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The striatum, the main input nucleus of the basal ganglia, receives topographically organized input from the cortex and gives rise to the direct and indirect output pathways, which have antagonistic effects on basal ganglia output directed to the cortex. We optogenetically stimulated the direct and indirect pathways in a visual and a working memory task in mice that responded by licking. Unilateral direct pathway stimulation increased the probability of lick responses toward the contralateral, non-stimulated side and increased cortical activity globally. In contrast, indirect pathway stimulation increased the probability of responses toward the stimulated side and decreased activity in the stimulated hemisphere. Moreover, direct pathway stimulation enhanced the neural representation of a contralateral visual stimulus during the delay of the working memory task, whereas indirect pathway stimulation had the opposite effect. Our results demonstrate how these two pathways influence perceptual decisions and working memory and modify activity in the dorsal cortex.

The magnitude of dopamine signals elicited by rewarding events and their predictors is updated when reward value changes. It is actively debated how readily these dopamine signals adapt and whether adaptation aligns with model-free or model-based reinforcement-learning principles. To investigate this, we trained male rats in a Pavlovian-conditioning paradigm and measured dopamine release in the nucleus accumbens core in response to food reward (unconditioned stimulus) and reward-predictive conditioned stimuli (CS), both before and after reward devaluation, induced via either sensory-specific or non-specific satiety. We demonstrate that 1) such devaluation reduces CS-induced dopamine release rapidly, without additional pairing of CS with devalued reward, and irrespective of whether the devaluation was sensory-specific or non-specific. In contrast, 2) reward devaluation did not decrease food reward-induced dopamine release. Surprisingly, 3) post-devaluation reconditioning, by additional pairing of CS with devalued reward, rapidly reinstated CS-induced dopamine signals to pre-devaluation levels. Taken together, we identify distinct, divergent adaptations in dopamine-signal magnitude when reward value is decreased: CS dopamine diminishes but reinstates fast, whereas reward dopamine is resistant to change. This implies that, respective to above-mentioned findings, 1) CS dopamine may be governed by a model-based mechanism, and 2) reward dopamine by a model-free one, where 3) the latter may contribute to swift reinstatement of the former. However, changes in CS dopamine were not selective for sensory-specificity of reward devaluation, which is inconsistent with model-based processes. Thus, mesolimbic dopamine signaling incorporates both model-free and model-based mechanisms, and is not exclusively governed by either.Significance Statement Although it is well-known that dopamine plays a principal role in reward learning, the temporal dynamics and the associated theoretic

Social attunement (SA)-the tendency to harmonize behavior with the social environment-has been proposed to drive the escalation of alcohol use in adolescence, while reducing use in adulthood. Little is known about how heightened social sensitivity in adolescence may interact with neural alcohol cue reactivity-a marker of alcohol use disorder-and its relationship to alcohol use severity over time. The aims of this study were to test whether (1) adolescents and adults differ in social alcohol cue reactivity in the nucleus accumbens, anterior cingulate cortex, and right medial prefrontal cortex (mPFC), and (2) age moderates the relationship between social alcohol cue reactivity and social attunement, measures of drinking at baseline, and changes in drinking over time. A sample of male adolescents (16-18 years) and adults (29-35 years) completed an fMRI social alcohol cue-exposure task at baseline and an online follow-up two to three years later. No main effects of age or drinking measures were observed in social alcohol cue reactivity. However, age significantly moderated associations of social alcohol cue reactivity in the mPFC and additional regions from exploratory whole-brain analyses with SA, with a positive association in adolescents and negative association in adults. Significant age interactions emerged only for SA in predicting drinking over time. Adolescents with higher SA scores escalated drinking, while adults with higher SA scores reduced drinking. These findings warrant further research on SA as a risk and protective factor and suggest that social processes influence cue reactivity differentially in male adolescents and adults.

