sulpiride administered into the VP induced CPP in the SAL-E17 animals but not in the MAM-E17 animals. These findings revealed that VP D2Rs play an important role in the formation of positive symptom-like habituation disturbances in MAM-E17 rats.

According to experimental and clinical studies, status epilepticus (SE) causes neurodegenerative morphological changes not only in the hippocampus and other limbic structures, it also affects the thalamus and the neocortex. In addition, several studies reported atrophy, metabolic changes, and neuronal degeneration in the dorsal striatum. The literature lacks studies investigating potential neuronal damage in the ventral component of the striatopallidal complex (ventral striatum [VS] and ventral pallidum) in SE experimentations. To better understand the development of neuronal damage in the striatopallidal complex associated with SE, the detected neuronal degeneration in the compartments of the VS, namely, the nucleus accumbens (NAc) and the olfactory tubercle (OT), was analyzed. The experiments were performed on Wistar rats at age of 25‐day‐old pups and 3‐month‐old adult animals. Lithium–pilocarpine model of SE was used. Lithium chloride (3 mmol/kg, ip) was injected 24 h before administering pilocarpine (40 mg/kg, ip). This presented study demonstrates the variability of post SE neuronal damage in 25‐day‐old pups in comparison with 3‐month‐old adult rats. The NAc exhibited small to moderate number of Fluoro‐Jade B (FJB)‐positive neurons detected 4 and 8 h post SE intervals. The number of degenerated neurons in the shell subdivision of the NAc significantly increased at survival interval of 12 h after the SE. FJB‐positive neurons were evidently more prominent occupying the whole anteroposterior and mediolateral extent of the nucleus at longer survival intervals of 24 and 48 h after the SE. This was also the case in the bordering vicinity between the shell and the core compartments but with clusters of degenerating cells. The severity of damage of the shell subdivision of the NAc reached its peak at an interval of 24 h post SE. Isolated FJB‐positive neurons were detected in the ventral peripheral part of the core compartment. Degenerated neurons persisted in the shell subdivision of the NAc 1 week after SE. However, the quantity of cell damage had significantly reduced in comparison with the aforementioned shorter intervals. The third layer of the OT exhibited more degenerated neurons than the second layer. The FJB‐positive cells in the young animals were higher than in the adult animals. The morphology of those cells was identical in the two age groups except in the OT. [ABSTRACT FROM AUTHOR]

Here, we describe a group of basal forebrain (BF) neurons expressing neuronal Per-Arnt-Sim (PAS) domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. Immunohistochemical staining in Npas1-cre-2A-TdTomato mice revealed BF Npas1+ neurons are distinct from well-studied parvalbumin or cholinergic neurons. Npas1 staining in GAD67-GFP knock-in mice confirmed that the vast majority of Npas1+ neurons are GABAergic, with minimal colocalization with glutamatergic neurons in vGlut1-cre-tdTomato or vGlut2-cre-tdTomato mice. The density of Npas1+ neurons was high, five to six times that of neighboring cholinergic, parvalbumin, or glutamatergic neurons. Anterograde tracing identified prominent projections of BF Npas1+ neurons to brain regions involved in sleep-wake control, motivated behaviors, and olfaction such as the lateral hypothalamus, lateral habenula, nucleus accumbens shell, ventral tegmental area, and olfactory bulb. Chemogenetic activation of BF Npas1+ neurons in the light period increased the amount of wakefulness and the latency to sleep for 2 to 3 h, due to an increase in long wake bouts and short NREM sleep bouts. NREM slow-wave and sigma power, as well as sleep spindle density, amplitude, and duration, were reduced, reminiscent of findings in several neuropsychiatric disorders. Together with previous findings implicating BF Npas1+ neurons in stress responsiveness, the anatomical projections of BF Npas1+ neurons and the effect of activating them suggest a possible role for BF Npas1+ neurons in motivationally driven wakefulness and stress-induced insomnia. Identification of this major subpopulation of BF GABAergic neurons will facilitate studies of their role in sleep disorders, dementia, and other neuropsychiatric conditions involving BF. [ABSTRACT FROM AUTHOR]

The ventral pallidum (VP) is a central hub in the reward circuitry with diverse projections that have different behavioral roles attributed mostly to the connectivity with the downstream target. However, different VP projections may represent, as in the striatum, separate neuronal populations that differ in more than just connectivity. In this study, we performed in mice of both sexes a multimodal dissection of four major projections of the VP—to the lateral hypothalamus (VP→LH), ventral tegmental area (VP→VTA), lateral habenula (VP→LHb), and mediodorsal thalamus (VP→MDT)—with physiological, anatomical, genetic, and behavioral tools. We also tested for physiological differences between VP neurons receiving input from nucleus accumbens medium spiny neurons (MSNs) that express either the D1 (D1-MSNs) or the D2 (D2-MSNs) dopamine receptor. We show that each VP projection (1) when inhibited during a cocaine conditioned place preference (CPP) test affects performance differently, (2) receives a different pattern of inputs using rabies retrograde labeling, (3) shows differentially expressed genes using RNA sequencing, and (4) has projection-specific characteristics in excitability and synaptic input characteristics using whole-cell patch clamp. VP→LH and VP→VTA projections have different effects on CPP and show low overlap in circuit tracing experiments, as VP→VTA neurons receive more striatal input, while VP→LH neurons receive more olfactory input. Additionally, VP→VTA neurons are less excitable, while VP→LH neurons are more excitable than the average VP neuron, a difference driven mainly by D2-MSN-responding neurons. Thus, VP→VTA and VP→LH neurons may represent largely distinct populations of VP neurons. [ABSTRACT FROM AUTHOR]

Objective: To investigate the volume change of ventral pallidum(VP) in alcohol-dependent patients(ADPs) and whether the volume of VP is related to relapse. Methods: This study was a combination of cross sectional and cohort study, which included 33 patients who met the diagnostic criteria for alcohol dependence syndrome in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition(DSM-IV).All the ADPs received clinical questionnaires within 14-28 days of alcohol withdrawal, including a semi-structured questionnaire, the Clinical Institute Withdrawal Assessment(CIWA) and Alcohol Use Disorders Identification Test(AUDIT).The volumes of VP were measured by using magnetic resonance imaging(MRI).A self-made follow-up questionnaire was used to assess post treatment outcome. The ADPs were divided into relapse group and abstinence group within the 6-month follow-up. The VP volume were compared between the ADPs and normal controls, and relapse group and abstinence group. Results: The VP volumes were smaller in the ADPs than in the normal controls [(1749±492) mm3 vs.(2116±189) mm³,P ＜0.05].The VP volumes were larger in the relapse group than in the abstinence group[(1956±452) mm³ vs.(1555±458) mm³,P ＜0.05]. Conclusion: It suggests that the ventral pallidum in alcohol-dependent patients may participate in pathological reward circuit function, which is related to relapse. [ABSTRACT FROM AUTHOR]

