The ventral striatopallidal system, a basal ganglia network thought to convert limbic information into behavioral action, includes the nucleus accumbens (NAc) and the ventral pallidum (VP), typically described as a major output of NAc. Here, to investigate how reward-related information is transformed across this circuit, we measure the activity of neurons in NAc and VP when rats receive two highly palatable but differentially preferred rewards, allowing us to track the reward-specific information contained within the neural activity of each region. In VP, we find a prominent preference-related signal that flexibly reports the relative value of reward outcomes across multiple conditions. This reward-specific firing in VP is present in a greater proportion of the population and arises sooner following reward delivery than in NAc. Our findings establish VP as a preeminent value signaler and challenge the existing model of information flow in the ventral basal ganglia.

Hypotheses of striatal orchestration of behavior ascribe distinct functions to striatal subregions, with the dorsolateral striatum (DLS) especially implicated in habitual and skilled performance. Thus neural activity patterns recorded from the DLS, but not the dorsomedial striatum (DMS), should be correlated with habitual and automatized performance. Here, we recorded DMS and DLS neural activity in rats during training in a task promoting habitual lever pressing. Despite improving performance across sessions, clear changes in corresponding neural activity patterns were not evident in DMS or DLS during early training. Although DMS and DLS activity patterns were distinct during early training, their activity was similar following extended training. Finally, performance after extended training was not associated with DMS disengagement, as would be predicted from prior work. These results suggest that behavioral sequences may continue to engage both striatal regions long after initial acquisition, when skilled performance is consolidated.

The nervous system is hypothesized to compute reward prediction errors (RPEs) to promote adaptive behavior. Correlates of RPEs have been observed in the midbrain dopamine system, but the extent to which RPE signals exist in other regions implicated in reward processing is less well understood. Here, we quantified outcome history-based RPE signals in the ventral pallidum (VP), a basal ganglia nucleus functionally linked to reward-seeking behavior. We trained rats to respond to reward-predicting cues and fit computational models to the firing rates of individual neurons at the time of reward delivery. We found that a subset of VP neurons encoded RPEs and did so more robustly than nucleus accumbens, an input to VP. VP RPEs predicted changes in task engagement, and optogenetic manipulation of VP during reward delivery bidirectionally altered rats' subsequent reward-seeking behavior. Our data suggest a pivotal role for VP in computing teaching signals that influence adaptive reward seeking.

While weight gain is clearly promoted by excessive energy intake and reduced expenditure, the underlying neural mechanisms of energy balance remain unclear. The nucleus accumbens (NAc) is one brain region that has received attention for its role in the regulation of energy balance; its D1 and D2 receptor containing neurons have distinct functions in regulating reward behavior and require further examination. The goal of the present study is to investigate how activation and inhibition of D1 and D2 neurons in the NAc influences behaviors related to energy intake and expenditure. Specific manipulation of D1 vs. D2 neurons was done in both low expenditure and high expenditure (wheel running) conditions to assess behavioral effects in these different states. Direct control of neural activity was achieved using a designer receptors exclusively activated by designer drugs (DREADD) strategy. Activation of NAc D1 neurons increased food intake, wheel running and locomotor activity. In contrast, activation of D2 neurons in the NAc reduced running and locomotion while D2 neuron inhibition had opposite effects. These results highlight the importance of considering both intake and expenditure in the analysis of D1 and D2 neuronal manipulations. Moreover, the behavioral outcomes from NAc D1 neuronal manipulations depend upon the activity state of the animals (wheel running vs. non-running). The data support and complement the hypothesis of specific NAc dopamine pathways facilitating energy expenditure and suggest a potential strategy for human weight control.

