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 (VP VGluT2)], 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 VP VGluT2 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 VP VGluT2 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 VP VGluT2 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 VP VGluT2 neurons to recruit aversion-related targets more readily and therefore be part of the mechanism underlying the aversive symptoms seen after withdrawal.

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, D1-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 VP GABA 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 VP GABA neurons, dynorphin surprisingly potentiated the inhibitory input on VP vGluT2 neurons, but this effect was abolished after cocaine CPP and abstinence. Thus, dynorphin has contrasting influences on GABA input to VP GABA and VP vGluT2 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 VP GABA and VP vGluT2 neurons have contrasting effects on drug-seeking behavior, our data may indicate a complex role for dynorphin in withdrawal from cocaine.

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.

No abstract

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 decreased the excitability of VP neurons, but without major change in synaptic inhibitory input. Within the HFHS group, obesity-prone (OP, top 33% weight gainers) mice had a less excitable VP compared to obesity-resistant (OR, bottom 33% weight gainers) mice and showed short- and long-term potentiation of incoming inhibitory inputs. Moreover, we found that long-term potentiation of the inhibitory inputs to the VP may exist in OP mice before exposure to HFHS and may thus serve as a marker for the predisposition to become obese. These data point to the VP as a critical player in obesity and suggest that hypoactivity in the VP may play a significant role in promoting overeating of palatable food.