Background and purpose: The ventral pallidum (VP) regulates involuntary movements, but it is unclear whether the VP regulates the abnormal involuntary movements in Parkinson's disease (PD) patients who have levodopa‐induced dyskinesia (LID). To further understand the role of the VP in PD patients with LID (PD‐LID), we explored the structural and functional characteristics of the VP in such patients using multimodal magnetic resonance imaging (MRI). Methods: Thirty‐one PD‐LID patients, 39 PD patients without LID (PD‐nLID), and 28 healthy controls (HCs) underwent T1‐weighted MRI, quantitative susceptibility mapping, multi‐shell diffusion MRI, and resting‐state functional MRI (rs‐fMRI). Different measures characterizing the VP were obtained using a region‐of‐interest‐based approach. Results: The left VP in the PD‐LID group showed significantly higher intracellular volume fraction (ICVF) and isotropic volume fraction (IsoVF) compared with the PD‐nLID and HC groups. Rs‐MRI revealed that, compared with the PD‐nLID group, the PD‐LID group in the medication 'off' state had higher functional connectivity (FC) between the left VP and the left anterior caudate, left middle frontal gyrus and left precentral gyrus, as well as between the right VP and the right posterior ventral putamen and right mediodorsal thalamus. In addition, the ICVF values of the left VP, the FC between the left VP and the left anterior caudate and left middle frontal gyrus were positively correlated with Unified Dyskinesia Rating Scale scores. Conclusion: Our multimodal imaging findings show that the microstructural changes of the VP (i.e., the higher ICVF and IsoVF) and the functional change in the ventral striatum–VP–mediodorsal thalamus–cortex network may be associated with pathophysiological mechanisms of PD‐LID. [ABSTRACT FROM AUTHOR]

Neurons of the basal forebrain nucleus basalis and posterior substantia innominata (NBM/SIp) comprise the major source of cholinergic input to the basolateral amygdala (BLA). Using a genetically encoded acetylcholine (ACh) sensor in mice, we demonstrate that BLA-projecting cholinergic neurons can ‘learn’ the association between a naive tone and a foot shock (training) and release ACh in the BLA in response to the conditioned tone 24 hr later (recall). In the NBM/SIp cholinergic neurons express the immediate early gene, Fos following both training and memory recall. Cholinergic neurons that express Fos following memory recall display increased intrinsic excitability. Chemogenetic silencing of these learning-activated cholinergic neurons prevents expression of the defensive behavior to the tone. In contrast, we show that NBM/SIp cholinergic neurons are not activated by an innately threatening stimulus (predator odor). Instead, VP/SIa cholinergic neurons are activated and contribute to defensive behaviors in response to predator odor, an innately threatening stimulus. Taken together, we find that distinct populations of cholinergic neurons are recruited to signal distinct aversive stimuli, demonstrating functionally refined organization of specific types of memory within the cholinergic basal forebrain of mice.

Background: General anesthesia has long been used in clinical practice, but its precise pharmacological effects on neural circuits are not fully understood. Recent investigations suggest that the sleep–wake system may play a role in the reversible loss of consciousness induced by general anesthetics. Studies in mice have shown that microinjection of dopamine receptor 1 (D1R) agonists into the nucleus accumbens (NAc) promotes recovery from isoflurane anesthesia, while microinjection of D1R antagonists has the opposite effect. Furthermore, during the induction and maintenance of sevoflurane anesthesia, there is a significant decrease in extracellular dopamine levels in the NAc, which subsequently increases during the recovery period. These findings suggest the involvement of the NAc in the regulation of general anesthesia. However, the specific role of D1R‐expressing neurons in the NAc during general anesthesia and the downstream effect pathways are still not well understood. Methods: In order to analyze the impact of sevoflurane anesthesia on NAcD1R neurons and the NAcD1R‐VP pathway, this study employed calcium fiber photometry to investigate alterations in the fluorescence intensity of calcium signals in dopamine D1‐receptor‐expressing neurons located in the nucleus accumbens (NAcD1R neurons) and the NAcD1R‐VP pathway during sevoflurane anesthesia. Subsequently, optogenetic techniques were utilized to activate or inhibit NAcD1R neurons and their synaptic terminals in the ventral pallidum (VP), aiming to elucidate the role of NAcD1R neurons and the NAcD1R‐VP pathway in sevoflurane anesthesia. These experiments were supplemented with electroencephalogram (EEG) recordings and behavioral tests. Lastly, a genetically‐encoded fluorescent sensor was employed to observe changes in extracellular GABA neurotransmitters in the VP during sevoflurane anesthesia. Results: Our findings revealed that sevoflurane administration led to the inhibition of NAcD1R neuron population activity, as well as their connections within the ventral pallidum (VP). We also observed a reversible reduction in extracellular GABA levels in the VP during both the induction and emergence phases of sevoflurane anesthesia. Additionally, the optogenetic activation of NAcD1R neurons and their synaptic terminals in the VP resulted in a promotion of wakefulness during sevoflurane anesthesia, accompanied by a decrease in EEG slow wave activity and burst suppression rate. Conversely, the optogenetic inhibition of the NAcD1R‐VP pathway exerted opposite effects. Conclusion: The NAcD1R‐VP pathway serves as a crucial downstream pathway of NAcD1R neurons, playing a significant role in regulating arousal during sevoflurane anesthesia. Importantly, this pathway appears to be associated with the release of GABA neurotransmitters from VP cells. [ABSTRACT FROM AUTHOR]

The ventral pallidum (VP) is involved in the regulation of a variety of behaviors such as motor, reward, and behavioral motivation, and the ability to perform these functions properly is dependent on a high degree of wakefulness. It is unknown whether VP CaMKIIa-expression (VPCaMKIIa) neurons also have a role in sleep–wake regulation and related neuronal circuit mechanisms. In the present experiment, we first used in vivo fiber photometry to find the population activity of VPCaMKIIa neurons which increased during the transitions from non-rapid-eye movement (NREM) sleep to wakefulness and NREM sleep to rapid-eye-movement (REM) sleep, with decreased during the transitions from wakefulness to NREM sleep. Then chemogenetic activation of VPCaMKIIa neurons induced an increase in wakefulness that lasted for 2 h. Mice that were exposed to short-term optogenetic stimulation woke up quickly from stable NREM sleep, and long-term optogenetic stimulation maintained wakefulness. In addition, optogenetic activation of the axons of VPCaMKIIa neurons in the lateral habenula (LHb) also facilitated the initiation and maintenance of wakefulness and mediated anxiety-like behavior. Finally, the method of chemogenetic inhibition was employed to suppress VPCaMKIIa neurons, and yet, inhibition of VPCaMKIIa neuronal activity did not result in an increase in NREM sleep and a decrease in wakefulness. Overall, our data illustrate that the activation of VPCaMKIIa neurons is of great importance for promoting wakefulness. [ABSTRACT FROM AUTHOR]

Background and Purpose: Incubation of craving, the progressive increase in drug seeking over the first weeks of abstinence, is associated with temporal changes during abstinence in the activity of several structures involved in drug‐seeking behaviour. Decreases of dopamine (DA) release and DA neuronal activity (hypodopaminergic state) have been reported in the ventral tegmental area (VTA) during cocaine abstinence, but the mechanisms underlying these neuroadaptations are not well understood. We investigated the potential involvement of a VTA inhibiting circuit (basolateral amygdala [BLA]–ventral pallidum [VP] pathway) in the hypodopaminergic state associated with abstinence from chronic cocaine. Experimental Approach: In a model of cocaine self‐administration, we performed in vivo electrophysiological recordings of DA VTA neurons and BLA neurons from anaesthetised rats during early and protracted abstinence and evaluated the involvement of the BLA–VP pathway using a pharmacological approach. Key Results: We found significant decreases in VTA DA population activity and significant increases in BLA activity after protracted but not after short‐term abstinence from chronic cocaine. The decrease in VTA DA activity was restored by pharmacological inhibition of the activity of either the BLA or the VP, suggesting that these regions exert a negative influence on DA activity. Conclusion and Implications: Our study sheds new lights on neuroadaptations occurring during incubation of craving leading to relapse. In particular, we describe the involvement of the BLA–VP pathway in cocaine‐induced decreases of DA activity in the VTA. This study adds important information about the specific brain network dysfunctions underlying hypodopaminergic activity during abstinence. [ABSTRACT FROM AUTHOR]