Cognitive deficits in psychiatric and age-related disorders generally involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), but there are few treatments for these debilitating symptoms. Group II metabotropic glutamate receptors (mGluR2/3), which couple to Gi/Go, have been a focus of therapeutics based on rodent research, where mGluR2/3 have been shown to reduce axonal glutamate release and increase glial glutamate uptake. However, this strategy has had mixed results in patients, and understanding mGluR2/3 mechanisms in primates will help guide therapeutic interventions. The current study examined mGluR2/3 localization and actions in the primate dlPFC layer III circuits underlying working memory, where the persistent firing of “Delay cells” is mediated by NMDA receptors and weakened by cAMP-PKA-potassium channel signaling in dendritic spines. Immunoelectron microscopy identified postsynaptic mGluR2/3 in the spines, in addition to the traditional presynaptic and astrocytic locations. In vivo iontophoretic application of the mGluR2/3 agonists (2R, 4R)-APDC or LY379268 onto dlPFC Delay cells produced an inverted-U effect on working memory representation, with enhanced neuronal firing following low doses of mGluR2/3 agonists. The enhancing effects were reversed by an mGluR2/3 antagonist or by activating cAMP signaling, consistent with mGluR2/3 inhibiting postsynaptic cAMP signaling in spines. Systemic administration of these agonists to monkeys performing a working memory task also produced an inverted-U dose-response, where low doses improved performance but higher doses, similar to clinical trials, had mixed effects. Our data suggest that low dose mGluR2/3 stimulation may have therapeutic effects through unexpected postsynaptic actions in dlPFC, strengthening synaptic connections and improving cognitive function.

BackgroundMatrix metalloproteinases (MMPs) are a family of enzymes that are typically released from intracellular stores to act on specific extracellular substrates. MMP expression and activity can be increased in a neuronal activity-dependent manner, and further increased in response to tissue injury. MMP substrates include cell adhesion molecules (CAMs) that are abundantly expressed in the brain and well positioned for membrane proximal cleavage. Importantly, CAM integrity is important to synaptic structure and axon-myelin interactions, and shed ectodomains may themselves influence cellular function.MethodsIn the present study, we have examined proteolysis of N-cadherin (N-cdh) by MMP-7, a family member that has been implicated in disorders including HIV dementia, multiple sclerosis, and major depression. With in vitro digest assays, we tested N-cdh cleavage by increasing concentrations of recombinant enzyme. We also tested MMP-7 for its potential to stimulate N-cdh shedding from cultured neural cells. Since select CAM ectodomains may interact with cell surface receptors that are expressed on microglial cells, we subsequently tested the N-cdh ectodomain for its ability to stimulate activation of this cell type as determined by nuclear translocation of NF-κB, Iba-1 expression, and TNF-α release.ResultsWe observed that soluble N-cdh increased Iba-1 levels in microglial lysates, and also increased microglial release of the cytokine TNF-α. Effects were associated with increased NF-κB immunoreactivity in microglial nuclei and diminished by an inhibitor of the toll-like receptor adaptor protein, MyD88.ConclusionsTogether, these in vitro results suggest that soluble N-cdh may represent a novel effector of microglial activation, and that disorders with increased MMP levels may stimulate a cycle in which the products of excess proteolysis further exacerbate microglial-mediated tissue injury. Additional in vivo studies are warranted to address this issue.

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A critical area of inquiry in the neurobiology of alcohol abuse is the mechanism by which cues gain the ability to elicit alcohol use. Previously, we found that cue‐evoked activity in rat ventral pallidum robustly encodes the value of sucrose cues trained under both Pavlovian and instrumental contingencies, despite a stronger relationship between cue‐evoked activity and behavioral latency after instrumental training (Richard et al., 2018, Elife, 7, e33107). Here, we assessed: (a) ventral pallidal representations of Pavlovian versus instrumental cues trained with alcohol reward, and (b) the impact of non‐associative alcohol exposure on ventral pallidal representations of sucrose cues. Decoding of cue identity based on ventral pallidum firing was blunted for the Pavlovian alcohol cue in comparison to both the instrumental cue trained with alcohol and either cue type trained with sucrose. Further, non‐associative alcohol exposure had opposing effects on ventral pallidal encoding of sucrose cues trained on instrumental versus Pavlovian associations, enhancing decoding accuracy for an instrumental discriminative stimulus and reducing decoding accuracy for a Pavlovian conditioned stimulus. These findings suggest that alcohol exposure can drive biased engagement of specific reward‐related signals in the ventral pallidum.