Vigor Encoding in the Ventral Pallidum.

The ventral pallidum (VP) is the major downstream nucleus of the nucleus accumbens (NAc). Both VP and NAc neurons are responsive to reward-predictive stimuli and are critical drivers of reward-seeking behavior. The cue-evoked excitations and inhibitions of NAc neurons predict the vigor (latency and speed) of the cue-elicited locomotor approach response and encode the animal's proximity to the movement target, but do not encode more specific movement features such as turn direction. VP neurons also encode certain vigor parameters, but it remains unknown whether they also encode more specific movement features, and whether such encoding could account for vigor encoding. To address these questions, we recorded the firing of neurons in the VP of freely moving male rats performing a discriminative stimulus (DS) task. Similar to NAc neurons, VP neurons' cue-evoked excitations were correlated with the speed of the upcoming approach movement and the animal's proximity to the movement target at cue onset. Unlike NAc neurons, VP neurons' firing reflected the efficiency of the approach movement path but not the latency to initiate locomotion. VP cue-evoked excitations are unlikely to be directly influenced by NAc cue-evoked excitations because unilateral treatment of the NAc with a dopamine D1 receptor antagonist, a manipulation that reduces NAc neurons' cue-evoked excitations, did not alter ipsilateral VP cue-evoked excitations. These observations suggest that the two structures receive simultaneous activation by inputs conveying similar but not identical information, and work in parallel to set the vigor of the behavioral response.

Subthalamic nucleus high frequency stimulation prevents and reverses escalated cocaine use.

One of the key features of addiction is the escalated drug intake. The neural mechanisms involved in the transition to addiction remain to be elucidated. Since abnormal neuronal activity within the subthalamic nucleus (STN) stands as potential general neuromarker common to impulse control spectrum deficits, as observed in obsessive-compulsive disorders, the present study recorded and manipulated STN neuronal activity during the initial transition to addiction (i.e., escalation) and post-abstinence relapse (i.e., re-escalation) in rats with extended drug access. We found that low-frequency (theta and beta bands) neuronal oscillations in the STN increase with escalation of cocaine intake and that either lesion or high-frequency stimulation prevents the escalation of cocaine intake. STN-HFS also reduces re-escalation after prolonged, but not short, protracted abstinence, suggesting that STN-HFS is an effective prevention for relapse when baseline rates of self-administration have been re-established. Thus, STN dysfunctions may represent an underlying mechanism for cocaine addiction and therefore a promising target for the treatment of addiction.

Intermittent-access binge consumption of sweet high-fat liquid does not require opioid or dopamine receptors in the nucleus accumbens.

Binge eating disorders are characterized by episodes of intense consumption of high-calorie food. In recently developed animal models of binge eating, rats given intermittent access to such food escalate their consumption over time. Consumption of calorie-dense food is associated with neurochemical changes in the nucleus accumbens, including dopamine release and alterations in dopamine and opioid receptor expression. Therefore, we hypothesized that binge-like consumption on intermittent access schedules is dependent on opioid and/or dopamine neurotransmission in the accumbens. To test this hypothesis, we asked whether injection of dopamine and opioid receptor antagonists into the core and shell of the accumbens reduced consumption of a sweet high-fat liquid in rats with and without a history of intermittent binge access to the liquid. Although injection of a µ opioid agonist increased consumption, none of the antagonists (including µ opioid, δ opioid, κ opioid, D1 dopamine and D2 dopamine receptor antagonists, as well as the broad-spectrum opioid receptor antagonist naltrexone) reduced consumption, and this was the case whether or not the animals had a prior history of intermittent access. These results suggest that consumption of sweet, fatty food does not require opioid or dopamine receptor activation in the accumbens even under intermittent access conditions that resemble human binge episodes.

Different populations of subthalamic neurons encode cocaine vs. sucrose reward and predict future error.

The search for treatment of cocaine addiction raises the challenge to find a way to diminish motivation for the drug without decreasing it for natural rewards. Subthalamic nucleus (STN) inactivation decreases motivation for cocaine while increasing motivation for food, suggesting that STN can dissociate different rewards. Here, we investigated how rat STN neurons respond to cues predicting cocaine or sucrose and to reward delivery while rats are performing a discriminative stimuli task. We show that different neuronal populations of STN neurons encode cocaine and sucrose. In addition, we show that STN activity at the cue onset predicts future error. When changing the reward predicted unexpectedly, STN neurons show capacities of adaptation, suggesting a role in reward-prediction error. Furthermore, some STN neurons show a response to executive error (i.e., "oops neurons") that is specific to the missed reward. These results position the STN as a nexus where natural rewards and drugs of abuse are coded differentially and can influence the performance. Therefore, STN can be viewed as a structure where action could be taken for the treatment of cocaine addiction.

Invigoration of reward seeking by cue and proximity encoding in the nucleus accumbens.

A key function of the nucleus accumbens is to promote vigorous reward seeking, but the corresponding neural mechanism has not been identified despite many years of research. Here, we study cued flexible approach behavior, a form of reward seeking that strongly depends on the accumbens, and we describe a robust, single-cell neural correlate of behavioral vigor in the excitatory response of accumbens neurons to reward-predictive cues. Well before locomotion begins, this cue-evoked excitation predicts both the movement initiation latency and the speed of subsequent flexible approach responses, but not those of stereotyped, inflexible responses. Moreover, the excitation simultaneously signals the subject's proximity to the approach target, a signal that appears to mediate greater response vigor on trials that begin with the subject closer to the target. These results demonstrate a neural mechanism for response invigoration whereby accumbens neuronal encoding of reward availability and target proximity together drive the onset and speed of reward-seeking locomotion.