Reward-seeking behavior is often initiated by environmental cues that signal reward availability. This is a necessary behavioral response; however, cue reactivity and reward-seeking behavior can become maladaptive. To better understand how cue-elicited reward seeking becomes maladaptive, it is important to understand the neural circuits involved in assigning appetitive value to rewarding cues and actions. Ventral pallidum (VP) neurons are known to contribute to cue-elicited rewardseeking behavior and have heterogeneous responses in a discriminative stimulus (DS) task. The VP neuronal subtypes and output pathways that encode distinct aspects of the DS task remain unknown. Here, we used an intersectional viral approach with fiber photometry to record bulk calcium activity in VP GABAergic (VP GABA) neurons in male and female rats as they learned and performed the DS task. We found that VP GABA neurons are excited by reward-predictive cues but not neutral cues and that this response develops over time. We also found that this cue-evoked response predicts reward-seeking behavior and that inhibiting this VP GABA activity during cue presentation decreases reward-seeking behavior. Additionally, we found increased VP GABA calcium activity at the time of expected reward delivery, which occurred even on trials when reward was omitted. Together, these findings suggest that VP GABA neurons encode reward expectation, and calcium activity in these neurons encodes the vigor of cue-elicited reward seeking. [ABSTRACT FROM AUTHOR]

Economic and decision-making theories suppose that people would disengage from a task with near zero success probability, because this implicates little normative utility values. However, humans often are motivated for an extremely challenging task, even without any extrinsic incentives. The current study aimed to address the nature of this challenge-based motivation and its neural correlates. We found that, when participants played a skill-based task without extrinsic incentives, their task enjoyment increased as the chance of success decreased, even if the task was almost impossible to achieve. However, such challenge-based motivation was not observed when participants were rewarded for the task or the reward was determined in a probabilistic manner. The activation in the ventral striatum/pallidum tracked the pattern of task enjoyment. These results suggest that people are intrinsically motivated to challenge a nearly impossible task but only when the task requires certain skills and extrinsic rewards are unavailable. [ABSTRACT FROM AUTHOR]

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 (Npas11) VP neurons are thought to send projections to brain regions critical for motivational behavior. While Npas11 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 Npas11 neurons and performed RNA-sequencing on ribosome-associated mRNA from VP Npas11 neurons to determine their molecular identity. Finally, we used a chemogenetic approach to manipulate VP Npas11 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 Npas11 projections to the nucleus accumbens, ventral tegmental area, medial and lateral habenula, lateral hypothalamus, thalamus, medial and lateral septum, and periaqueductal gray area. VP Npas11 neurons displayed distinct translatome representing distinct biological processes. Chemogenetic activation of hM3D(Gq) receptors in VP Npas11 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 Npas11 neurons enhanced resilience to chronic SDS and CWDS. Thus, the activity of VP Npas11 neurons modulates susceptibility to social stressors and anxiety-like behavior. Our studies provide new information on VP Npas11 neuron circuitry, molecular identity, and their role in stress response. [ABSTRACT FROM AUTHOR]

The full mechanism of action of propofol, a commonly administered intravenous anesthetic drug in clinical practice, remains elusive. The focus of this study was the role of GABAergic neurons which are the main neuron group in the ventral pallidum (VP) closely associated with anesthetic effects in propofol anesthesia. The activity of VP GABAergic neurons following propofol anesthesia in Vgat-Cre mice was observed via detecting c-Fos immunoreactivity by immunofluorescence and western blotting. Subsequently, chemogenetic techniques were employed in Vgat-Cre mice to regulate the activity of VP GABAergic neurons. The role of VP GABAergic neurons in generating the effects of general anesthesia induced by intravenous propofol was further explored through behavioral tests of the righting reflex. The results revealed that c-Fos expression in VP GABAergic neurons in Vgat-Cre mice dramatically decreased after propofol injection. Further studies demonstrated that chemogenetic activation of VP GABAergic neurons during propofol anesthesia shortened the duration of anesthesia and promoted wakefulness. Conversely, the inhibition of VP GABAergic neurons extended the duration of anesthesia and facilitated the effects of anesthesia. The results obtained in this study suggested that regulating the activity of GABAergic neurons in the ventral pallidum altered the effect of propofol on general anesthesia. • GABAergic neurons in VP are involved in anesthesia effects of propofol. • Propofol anesthesia inhibits the activity of VP GABAergic neurons. • Activating VP GABAergic neurons attenuates anesthesia effects of propofol. • Inhibiting VP GABAergic neurons enhances anesthesia effects of propofol. [ABSTRACT FROM AUTHOR]

Aim: Endogenous dynorphin signaling via kappa opioid receptors (KORs) plays a key role in producing the depressive and aversive consequences of stress. We investigated the behavioral effects of the dynorphin/KOR system in the ventral pallidum (VP) and studied the underlying mechanisms. Methods: To investigate the effects of dynorphin on the VP, we conducted behavioral experiments after microinjection of drugs or shRNA and brain‐slice electrophysiological recordings. Histological tracing and molecular biological experiments were used to identify the distribution of KORs and the possible sources of dynorphin projections to the VP. Results: An elevated dynorphin concentration and increased KOR activity were observed in the VP after acute stress. Infusion of dynorphin‐A into the VP produced depressive‐like phenotypes including anhedonia and despair and anxiety behaviors, but did not alter locomotor behavior. Mechanistically, dynorphin had an inhibitory effect on VP neurons—reducing their firing rate and inhibiting excitatory transmission—through direct activation of KORs and modulation of downstream G‐protein‐gated inwardly rectifying potassium (GIRK) channels and high‐voltage gated calcium channels (VGCCs). Tracing revealed direct innervation of VP neurons by dynorphin‐positive projections; potential sources of these dynorphinergic projections include the nucleus accumbens, amygdala, and hypothalamus. Blockade of dynorphin/KOR signaling in the VP by drugs or viral knock‐down of KORs significantly reduced despair behavior in rats. Conclusions: Endogenous dynorphinergic modulation of the VP plays a critical role in mediating depressive reactions to stress. [ABSTRACT FROM AUTHOR]

Background: Neurotensin (NT) acts as a neurotransmitter and neuromodulator in the central nervous system. It was shown previously that NT in the ventral pallidum (VP) has rewarding and anxiolytic effects. NT exerts its effect in interaction with dopamine (DA) receptors in numerous brain areas; however, this has not yet been investigated in the VP. The aim of this study was to examine whether the inhibition of D1-like and D2-like DA receptors of the VP can modify the above mentioned effects of NT. Methods: Microinjection cannulas were implanted by means of stereotaxic operations into the VP of male Wistar rats. The rewarding effect of NT was examined by means of a conditioned place preference test. Anxiety was investigated with an elevated plus maze test. To investigate the possible interaction, D1-like DA receptor antagonist SCH23390 or D2-like DA receptor antagonist sulpiride were microinjected prior to NT. All of the drugs were also injected independently to analyze their effects alone. Results: In the present experiments, both the rewarding and anxiolytic effects of NT in the VP were prevented by both D1-like and D2-like DA receptor antagonists. Administered on their own, the antagonists did not influence reward and anxiety. Conclusion: Our present results show that the activity of the D1-like and D2-like DA receptors of the VP is a necessary requirement for both the rewarding and anxiolytic effects of NT. [ABSTRACT FROM AUTHOR]

