Project description:Addictions are defined by a loss of flexible control over behavior. The development of response habits might reflect early changes in behavioral control. The following experiments examined the flexibility of alcohol-seeking after different durations of self-administration training and tested the role of the dorsal striatum in the control of flexible and habitual alcohol self-administration.Rats were trained to lever-press to earn unsweetened ethanol (EtOH) (10%). The sensitivity of the lever-press response to devaluation was assessed by prefeeding the rats either EtOH or sucrose before an extinction test after different amounts of training (1, 2, 4, and 8 weeks). We subsequently tested the role of the dorsomedial striatum (DMS) and dorsolateral striatum (DLS) in controlling alcohol seeking with reversible inactivation techniques (baclofen/muscimol: 1.0/.1 mmol/L, .3 ?L/side).We find that operant responding for EtOH early in training is goal-directed and reduced by devaluation, but after 8 weeks of daily operant training, control has shifted to a habit-based system no longer sensitive to devaluation. Furthermore, after relatively limited training, when responding is sensitive to devaluation, inactivation of the DMS greatly attenuates the alcohol-seeking response, whereas inactivation of the DLS is without effect. In contrast, responding that is insensitive to devaluation after 8 weeks of training becomes sensitive to devaluation after inactivation of the DLS but is unaffected by inactivation of the DMS.These experiments demonstrate that extended alcohol self-administration produces habit-like responding and that response control shifts from the DMS to the DLS across the course of training.
Project description:The external globus pallidus (GPe) coordinates action-selection through GABAergic projections throughout the basal ganglia. GPe arkypallidal (arky) neurons project exclusively to the dorsal striatum, which regulates goal-directed and habitual seeking. However, the role of GPe arky neurons in reward-seeking remains unknown. Here, we identified that a majority of arky neurons target the dorsolateral striatum (DLS). Using fiber photometry, we found that arky activities were higher during random interval (RI; habit) compared to random ratio (RR; goal) operant conditioning. Support vector machine analysis demonstrated that arky neuron activities have sufficient information to distinguish between RR and RI behavior. Genetic ablation of this arkyGPe→DLS circuit facilitated a shift from goal-directed to habitual behavior. Conversely, chemogenetic activation globally reduced seeking behaviors, which was blocked by systemic D1R agonism. Our findings reveal a role of this arkyGPe→DLS circuit in constraining habitual seeking in male mice, which is relevant to addictive behaviors and other compulsive disorders.
Project description:Deciphering the striatal interneuron diversity is key to understanding the basal ganglia circuit and to untangle the complex neurological and psychiatric diseases affecting this brain structure. We performed snRNA-seq of postmortem human caudate nucleus and putamen samples to elucidate the diversity and abundance of interneuron populations and their transcriptional structure in the human dorsal striatum. We propose a new taxonomy of striatal interneurons with eight main classes and fourteen subclasses and provide their specific markers and some quantitative FISH validation, particularly for a novel PTHLH-expressing population. For the most abundant populations, PTHLH and TAC3, we found matching known mouse interneuron populations based on key functional genes such as ion channels and synaptic receptors. Remarkably, human TAC3 and mouse Th populations share important similarities including the expression of the neuropeptide tachykinin 3. Finally, we were able to integrate other published datasets supporting the generalizability of this new harmonized taxonomy.
Project description:Deciphering the striatal interneuron diversity is key to understanding the basal ganglia circuit and to untangling the complex neurological and psychiatric diseases affecting this brain structure. We performed snRNA-seq and spatial transcriptomics of postmortem human caudate nucleus and putamen samples to elucidate the diversity and abundance of interneuron populations and their inherent transcriptional structure in the human dorsal striatum. We propose a comprehensive taxonomy of striatal interneurons with eight main classes and fourteen subclasses, providing their full transcriptomic identity and spatial expression profile as well as additional quantitative FISH validation for specific populations. We have also delineated the correspondence of our taxonomy with previous standardized classifications and shown the main transcriptomic and class abundance differences between caudate nucleus and putamen. Notably, based on key functional genes such as ion channels and synaptic receptors, we found matching known mouse interneuron populations for the most abundant populations, the recently described PTHLH and TAC3 interneurons. Finally, we were able to integrate other published datasets with ours, supporting the generalizability of this harmonized taxonomy.
Project description:Cognitive flexibility is a hallmark of prefrontal cortical (PFC) function yet little is known about downstream area involvement. The medial dorsal striatum (mDS) receives major projections from the PFC and is uniquely situated to perform the integration of responses with rule information. In this study, we use a novel rule shifting task in rats that mirrors non-human primate and human studies in its temporal precision and counterbalanced responses. We record activity from single neurons in the mDS while rats switch between different rules for reward. Additionally, we pharmacologically inactivate mDS by infusion of a baclofen/muscimol cocktail. Inactivation of mDS impaired the ability to shift to a new rule and increased the number of regressive errors. While recording in mDS, we identified neurons modulated by direction whose activity reflected the conflict between competing rule information. We show that a subset of these neurons was also rule selective, and that the conflict between competing rule cues was resolved as behavioural performance improved. Other neurons were modulated by rule, but not direction. These neurons became selective before behavioural performance accurately reflected the current rule. These data provide an additional locus for investigating the mechanisms underlying behavioural flexibility. Converging lines of evidence from multiple human psychiatric disorders have implicated dorsal striatum as an important and understudied neural substrate of flexible cognition. Our data confirm the importance of mDS, and suggest a mechanism by which mDS mediates abstract cognition functions.