BACKGROUND: Adolescence is marked not only by rapid surges in the prevalence of alcohol use disorders (AUDs) but also by remarkable recovery rates, as most adolescent-onset AUDs naturally resolve over time. Little is known about the differential vulnerability of adolescents and adults. Therefore, this study aimed to unravel the moderating role of age by comparing neural alcohol cue-reactivity, an important AUD biomarker, between low-to-high beer-drinking adolescent (n = 50, 16 to 18 years), and adult (n = 51, 30 to 35 years) males matched on drinking severity.METHODS: Associations between beer odor-induced brain activity and AUD diagnosis, severity of alcohol use-related problems, recent alcohol use, binge-drinking frequency, and task-induced craving were investigated across and between age groups in regions of interest thought to be central in alcohol cue-reactivity: the medial prefrontal cortex, anterior cingulate cortex, and striatal subregions (nucleus accumbens and caudate putamen). These analyses were complemented by exploratory whole-brain analyses.RESULTS: Pre-task beer craving increased pre-to-post task in adolescents only. Individual differences in alcohol use, binge drinking, and craving did not relate to beer odor-induced activity. Although region-of-interest analyses did not reach significance, whole-brain analyses showed that adolescents with AUD, compared with adolescents without AUD and adults with AUD, had higher beer odor-induced activity in a large mesocorticolimbic cluster encompassing the right caudate, nucleus accumbens, orbitofrontal cortex, and the olfactory sulcus. Activity in the right caudate and putamen was positively associated with the severity of alcohol use-related problems in adolescents but negatively associated in adults.CONCLUSION: These findings suggest a differential role of alcohol cue-reactivity in adolescents compared with adults with AUD and highlight the need for further studies investigating the rol

Deep-brain stimulation (DBS) is an effective treatment for patients suffering from otherwise therapy-resistant psychiatric disorders, including obsessive-compulsive disorder. Modulation of cortico-striatal circuits has been suggested as a mechanism of action. To gain mechanistic insight, we monitored neuronal activity in cortico-striatal regions in a mouse model for compulsive behavior, while systematically varying clinically-relevant parameters of internal-capsule DBS. DBS showed dose-dependent effects on both brain and behavior: An increasing, yet balanced, number of excited and inhibited neurons was recruited, scattered throughout cortico-striatal regions, while excessive grooming decreased. Such neuronal recruitment did not alter basic brain function such as resting-state activity, and only occurred in awake animals, indicating a dependency on network activity. In addition to these widespread effects, we observed specific involvement of the medial orbitofrontal cortex in therapeutic outcomes, which was corroborated by optogenetic stimulation. Together, our findings provide mechanistic insight into how DBS exerts its therapeutic effects on compulsive behaviors.

Social attunement (SA)-the tendency to harmonize behavior with the social environment-has been proposed to drive the escalation of alcohol use in adolescence, while reducing use in adulthood. Little is known about how heightened social sensitivity in adolescence may interact with neural alcohol cue reactivity-a marker of alcohol use disorder-and its relationship to alcohol use severity over time. The aims of this study were to test whether (1) adolescents and adults differ in social alcohol cue reactivity in the nucleus accumbens, anterior cingulate cortex, and right medial prefrontal cortex (mPFC), and (2) age moderates the relationship between social alcohol cue reactivity and social attunement, measures of drinking at baseline, and changes in drinking over time. A sample of male adolescents (16-18 years) and adults (29-35 years) completed an fMRI social alcohol cue-exposure task at baseline and an online follow-up two to three years later. No main effects of age or drinking measures were observed in social alcohol cue reactivity. However, age significantly moderated associations of social alcohol cue reactivity in the mPFC and additional regions from exploratory whole-brain analyses with SA, with a positive association in adolescents and negative association in adults. Significant age interactions emerged only for SA in predicting drinking over time. Adolescents with higher SA scores escalated drinking, while adults with higher SA scores reduced drinking. These findings warrant further research on SA as a risk and protective factor and suggest that social processes influence cue reactivity differentially in male adolescents and adults.