Medial prefrontal cortex (mPFC) interacts with distributed networks that give rise to goal-directed behavior through afferent and efferent connections with multiple thalamic nuclei and recurrent basal ganglia-thalamocortical circuits. Recent studies have revealed individual roles for different thalamic nuclei: mediodorsal (MD) regulation of signaling properties in mPFC neurons, intralaminar control of cortico-basal ganglia networks, ventral medial facilitation of integrative motor function, and hippocampal functions supported by ventral midline and anterior nuclei. Large scale mapping studies have identified functionally distinct cortico-basal ganglia-thalamocortical subnetworks that provide a structural basis for understanding information processing and functional heterogeneity within the basal ganglia. Behavioral analyses comparing functional deficits produced by lesions or inactivation of specific thalamic nuclei or subregions of mPFC or the basal ganglia have elucidated the interdependent roles of these areas in adaptive goal-directed behavior. Electrophysiological recordings of mPFC neurons in rats performing delayed non-matching-to position (DNMTP) and other complex decision making tasks have revealed populations of neurons with activity related to actions and outcomes that underlie these behaviors. These include responses related to motor preparation, instrumental actions, movement, anticipation and delivery of action outcomes, memory delay, and spatial context. Comparison of results for mPFC, MD, and ventral pallidum (VP) suggest critical roles for mPFC in prospective processes that precede actions, MD for reinforcing task-relevant responses in mPFC, and VP for providing feedback about action outcomes. Synthesis of electrophysiological and behavioral results indicates that different networks connecting mPFC with thalamus and the basal ganglia are organized to support distinct functions that allow organisms to act efficiently to obtain intended outcomes. [ABSTRACT FROM AUTHOR]

Background The ventral pallidum (VP) is a dopaminoceptive forebrain structure regulating the ventral tegmental area (VTA) dopaminergic population activity. We have recently demonstrated that in the VP, the D2-like dopamine (DA) receptor agonist quinpirole dose dependently facilitates memory consolidation in inhibitory avoidance and spatial learning. According to our hypothesis, quinpirole microinjected into the VP can modulate the VTA DAergic activity and influence motivation and learning processes of rats. Methods Quinpirole was microinjected at 3 different doses into the VP of male rats, and controls received vehicle. Single unit recordings were employed to assess VTA DAergic activity. To investigate the possible reinforcing or aversive effect of quinpirole in the VP, the conditioned place preference paradigm was used. Results Our results showed that intra-VP quinpirole microinjection regulates VTA DAergic neurons according to an inverted U-shaped dose-response curve. The largest dose of quinpirole decreased the population activity and strongly reduced burst activity of the DAergic neurons in the first hour after its application. In contrast, the 2 smaller doses increased DA population activity, but their effect started with a delay 1 hour after their microinjection. The CPP experiments revealed that the largest dose of quinpirole in the VP induced place aversion in the rats. Furthermore, the largest dose of quinpirole induced an acute locomotor activity reduction, while the medium dose led to a long-duration increase in locomotion. Conclusions In summary, quinpirole dose dependently regulates VTA DAergic activity as well as the motivation and motor behavior of the rats at the level of the VP. [ABSTRACT FROM AUTHOR]

Predictive learning can engage a selective form of cognitive control that biases choice between actions based on information about future outcomes that the learning provides. This influence has been hypothesized to depend on a feedback circuit in the brain through which the basal ganglia modulate activity in the prefrontal cortex; however, direct evidence for this functional circuit has proven elusive. Here, using an animal model of cognitive control, we found that the influence of predictive learning on decision making is mediated by an inhibitory feedback circuit linking the medial ventral pallidum and the mediodorsal thalamus, the activation of which causes disinhibition of the orbitofrontal cortex via reduced activation of inhibitory parvalbumin interneurons during choice. Thus, we found that, for this function, the mediodorsal thalamus serves as a pallidal-cortical relay through which predictive learning controls action selection, which has important implications for understanding cognitive control and its vicissitudes in various psychiatric disorders and addiction. • Predictive learning affects choice via a ventral pallidum to MD-thalamus to OFC circuit • MD-thalamus activity inhibits the OFC via a projection onto OFC-PV neurons • The ventral pallidum releases choice by inhibiting this MD-thalamus to OFC-PV projection • Cognitive control involves a disinhibitory basal ganglia-cortical feedback circuit Cognitive control allows us and other animals to use predictive information to control choices between actions. Here, Leung et al. establish that this control process is mediated by a disinhibitory basal ganglia-cortical feedback circuit, via which the ventral pallidum inhibits the mediodorsal thalamus to disinhibit the orbitofrontal cortex and release choice. [ABSTRACT FROM AUTHOR]

Despite our close genetic relationship with chimpanzees, there are notable differences between chimpanzee and human social behavior. Oxytocin and vasopressin are neuropeptides involved in regulating social behavior across vertebrate taxa, including pair bonding, social communication, and aggression, yet little is known about the neuroanatomy of these systems in primates, particularly in great apes. Here, we used receptor autoradiography to localize oxytocin and vasopressin V1a receptors, OXTR and AVPR1a respectively, in seven chimpanzee brains. OXTR binding was detected in the lateral septum, hypothalamus, medial amygdala, and substantia nigra. AVPR1a binding was observed in the cortex, lateral septum, hypothalamus, mammillary body, entire amygdala, hilus of the dentate gyrus, and substantia nigra. Chimpanzee OXTR/AVPR1a receptor distribution is compared to previous studies in several other primate species. One notable difference is the lack of OXTR in reward regions such as the ventral pallidum and nucleus accumbens in chimpanzees, whereas OXTR is found in these regions in humans. Our results suggest that in chimpanzees, like in most other anthropoid primates studied to date, OXTR has a more restricted distribution than AVPR1a, while in humans the reverse pattern has been reported. Altogether, our study provides a neuroanatomical basis for understanding the function of the oxytocin and vasopressin systems in chimpanzees. [ABSTRACT FROM AUTHOR]

• The ventral pallidum (VP) is a critical regulator of relapse to a variety of drugs. • Recent advancements reveal VP cellular heterogeneity forms segregated circuitry that contribute to functional role of VP in addiction. • Specific neurotransmitters and peptides contribute to functional role of VP in addiction. • VP contributes to relapse of drug seeking both dependent and independent of the common final pathway in relapse to drug seeking. • Manipulation of specific VP domains, cellular types, pathways and peptides can reduce relapse to drug seeking. The ventral pallidum (VP) is central to the reinforcing effects across a variety of drugs and relapse to drug seeking. Emerging studies from animal models of reinstatement reveal a complex neurobiology of the VP that contributes to different aspects of relapse to drug seeking. This review builds on classical understanding of the VP as part of the final common pathway of relapse but also discusses the properties of the VP as an independent structure. These include VP neural anatomical subregions, cellular heterogeneity, circuitry, neurotransmitters and peptides. Collectively, this review provides a current understanding of the VP from molecular to circuit level architecture that contributes to both the appetitive and aversive symptoms of drug addiction. We show the complex neurobiology of the VP in drug seeking, emphasizing its critical role in addiction, and review strategic approaches that target the VP to reduce relapse rates. [ABSTRACT FROM AUTHOR]

Daily life requires transitions between performance of well-practiced, automatized behaviors reliant upon internalized representations and behaviors requiring external focus. Such transitions involve differential activation of the default mode network (DMN), a group of brain areas associated with inward focus. We asked how optogenetic modulation of the ventral pallidum (VP), a subcortical DMN node, impacts task switching between internally to externally guided lever-pressing behavior in the rat. Excitation of the VP dramatically compromised acquisition of an auditory discrimination task, trapping animals in a DMN state of automatized internally focused behavior and impairing their ability to direct attention to external sensory stimuli. VP inhibition, on the other hand, facilitated task acquisition, expediting escape from the DMN brain state, thereby allowing rats to incorporate the contingency changes associated with the auditory stimuli. We suggest that VP, instant by instant, regulates the DMN and plays a deterministic role in transitions between internally and externally guided behaviors. [ABSTRACT FROM AUTHOR]