Intermittent access to sweet high-fat liquid induces increased palatability and motivation to consume in a rat model of binge consumption.

Binge eating disorders are characterized by discrete episodes of rapid and excessive food consumption. In rats, giving intermittent access to sweet fat food mimics this aspect of binge eating. These models typically employ solid food; however, the total amount consumed depends on motivation, palatability and satiety, which are difficult to dissociate with solid food. In contrast, lick microstructure analysis can be used to dissociate these parameters when the ingestant is a liquid. Therefore, we developed a binge model using a liquid emulsion composed of corn oil, heavy cream and sugar. We show that rats given intermittent access to this high-fat emulsion develop binge-like behavior comparable to that previously observed with solid high-fat food. One feature of this behavior was a gradual escalation in consumption across 2.5 weeks of intermittent access, which was not apparent in rats given lower-fat liquid on the same access schedule. Lick microstructure analysis suggests that this escalation was due at least in part to increases in both motivation to consume and palatability-driven consumption.

Frontal cortex-like functions of the subthalamic nucleus.

The subthalamic nucleus (STN) has been considered a motor structure for a long time. Over the last 20 years, anatomical and behavioral data have highlighted the position of the STN within a prefrontal-associative and a limbic loops, suggesting that the STN should play a critical role in frontal functions such as attention, inhibitory control (including impulsive action, compulsivity, impulsive choice), and motivation. Here we will review the work highlighting these functions of the STN.

Reducing the desire for cocaine with subthalamic nucleus deep brain stimulation.

Deep brain stimulation (DBS) is a reversible technique that is currently used for the treatment of Parkinson disease and may be suitable for the treatment of psychiatric disorders. Whether DBS inactivates the target structure is still a matter of debate. Here, from findings obtained in rats, we propose DBS of the subthalamic nucleus (STN) as a possible treatment for cocaine addiction to be further tested in human studies. We show that STN DBS reversibly reduces the motivation to work for an i.v. injection of cocaine, and it increases motivation to work for sucrose pellets. These opposite effects may result from STN DBS effect on the positive affective properties of these rewards. Indeed, we further show that STN DBS reduces the preference for a place previously associated with the rewarding properties of cocaine, and it increases the preference for a place associated with food. Because these findings are consistent with those observed after STN lesions [Baunez C, Dias C, Cador M, Amalric M (2005) Nat Neurosci 8:484-489], they suggest that STN DBS mimics an inactivation of the STN on motivational processes. Furthermore, given that one of the major challenges for cocaine addiction is to find a treatment that reduces the craving for the drug without diminishing the motivation for naturally rewarding activities, our findings validate STN as a good target and DBS as the appropriate technique for a promising therapeutic strategy in the treatment of cocaine addiction.

Beyond the reward pathway: coding reward magnitude and error in the rat subthalamic nucleus.

It was recently shown that subthalamic nucleus (STN) lesions affect motivation for food, cocaine, and alcohol, differentially, according to either the nature of the reward or the preference for it. The STN may thus code a reward according to its value. Here, we investigated how the firing of subthalamic neurons is modulated during expectation of a predicted reward between two possibilities (4 or 32% sucrose solution). The firing pattern of neurons responding to predictive cues and to reward delivery indicates that STN neurons can be divided into subpopulations responding specifically to one reward and less or giving no response to the other. In addition, some neurons ("oops" neurons) specifically encode errors as they respond only during error trials. These results reveal that the STN plays a critical role in ascertaining the value of the reward and seems to encode that value differently depending on the magnitude of the reward. These data highlight the importance of the STN in the reward circuitry of the brain.

Cognitive and limbic effects of deep brain stimulation in preclinical studies.

The use of deep brain stimulation (DBS) to control severely disabling neurological and psychiatric conditions is an exciting and fast emerging area of neuroscience. Deep brain stimulation has generally the same clinical effects as a lesion with respect to the improvement of clinical disability, but has more advantages such as its adjustability and reversibility. To this day, fundamental knowledge regarding the application of electrical currents to deep brain structures is far from complete. Despite improving key symptoms in movement disorders, DBS can be associated with the occurrence of a variety of changes in cognitive and limbic functions both in humans and animals. Furthermore, in psychiatric disorders, DBS is primarily used to evoke cognitive and limbic changes to reduce the psychiatric disability. Preclinical DBS experiments have been carried out to investigate the mechanisms underlying the clinical effects of DBS for at least three (interrelated) reasons: to increase our scientific knowledge, to optimize/refine the technology, or to prevent/reduce side-effects. In this review, we will discuss the limbic and cognitive effects of DBS in preclinical studies.

Alcohol preference influences the subthalamic nucleus control on motivation for alcohol in rats.

In addition to its role in motor and attentional processes, the subthalamic nucleus (STN) has also been recently demonstrated to be involved in motivational function. Indeed, bilateral STN lesions modulate differentially the motivation for natural rewards and drugs of abuse, increasing motivation for food and decreasing motivation for cocaine in rats. Here, we show that in outbred rats, the STN can modulate the motivation for alcohol according to alcohol preference, without affecting alcohol intake. When performed on 'High-Drinker' rats, STN lesions enhanced the breaking point (BP) under a progressive ratio schedule of reinforcement and increased the time spent in the environment previously paired with alcohol access in the place preference paradigm. In contrast, when performed on 'Low-Drinker' rats, STN lesions decreased the BP and increased the time spent in the environment paired with water. These results show that STN lesions enhance the motivation for alcohol in rats showing a high alcohol preference, whereas they decrease it in rats showing a low preference for alcohol. These results suggest that the STN plays a complex role in the reward circuit, that is not limited to a