BACKGROUND: Adolescence is marked not only by rapid surges in the prevalence of alcohol use disorders (AUDs) but also by remarkable recovery rates, as most adolescent-onset AUDs naturally resolve over time. Little is known about the differential vulnerability of adolescents and adults. Therefore, this study aimed to unravel the moderating role of age by comparing neural alcohol cue-reactivity, an important AUD biomarker, between low-to-high beer-drinking adolescent (n = 50, 16 to 18 years), and adult (n = 51, 30 to 35 years) males matched on drinking severity.METHODS: Associations between beer odor-induced brain activity and AUD diagnosis, severity of alcohol use-related problems, recent alcohol use, binge-drinking frequency, and task-induced craving were investigated across and between age groups in regions of interest thought to be central in alcohol cue-reactivity: the medial prefrontal cortex, anterior cingulate cortex, and striatal subregions (nucleus accumbens and caudate putamen). These analyses were complemented by exploratory whole-brain analyses.RESULTS: Pre-task beer craving increased pre-to-post task in adolescents only. Individual differences in alcohol use, binge drinking, and craving did not relate to beer odor-induced activity. Although region-of-interest analyses did not reach significance, whole-brain analyses showed that adolescents with AUD, compared with adolescents without AUD and adults with AUD, had higher beer odor-induced activity in a large mesocorticolimbic cluster encompassing the right caudate, nucleus accumbens, orbitofrontal cortex, and the olfactory sulcus. Activity in the right caudate and putamen was positively associated with the severity of alcohol use-related problems in adolescents but negatively associated in adults.CONCLUSION: These findings suggest a differential role of alcohol cue-reactivity in adolescents compared with adults with AUD and highlight the need for further studies investigating the rol

Deep brain stimulation (DBS) is an established neuromodulatory intervention against otherwise treatment-refractory obsessive-compulsive disorder (OCD). Several DBS targets, all of which are part of brain networks connecting basal ganglia and prefrontal cortex, alleviate OCD symptoms. Stimulation of these targets is thought to unfold its therapeutic effect by modulation of network activity through internal capsule (IC) connections. Research into DBS-induced network changes and the nature of IC-related effects of DBS in OCD is needed to further improve DBS. Here, we studied the effects of DBS at the ventral medial striatum (VMS) and IC on blood-oxygen level dependent (BOLD) responses in awake rats using functional magnetic resonance imaging (fMRI). BOLD-signal intensity was measured in five regions of interest (ROIs): medial and orbital prefrontal cortex, nucleus accumbens (NAc), IC area, and mediodorsal thalamus. In previous rodent studies, stimulation at both target locations resulted in a reduction of OCD-like behavior and activation of prefrontal cortical areas. Therefore, we hypothesized that stimulation at both targets would result in partially overlapping BOLD responses. Both differential and overlapping activity between VMS and IC stimulation was found. Stimulating the caudal part of the IC resulted in activation around the electrode, while stimulating the rostral part of the IC resulted in increased cross-correlations between the IC area, orbitofrontal cortex, and NAc. Stimulation of the dorsal part of the VMS resulted in increased activity in the IC area, suggesting this area is activated during both VMS and IC stimulation. This activation is also indicative of VMS-DBS impacting corticofugal fibers running through the medial caudate into the anterior IC, and both VMS and IC DBS might act on these fibers to induce OCD-reducing effects. These results show that rodent fMRI with simultaneous electrode stimulation is a promising approach to study the neural me

The mesolimbic dopamine system is implicated in signaling reward-related information as well as in actions that generate rewarding outcomes. These implications are commonly investigated in either Pavlovian or operant reinforcement paradigms, where only the latter requires instrumental action. To parse contributions of reward- and action-related information to dopamine signals, we directly compared the two paradigms: male rats underwent either Pavlovian or operant conditioning while dopamine release was measured in the nucleus accumbens, a brain region central for processing this information. Task conditions were identical with the exception of the operant-lever response requirement. Rats in both groups released the same quantity of dopamine at the onset of the reward-predictive cue. However, only the operant-conditioning group showed a subsequent, sustained plateau in dopamine concentration throughout the entire five-second cue presentation (preceding the required action). This dopamine "ramp" was unaffected by probabilistic reward delivery, occurred exclusively prior to operant actions, and was not related to task performance or task acquisition, as it persisted throughout the two-week daily behavioral training. Instead, the ramp flexibly increased in duration with longer cue presentation, seemingly modulating the initial cue-onset triggered dopamine release (i.e., the reward-prediction error (RPE) signal), as both signal amplitude and sustain diminished when reward timing was made more predictable. Thus, our findings suggest that RPE and action components of dopamine release can be differentiated temporally into phasic and ramping/sustained signals, respectively, where the latter depends on the former and presumably reflects the anticipation or incentivization of appetitive action, conceptually akin to motivation.Significance StatementIt is unclear whether the components of dopamine signals that are related to reward-associated information and reward-driven app