Anhedonia is common in individuals with traumatic experience. Anhedonia symptoms play an important role in posttraumatic psychopathology, and are related to various adverse outcomes. The current study is a preliminary neuroimaging study of the neural correlates of posttraumatic anhedonia symptoms. Resting-state fMRI data were acquired from 88 Chinese earthquake survivors. Whole brain analyses and exploratory ROI-to-ROI analyses were performed to examine the relationship between posttraumatic anhedonia symptoms and resting-state functional connectivity (rsFC) of reward-related subcortical nucleus including nucleus accumbens and ventral pallidum. The rsFC between left ventral pallidum and areas of bilateral posterior cingulate cortex (PCC) and precuneus cortex were found lower in the high posttraumatic anhedonia group, after controlling for sex, age and other posttraumatic stress symptoms. The rsFC between left ventral pallidum and PCC and the rsFC between left ventral pallidum and lateral parietal cortex were significantly lower in the high anhedonia group. Our findings suggest that decreased functional connectivity between the ventral pallidum and the brain default mode network (DMN) regions could be the neural correlates of posttraumatic anhedonia symptoms. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that increased dopaminergic signaling within the dorsal striatum played a central role in the evolution of the human brain. This increase has been linked to human prosociality and language in what has been described as a dopamine-dominated striatum personality style. Increased striatal dopamine is associated with an increase in ventral striatal activity and promotes externally driven behaviors, including cooperation and social conformity. In contrast, decreased striatal dopamine is associated with increased dorsal striatal activity and favors internally driven and goal-oriented behaviors. Previous comparative studies have focused on the dorsal striatum, measuring dopaminergic innervation in the dorsal and medial caudate nucleus and putamen. Here, we add to this knowledge by examining regions of the ventral striatum. We quantified the density of tyrosine hydroxylase–immunoreactive axons, as a measure of dopaminergic innervation, in the nucleus accumbens and ventral pallidum of humans, great apes, platyrrhine and cercopithecid monkeys. Our data show that humans have a significantly greater dopaminergic innervation in both structures, supporting the hypothesis that selection for a prosocial neurochemistry in the human basal ganglia may have contributed to the evolution of our uniquely social behavior profile. [ABSTRACT FROM AUTHOR]

The basal forebrain (BF) is involved in arousal, attention, and reward processing but the role of individual BF neuronal subtypes is still being uncovered. Glutamatergic neurons are the least well-understood of the three main BF neurotransmitter phenotypes. Here we analyzed the distribution, size, calcium-binding protein content and projections of the major group of BF glutamatergic neurons expressing the vesicular glutamate transporter subtype 2 (vGluT2) and tested the functional effect of activating them. Mice expressing Cre recombinase under the control of the vGluT2 promoter were crossed with a reporter strain expressing the red fluorescent protein, tdTomato, to generate vGluT2-cre-tdTomato mice. Immunohistochemical staining for choline acetyltransferase and a cross with mice expressing green fluorescent protein selectively in GABAergic neurons confirmed that cholinergic, GABAergic and vGluT2+ neurons represent distinct BF subpopulations. Subsets of BF vGluT2+ neurons expressed the calcium-binding proteins calbindin or calretinin, suggesting that multiple subtypes of BF vGluT2+ neurons exist. Anterograde tracing using adeno-associated viral vectors expressing channelrhodopsin2-enhanced yellow fluorescent fusion proteins revealed major projections of BF vGluT2+ neurons to neighboring BF cholinergic and parvalbumin neurons, as well as to extra-BF areas involved in the control of arousal or aversive/rewarding behavior such as the lateral habenula and ventral tegmental area. Optogenetic activation of BF vGluT2+ neurons elicited a striking avoidance of the area where stimulation was given, whereas stimulation of BF parvalbumin or cholinergic neurons did not. Together with previous optogenetic findings suggesting an arousal-promoting role, our findings suggest that BF vGluT2 neurons play a dual role in promoting wakefulness and avoidance behavior. [ABSTRACT FROM AUTHOR]

To better understand the function of cholinergic projection neurons in the ventral pallidum (VP), we examined behavioral responses to appetitive (APP) and aversive (AV) odors that elicited approach or avoidance, respectively. Exposure to each odor increased cFos expression and calcium signaling in VP cholinergic neurons. Activity and Cre-dependent viral vectors selectively labeled VP cholinergic neurons that were activated and reactivated in response to either APP or AV odors, but not both, identifying two non-overlapping populations of VP cholinergic neurons differentially activated by the valence of olfactory stimuli. These two subpopulations showed differences in electrophysiological properties, morphology, and projections to the basolateral amygdala. Although VP neurons are engaged in both approach and avoidance behavioral responses, cholinergic signaling is only required for approach behavior. Thus, two distinct subpopulations of VP cholinergic neurons differentially encode valence of olfactory stimuli and play distinct roles in approach and avoidance behaviors. [Display omitted] • VP cholinergic projection neurons are engaged in approach and avoidance behaviors • Opposing valence odors activate distinct subpopulations of VP cholinergic neurons • These two subpopulations differentially integrate into VP circuits • VP cholinergic signaling is required for approach behavior Kim et al. identify two distinct subpopulations of VP cholinergic projection neurons activated by an appetitive vs. aversive odor. These two subpopulations display different properties, which indicate differential integration of each subpopulation into neural circuits. These results demonstrate functional heterogeneity of VP cholinergic neurons. [ABSTRACT FROM AUTHOR]

Background: Neurotensin (NT) acts as a neurotransmitter and neuromodulator in the central nervous system. It was shown previously that NT in the ventral pallidum (VP) has rewarding and anxiolytic effects. NT exerts its effect in interaction with dopamine (DA) receptors in numerous brain areas; however, this has not yet been investigated in the VP. The aim of this study was to examine whether the inhibition of D1-like and D2-like DA receptors of the VP can modify the above mentioned effects of NT. Methods: Microinjection cannulas were implanted by means of stereotaxic operations into the VP of male Wistar rats. The rewarding effect of NT was examined by means of a conditioned place preference test. Anxiety was investigated with an elevated plus maze test. To investigate the possible interaction, D1-like DA receptor antagonist SCH23390 or D2-like DA receptor antagonist sulpiride were microinjected prior to NT. All of the drugs were also injected independently to analyze their effects alone. Results: In the present experiments, both the rewarding and anxiolytic effects of NT in the VP were prevented by both D1-like and D2-like DA receptor antagonists. Administered on their own, the antagonists did not influence reward and anxiety. Conclusion: Our present results show that the activity of the D1-like and D2-like DA receptors of the VP is a necessary requirement for both the rewarding and anxiolytic effects of NT.

Movement-related neuronal discharge in ventral tegmental area (VTA) and ventral pallidum (VP) is inconsistently observed across studies. One possibility is that some neurons are movement related and others are not. Another possibility is that the precise behavioral conditions matter—that a single neuron can be movement related under certain behavioral states but not others. We recorded single VTA and VP neurons in birds transitioning between singing and nonsinging states while monitoring body movement with microdrive-mounted accelerometers. Many VP and VTA neurons exhibited body movement-locked activity exclusively when the bird was not singing. During singing, VP and VTA neurons could switch off their tuning to body movement and become instead precisely time-locked to specific song syllables. These changes in neuronal tuning occurred rapidly at state boundaries. Our findings show that movement-related activity in limbic circuits can be gated by behavioral context. [ABSTRACT FROM AUTHOR]

Background: Pair bonding with a reproductive partner is rare among mammals but is an important feature of human social behavior. Decades of research on monogamous prairie voles (Microtus ochrogaster), along with comparative studies using the related non-bonding meadow vole (M. pennsylvanicus), have revealed many of the neural and molecular mechanisms necessary for pair-bond formation in that species. However, these studies have largely focused on just a few neuromodulatory systems. To test the hypothesis that neural gene expression differences underlie differential capacities to bond, we performed RNA-sequencing on tissue from three brain regions important for bonding and other social behaviors across bond-forming prairie voles and non-bonding meadow voles. We examined gene expression in the amygdala, hypothalamus, and combined ventral pallidum/nucleus accumbens in virgins and at three time points after mating to understand species differences in gene expression at baseline, in response to mating, and during bond formation. Results: We first identified species and brain region as the factors most strongly associated with gene expression in our samples. Next, we found gene categories related to cell structure, translation, and metabolism that differed in expression across species in virgins, as well as categories associated with cell structure, synaptic and neuroendocrine signaling, and transcription and translation that varied among the focal regions in our study. Additionally, we identified genes that were differentially expressed across species after mating in each of our regions of interest. These include genes involved in regulating transcription, neuron structure, and synaptic plasticity. Finally, we identified modules of co-regulated genes that were strongly correlated with brain region in both species, and modules that were correlated with post-mating time points in prairie voles but not meadow voles. Conclusions: These results reinforce the importance of pre-mating differences that confer the ability to form pair bonds in prairie voles but not promiscuous species such as meadow voles. Gene ontology analysis supports the hypothesis that pair-bond formation involves transcriptional regulation, and changes in neuronal structure. Together, our results expand knowledge of the genes involved in the pair bonding process and open new avenues of research in the molecular mechanisms of bond formation. [ABSTRACT FROM AUTHOR]

The nucleus accumbens shell (NAcSh) plays an important role in reward and aversion. Traditionally, NAc dopamine receptor 2-expressing (D2) neurons are assumed to function in aversion. However, this has been challenged by recent reports which attribute positive motivational roles to D2 neurons. Using optogenetics and multiple behavioral tasks, we found that activation of D2 neurons in the dorsomedial NAcSh drives preference and increases the motivation for rewards, whereas activation of ventral NAcSh D2 neurons induces aversion. Stimulation of D2 neurons in the ventromedial NAcSh increases movement speed and stimulation of D2 neurons in the ventrolateral NAcSh decreases movement speed. Combining retrograde tracing and in situ hybridization, we demonstrated that glutamatergic and GABAergic neurons in the ventral pallidum receive inputs differentially from the dorsomedial and ventral NAcSh. All together, these findings shed light on the controversy regarding the function of NAcSh D2 neurons, and provide new insights into understanding the heterogeneity of the NAcSh. [ABSTRACT FROM AUTHOR]

Afferents from the nucleus accumbens (NAc) are a major source of input into the ventral pallidum (VP). Research reveals that these afferents are GABAergic, however, stimulation of these afferents induces both excitatory and inhibitory responses within the VP. These are likely to be partially mediated by enkephalin and substance P (SP), which are also released by these afferents, and are known to modulate VP neurons. However, less is known about the potentially differential effects stimulation of these afferents has on subpopulations of neurons within the VP and the cellular mechanisms by which they exert their effects. The current study aimed to research this further using brain slices containing the VP, stimulation of the NAc afferents, and multi-electrode array (MEA) recordings of their VP targets. Stimulation of the NAc afferents induced a pause in the tonic firing in 58% of the neurons studied in the VP, while 42% were not affected. Measures used to reveal the electrophysiological difference between these groups found no significant differences in firing frequency, coefficient of variation, and spike half-width. There were however significant differences in the pause duration between neurons in the dorsal and ventral VP, with stimulation of NAc afferents producing a significantly longer pause (0.48 ± 0.06 s) in tonic firing in dorsal VP neurons, compared to neurons in the ventral VP (0.21 ± 0.09 s). Pauses in the tonic firing of VP neurons, as a result of NAc afferent stimulation, were found to be largely mediated by GABAA receptors, as the application of picrotoxin significantly reduced their duration. Opioid agonists and antagonists were found to have no significant effects on the pause in tonic activity induced by NAc afferent stimulation. However, NK-1 receptor antagonists caused significant decreases in the pause duration, suggesting that SP may contribute to the inhibitory effect of NAc afferent stimulation via activation of NK-1 receptors.

A major driver of obesity is the increasing palatability of processed foods. Although reward circuits promote the consumption of palatable food, their involvement in obesity remains unclear. The ventral pallidum (VP) is a key hub in the reward system that encodes the hedonic aspects of palatable food consumption and participates in various proposed feeding circuits. However, there is still no evidence for its involvement in developing diet-induced obesity. Here we examine, using male C57BL6/J mice and patch-clamp electrophysiology, how chronic high-fat high-sugar (HFHS) diet changes the physiology of the VP and whether mice that gain the most weight differ in their VP physiology from others. We found that 10-12 weeks of HFHS diet hyperpolarized and decreased the firing rate of VP neurons without a major change in synaptic inhibitory input. Within the HFHS group, the top 33% weight gainers (WGs) had a more hyperpolarized VP with longer latency to fire action potentials on depolarization compared with bottom 33% of weight gainers (i.e., non-weight gainers). WGs also showed synaptic potentiation of inhibitory inputs both at the millisecond and minute ranges. Moreover, we found that the tendency to potentiate the inhibitory inputs to the VP might exist in overeating mice even before exposure to HFHS, thus making it a potential property of being an overeater. These data point to the VP as a critical player in obesity and suggest that hyperpolarized membrane potential of, and potentiated inhibitory inputs to, VP neurons may play a significant role in promoting the overeating of palatable food. [ABSTRACT FROM AUTHOR]

In rodents, stimulation of the nucleus accumbens shell (AcbSh) directly or via its projection to the lateral hypothalamus (LH) attenuates food intake. The ventral pallidum (VP) receives dense projections from the AcbSh and is sensitive to the hedonic aspect of food and motivation for reward. However, the role of accumbal projections to the VP in the regulation of food intake was not well investigated. In the present study conducted on female rats, we examined the effects of stimulation of the AcbSh using optogenetics, or pharmacological inhibition of the rostral VP, or stimulation of projections from the AcbSh to the rostral VP using optogenetics on the consumption of 10% sucrose, lick microstructure and the expression of c-fos mRNA. Stimulation of the AcbSh, inhibition of the rostral VP with muscimol, or stimulation of axonal terminals from the AcbSh to the rostral VP resulted in a decrease in sucrose intake, meal duration, and total number of licks. The licking microstructure analysis showed that optogenetic stimulation of AcbSh or axonal terminals from the AcbSh to the rostral VP decreased the hedonic value of the sucrose. However, inhibition of the rostral VP decreased the motivation, whereas stimulation of the accumbal projections in the rostral VP increased the motivation to drink. This difference could be due to differential involvement of GABAergic and glutamatergic VP neurons. Stimulation of the AcbSh resulted in a decrease of c-fos mRNA expression in the LH and rostral VP, and stimulation of axonal terminals from the AcbSh to the rostral VP decreased c-fos mRNA expression only in the rostral VP. This study demonstrates that in adult female rats, in addition to the already known role of the AcbSh projections to the LH, AcbSh projections to the VP play a major role in the regulation of sucrose intake. [ABSTRACT FROM AUTHOR]