SignificanceAlthough it is undisputed that striatal dopamine plays a prominent role in motivated behavior and learning, the precise information conveyed by dopamine signals as such is under active debate. For a long time, the idea dominated that dopamine encodes a reward prediction error and that this signal is broadcast uniformly throughout the brain. However, here, we capture dopamine dynamics across many striatal regions and demonstrate that dopamine release is, regionally, extremely heterogeneous and that a reward prediction error-like signal is predominantly found in the relatively small limbic domain of the striatum. Another striking organizing principle is that stimulus valence directs dopamine concentration homogeneously across all regions (i.e., appetitive stimuli increase dopamine and aversive stimuli decrease dopamine).

The marble burying test is a commonly used paradigm to describe phenotypes in mouse models of neurodevelopmental and psychiatric disorders. The current methodological approach relies predominantly on reporting the number of buried marbles at the end of the test. By measuring the proxy of the behavior (buried marbles), many important characteristics regarding the temporal aspect of this assay are lost. Here we introduce a novel, automated method to quantify mouse behavior during the marble burying test with the focus on the burying bouts and movement dynamics. Using open-source software packages, we trained a supervised machine learning algorithm (the "classifier") to distinguish burying behavior in freely moving mice. In order to confirm the classifier's accuracy and characterize burying events in high detail, we performed the marble burying test in three mouse models: Ube3am-/p+ (Angelman Syndrome model), Shank2-/- (autism model), and Sapap3-/- (obsessive-compulsive disorder model) mice. The classifier scored burying behavior accurately and consistent with the previously reported phenotype of the Ube3am-/p+ mice, which showed decreased levels of burying compared to controls. Shank2-/- mice showed a similar pattern of decreased burying behavior, which was not found in Sapap3-/- mice. Tracking mouse behavior throughout the test revealed hypoactivity in Ube3am-/p+ and hyperactivity in the Shank2-/- mice, indicating that mouse activity is unrelated to burying behavior. Reducing activity with midazolam in Shank2-/- mice did not alter the burying behavior. Together, we demonstrate that our classifier is an accurate method for the analysis of the marble burying test, providing more information than currently used methods.Significance StatementThe marble burying test is widely used in phenotyping neurodevelopmental and neuropsychiatric disorder mouse models. Currently, its analysis consists largely of manually scoring the number of buried marbles upon the completion of the

SignificanceAlthough it is undisputed that striatal dopamine plays a prominent role in motivated behavior and learning, the precise information conveyed by dopamine signals as such is under active debate. For a long time, the idea dominated that dopamine encodes a reward prediction error and that this signal is broadcast uniformly throughout the brain. However, here, we capture dopamine dynamics across many striatal regions and demonstrate that dopamine release is, regionally, extremely heterogeneous and that a reward prediction error-like signal is predominantly found in the relatively small limbic domain of the striatum. Another striking organizing principle is that stimulus valence directs dopamine concentration homogeneously across all regions (i.e., appetitive stimuli increase dopamine and aversive stimuli decrease dopamine).

There is active debate on the role of dopamine in processing aversive stimuli, where inferred roles range from no involvement at all, to signaling an aversive prediction error (APE). Here, we systematically investigate dopamine release in the nucleus accumbens core (NAC), which is closely linked to reward prediction errors, in rats exposed to white noise (WN, a versatile, underutilized, aversive stimulus) and its predictive cues. Both induced a negative dopamine ramp, followed by slow signal recovery upon stimulus cessation. In contrast to reward conditioning, this dopamine signal was unaffected by WN value, context valence, or probabilistic contingencies, and the WN dopamine response shifted only partially toward its predictive cue. However, unpredicted WN provoked slower post-stimulus signal recovery than predicted WN. Despite differing signal qualities, dopamine responses to simultaneous presentation of rewarding and aversive stimuli were additive. Together, our findings demonstrate that instead of an APE, NAC dopamine primarily tracks prediction and duration of aversive events.