Afferents from the nucleus accumbens (NAc) are a major source of input into the ventral pallidum (VP). Research reveals that these afferents are GABAergic, however, stimulation of these afferents induces both excitatory and inhibitory responses within the VP. These are likely to be partially mediated by enkephalin and substance P (SP), which are also released by these afferents, and are known to modulate VP neurons. However, less is known about the potentially differential effects stimulation of these afferents has on subpopulations of neurons within the VP and the cellular mechanisms by which they exert their effects. The current study aimed to research this further using brain slices containing the VP, stimulation of the NAc afferents, and multi-electrode array (MEA) recordings of their VP targets. Stimulation of the NAc afferents induced a pause in the tonic firing in 58% of the neurons studied in the VP, while 42% were not affected. Measures used to reveal the electrophysiological difference between these groups found no significant differences in firing frequency, coefficient of variation, and spike half-width. There were however significant differences in the pause duration between neurons in the dorsal and ventral VP, with stimulation of NAc afferents producing a significantly longer pause (0.48 ± 0.06 s) in tonic firing in dorsal VP neurons, compared to neurons in the ventral VP (0.21 ± 0.09 s). Pauses in the tonic firing of VP neurons, as a result of NAc afferent stimulation, were found to be largely mediated by GABAA receptors, as the application of picrotoxin significantly reduced their duration. Opioid agonists and antagonists were found to have no significant effects on the pause in tonic activity induced by NAc afferent stimulation. However, NK-1 receptor antagonists caused significant decreases in the pause duration, suggesting that SP may contribute to the inhibitory effect of NAc afferent stimulation via activation of NK-1 receptors. [ABSTRACT FROM AUTHOR]

Objectives: Lateral habenula (LHb) is a key brain structure for mediating behavioural responses to aversive stimuli. It receives presynaptic inputs from ventral pallidum (VP) which relates to reward, motivation and hedonics. This study investigated the role of glutamatergic VP-LH projection in negative emotions and depression-like behaviour. Methods: The glutamatergic VP-LHb circuits in Vglut2-Cre mice were activated or inhibited using optogenetic manipulation. Real time place aversion test was performed to access aversive behaviour. Mice underwent chronic social defeat stress or subthreshold social defeat stress paradigm. Then social interaction test and tail suspension test were carried out to evaluate the stress-induced depression-like behaviours. Results: Activation of VP-LHb glutamatergic projections induced aversive behaviour in the real time place aversion test. Activation of this circuit induced depressive-like phenotype after social stress, while optogenetic inhibition of this circuit exerted an antidepressant effect in social stress susceptible mice. Local LHb ketamine administration rescued the depression-like phenotype caused by activation of this circuit. Conclusions: Data from our study demonstrated an involvement of the glutamatergic VP-LHb circuit in the stress-induced depression-related behaviours. [ABSTRACT FROM AUTHOR]

GABA, the most abundant inhibitory neurotransmitter in the brain, is closely linked with sleep and wakefulness. As the largest area input to the ventral pallidum (VP), the nucleus accumbens (NAc) has been confirmed to play a pivotal role in promoting non-rapid eye movement (NREM) sleep through inhibitory projections from NAc adenosine A2A receptor-expressing neurons to VP GABAergic neurons which mostly express GABAA receptors. Although these studies demonstrate the possible role of VP GABAergic neurons in sleep–wake regulation, whether and how its modulate sleep–wake cycle is not completely clear. In our study, pharmacological manipulations were implemented in freely moving rats and then the EEG and the EMG were recorded to monitor the sleep–wake states. We found that microinjection of muscimol, a GABAA receptor agonist, into the VP increased NREM sleep in both light and dark period. Microinjection of bicuculline, a GABAA receptor antagonist, into the VP increased wakefulness in the light period. Collectively, our data identify the important role of VP GABAA receptor-expressing neurons in NREM sleep of rats which may help improve the understanding of the pathological sleep disorders. [ABSTRACT FROM AUTHOR]

Cocaine-driven changes in the modulation of neurotransmission by neuromodulators are poorly understood. The ventral pallidum (VP) is a key structure in the reward system, in which GABA neurotransmission is regulated by opioid neuropeptides, including dynorphin. However, it is not known whether dynorphin acts differently on different cell types in the VP and whether its effects are altered by withdrawal from cocaine. Here, we trained wild-type, Dl-Cre, A2A-Cre, or vGluT2-Cre:Ai9 male and female mice in a cocaine conditioned place preference protocol followed by 2 weeks of abstinence, and then recorded GABAergic synaptic input evoked either electrically or optogenetically onto identified VP neurons before and after applying dynorphin. We found that after cocaine CPP and abstinence dynorphin attenuated inhibitory input to VPGABA neurons through a postsynaptic mechanism. This effect was absent in saline mice. Furthermore, this effect was seen specifically on the inputs from nucleus accumbens medium spiny neurons expressing either the D1 or the D2 dopamine receptor. Unlike its effect on VPGABA neurons, dynorphin surprisingly potentiated the inhibitory input on VPvGluT2 neurons, but this effect was abolished after cocaine CPP and abstinence. Thus, dynorphin has contrasting influences on GABA input to VPGABA and VPvGluT2 neurons and these influences are affected differentially by cocaine CPP and abstinence. Collectively, our data suggest a role for dynorphin in withdrawal through its actions in the VP. As VPGABA and VPvGluT2 neurons have contrasting effects on drug-seeking behavior, our data may indicate a complex role for dynorphin in withdrawal from cocaine. [ABSTRACT FROM AUTHOR]

The ventral pallidum (VP) is a central node in the reward system that is strongly implicated in reward and addiction. Although the majority of VP neurons are GABAergic and encode reward, recent studies revealed a novel glutamatergic neuronal population in the VP [VP neurons expressing the vesicular glutamate transporter 2 (VPVGluT2)], whose activation generates aversion. Withdrawal from drugs has been shown to induce drastic synaptic changes in neuronal populations associated with reward, such as the ventral tegmental area (VTA) or nucleus accumbens neurons, but less is known about cocaine-induced synaptic changes in neurons classically linked with aversion. Here, we demonstrate that VPVGluT2 neurons contact different targets with different intensities, and that cocaine conditioned place preference (CPP) training followed by abstinence selectively potentiates their synapses on targets that encode aversion. Using whole-cell patch-clamp recordings combined with optogenetics in male and female transgenic mice, we show that VPVGluT2 neurons preferentially contact aversion-related neurons, such as lateral habenula neurons and VTA GABAergic neurons, with minor input to reward-related neurons, such as VTA dopamine and VP GABA neurons. Moreover, after cocaine CPP and abstinence, the VPVGluT2 input to the aversionrelated structures is potentiated, whereas the input to the reward-related structures is depressed. Thus, cocaine CPP followed by abstinence may allow VPVGluT2 neurons to recruit aversion-related targets more readily and therefore be part of the mechanism underlying the aversive symptoms seen after withdrawal. [ABSTRACT FROM AUTHOR]

The ventral pallidum (VP) is a key node in the neural circuits controlling relapse to drug seeking. How this role relates to different VP cell types and their projections is poorly understood. Using male rats, we show how different forms of relapse to alcohol-seeking are assembled from VP cell types and their projections to lateral hypothalamus (LH) and ventral tegmental area (VTA). Using RNAScope in situ hybridization to characterize activity of different VP cell types during relapse to alcohol-seeking provoked by renewal (contextinduced reinstatement), we found that VP Gadl and parvalbumin (PV), but not vGlut2, neurons show relapse-associated changes in c-Fos expression. Next, we used retrograde tracing, chemogenetic, and electrophysiological approaches to study the roles of VPGadl and VPpv neurons in relapse. We show that VPGadl neurons contribute to contextual control over relapse (renewal), but not to relapse during reacquisition, via projections to LH, where they converge with ventral striatal inputs onto LHGadl neurons. This convergence of striatopallidal inputs at the level of individual LH Gad 1 neurons may be critical to balancing propensity for relapse versus abstinence. In contrast, VPpv neurons contribute to relapse during both renewal and reacquisition via projections to VTA. These findings identify a double dissociation in the roles for different VP cell types and their projections in relapse. VPGadl neurons control relapse during renewal via projections to LH. VP P' neurons control relapse during both renewal and reacquisition via projections to VTA. Targeting these different pathways may provide tailored interventions for different forms of relapse. [ABSTRACT FROM AUTHOR]

Reward-predictive cues acquire motivating and reinforcing properties that contribute to the escalation and relapse of drug use in addiction. The ventral pallidum (VP) and ventral tegmental area (VTA) are two key nodes in brain reward circuitry implicated in addiction and cue-driven behavior. In the current study, we use in vivo fiber photometry and optogenetics to record from and manipulate VP→VTA in rats performing a discriminative stimulus task to determine the role these neurons play in invigoration and reinforcement by reward cues. We find that VP→VTA neurons are active during reward consumption and that optogenetic stimulation of these neurons biases choice behavior and is reinforcing. Critically, we find no encoding of reward-seeking vigor, and optogenetic stimulation does not enhance the probability or vigor of reward seeking in response to cues. Our results suggest that VP→VTA activity is more important for reinforcement than for invigoration of reward seeking by cues. [Display omitted] • Cued reward seeking activates calcium in VTA-projecting ventral pallidum neurons • Calcium activity more strongly reflects reward seeking and consumption than cues • Optogenetic stimulation during the cue does not alter cued reward seeking • Stimulation during reward consumption can bias choice behavior Palmer et al. show that ventral pallidum neurons projecting to the ventral tegmental area do not encode or drive cue-elicited reward seeking but can drive reinforcement and alter choice behavior in response to rewards themselves. This suggests that these neurons are more involved in reinforcement than in motivation or invigoration. [ABSTRACT FROM AUTHOR]

Intoduction: The ventral pallidum (VP) plays a distinct role in reward-related learning. Since the cannabinoid CB1 and mu-opioid receptors are expressed in the VP, the presynaptic CB1 receptors may be involved in the activity of the endogenous opioid reward system. The prefrontal cortex (PFC) contributes to the changes in synaptic plasticity under drug abuse and interestingly, is neuroanatomically connected to the VP. MicroRNAs (miRNAs) as valuable biomarkers mediate the expression level of brain-derived neurotrophic factor (BDNF) in the PFC. The present study aimed to investigate the contributions of the PFC miRNA-10a-5p and BDNF in the interaction between the opioidergic and ventral pallidal endocannabinoid systems in the conditioned place preference procedure to assess the drugs’ rewarding properties. Methods and Materials: Adult male Wistar rats were bilaterally cannulated into the VP by stereotaxic surgery. Intraperitoneal administration of morphine was done via a 3-day schedule of conditioned place preference (CPP) paradigm. The different doses of AM251, as a selective antagonist of cannabinoid CB1 receptors, were injected into the VP during the conditioning phase. The real-time PCR technique was used to measure the expression levels of miR-10a-5p and BDNF mRNA under the drug administrations. Results: The results showed that morphine produced a significant CPP during the conditioning phase. Intra-VP microinjection of AM251 did not induce CPP by itself. Interestingly, intra-ventral pallidal microinjection of AM251 inhibited the morphine-induced CPP. The locomotor activity did not change in all experimental groups. The RT-PCR results showed the induction of morphine-induced reward and its suppression by inhibiting the ventral pallidal endocannabinoid system changed the PFC BDNF mRNA and miR-10a-5p. Conclusions: These results indicate that the ventral pallidal endocannabinoid system may be involved in morphine-induced CPP. The PFC expression changes of BDNF mRNA and miR-10a-5p may be associated with the inhibitory effect of the VP CB1 receptors on morphine reward. [ABSTRACT FROM AUTHOR]

Obesity has become a global issue, and the overconsumption of food is thought to be a major contributor. However, the regulatory neural circuits that regulate palatable food consumption remain unclear. Here, we report that somatostatin (SOM) neurons and GABAergic (VGAT) neurons in the basal forebrain (BF) play specific roles in regulating feeding. Optogenetic stimulation of BF SOM neurons increased fat and sucrose intake within minutes and promoted anxiety-like behaviors. Furthermore, optogenetic stimulation of projections from BF SOM neurons to the lateral hypothalamic area (LHA) selectively resulted in fat intake. In addition, activation of BF VGAT neurons rapidly induced general food intake and gnawing behaviors. Whole-brain mapping of inputs and outputs showed that BF SOM neurons form bidirectional connections with several brain areas important in feeding and regulation of emotion. Collectively, these results suggest that BF SOM neurons play a selective role in hedonic feeding.

Signaling at the orexin-1 receptor (OxRl) is important for motivated drug taking. Using a within-session behavioral economics (BE) procedure, we previously found that pharmacologic blockade of the OxRl decreased motivation (increased demand elasticity) for the potent and short-acting opioid remifentanil and reduced low-effort remifentanil consumption. However, the mechanism through which orexin regulates remifentanil demand is currently unknown. Previous work implicated OxRl signaling within ventral pallidum (VP) as a potential target. VP is densely innervated by orexin fibers and is known to regulate opioid reward. Accordingly, this study sought to determine the role of VP OxRl signaling in remifentanil demand and cue-induced reinstatement of remifentanil seeking in male rats. Intra-VP microinjections of the OxRl antagonist SB-334867 (SB) decreased motivation (increased demand elasticity; a) for remifentanil without affecting remifentanil consumption at low effort. Baseline α values predicted the degree of cue-induced remifentanil seeking, and microinjection of SB into VP attenuated this behavior without affecting extinction responding. Baseline a values also predicted SB efficacy, such that SB was most effective in attenuating reinstatement behavior in highly motivated rats. Together, these findings support a selective role for VP OxRl signaling in motivation for the opioid remifentanil. Our findings also highlight the utility of BE in predicting relapse propensity and efficacy of treatment with OxRl antagonists. [ABSTRACT FROM AUTHOR]

Axonal transport of retrograde markers was used to study the characteristics of the organization of the projection systems connecting different parts of the dorsal raphe nucleus (DRN) with functionally diverse segments of striopallidal structures. The possible pathways by which the DRN may modulate the structures of the morphofunctional system of the basal ganglia are detailed. The projections to the limbic segments of the input nuclei of the basal ganglia from the dorsal part of the DRN, which is innervated by limbic structures, found here are evidence that limbic information may be conducted via these pathways. Projections from all parts of the DRN are directed to the input nuclei of the basal ganglia but not to the functionally diverse segments of the pallidal nuclei. The overlap found in the entopeduncular nucleus of the terminal fields of neurons from all parts of the DRN receiving and sending functionally diverse information to and from the basal ganglia system is evidence for the possible interaction of this information in this nucleus. The importance of these data for creating models aiding our understanding of the functioning of the basal ganglia in health and disease is assessed. [ABSTRACT FROM AUTHOR]