Project description:Recent evidence has shown that the dorsal striatum of the rat is arranged as a patchwork of domains that exhibit distinct dopamine kinetics and concentrations. This raises the pressing question of how these distinct domains are maintained, especially if dopamine is able to diffuse through the extracellular space. Diffusion between the domains would eliminate the concentration differences and, thereby, the domains themselves. The present study is a closer examination of dopamine's ability to diffuse in the extracellular space. We used voltammetry to record dopamine overflow in dorsal striatum while stimulating the medial forebrain bundle over a range of stimulus currents and frequencies. We also examined the effects of drugs that modulated the dopamine release (raclopride and quinpirole) and uptake (nomifensine). Examining the details of the temporal features of the evoked profiles reveals no clear evidence for long-distance diffusion of dopamine between fast and slow domains, even though uptake inhibition by nomifensine clearly prolongs the time that dopamine resides in the extracellular space. Our observations support the conclusion that striatal tissue has the capacity to retain dopamine molecules, thereby limiting its tendency to diffuse through the extracellular space.
Project description:The human striatum can be subdivided into the caudate, putamen, and nucleus accumbens (NAc). Each of these structures have some overlapping and some distinct functions related to motor control, cognitive processing, motivation, and reward. Previously, we used a "time-of-death" approach to identify diurnal rhythms in RNA transcripts in human cortical regions. Here, we identify molecular rhythms across the three striatal subregions collected from postmortem human brain tissue in subjects without psychiatric or neurological disorders. Core circadian clock genes are rhythmic across all three regions and show strong phase concordance across regions. However, the putamen contains a much larger number of significantly rhythmic transcripts than the other two regions. Moreover, there are many differences in pathways that are rhythmic across regions. Strikingly, the top rhythmic transcripts in NAc (but not the other regions) are predominantly small nucleolar RNAs and long noncoding RNAs, suggesting that a completely different mechanism might be used for the regulation of diurnal rhythms in translation and/or RNA processing in the NAc versus the other regions. Further, although the NAc and putamen are generally in phase with regard to timing of expression rhythms, the NAc and caudate, and caudate and putamen, have several clusters of discordant rhythmic transcripts, suggesting a temporal wave of specific cellular processes across the striatum. Taken together, these studies reveal distinct transcriptome rhythms across the human striatum and are an important step in helping to understand the normal function of diurnal rhythms in these regions and how disruption could lead to pathology.
Project description:In previous functional magnetic resonance imaging (fMRI) studies concerning romantic love, several brain regions including the caudate and putamen have consistently been found to be more responsive to beloved-related than control stimuli. In those studies, infatuated individuals were typically instructed to passively view the stimuli or to think of the viewed person. In the current study, we examined how the instruction to attend to, or ignore the beloved modulates the response of these brain areas. Infatuated individuals performed an oddball task in which pictures of their beloved and friend served as targets and distractors. The dorsal striatum showed greater activation for the beloved than friend, but only when they were targets. The dorsal striatum actually tended to show less activation for the beloved than the friend when they were distractors. The longer the love and relationship duration, the smaller the response of the dorsal striatum to beloved-distractor stimuli was. We interpret our findings in terms of reinforcement learning. By virtue of using a cognitive task with a full factorial design, we show that the dorsal striatum is not activated by beloved-related information per se, but only by beloved-related information that is attended.
Project description:We recorded neuronal activity simultaneously in the medial and lateral regions of the dorsal striatum as rats learned an operant task. The task involved making head entries into a response port followed by movements to collect rewards at an adjacent reward port. The availability of sucrose reward was signaled by an acoustic stimulus. During training, animals showed increased rates of responding and came to move rapidly and selectively, following the stimulus, from the response port to the reward port. Behavioral "devaluation" studies, pairing sucrose with lithium chloride, established that entries into the response port were habitual (insensitive to devaluation of sucrose) from early in training and entries into the reward port remained goal-directed (sensitive to devaluation) throughout training. Learning-related changes in behavior were paralleled by changes in neuronal activity in the dorsal striatum, with an increasing number of neurons showing task-related firing over the training period. Throughout training, we observed more task-related neurons in the lateral striatum compared with those in the medial striatum. Many of these neurons fired at higher rates during initiation of movements in the presence of the stimulus, compared with similar movements in the absence of the stimulus. Learning was also accompanied by progressive increases in movement-related potentials and transiently increased theta-band oscillations (5-8 Hz) in simultaneously recorded field potentials. Together, these data suggest that representations of task-relevant stimuli and movements develop in the dorsal striatum during instrumental learning.
Project description:Dopamine (DA), a highly significant neurotransmitter in the mammalian central nervous system, operates on multiple time scales to affect a diverse array of physiological functions. The significance of DA in human health is heightened by its role in a variety of pathologies. Voltammetric measurements of electrically evoked DA release have brought to light the existence of a patchwork of DA kinetic domains in the dorsal striatum (DS) of the rat. Thus, it becomes necessary to consider how these domains might be related to specific aspects of DA's functions. Responses evoked in the fast and slow domains are distinct in both amplitude and temporal profile. Herein, we report that responses evoked in fast domains can be further classified into four distinct types, types 1-4. The DS, therefore, exhibits a total of at least five distinct evoked responses (four fast types and one slow type). All five response types conform to kinetic models based entirely on first-order rate expressions, which indicates that the heterogeneity among the response types arises from kinetic diversity within the DS terminal field. We report also that functionally distinct subregions of the DS express DA kinetic diversity in a selective manner. Thus, this study documents five response types, provides a thorough kinetic explanation for each of them, and confirms their differential association with functionally distinct subregions of this key DA terminal field. The dorsal striatum is composed of five significantly different dopamine domains (types 1-4 and slow, average ± SEM responses to medial forebrain bundle (MFB) stimulation are shown in the figure). Responses from each of these five domains exhibit significantly different ascending and descending kinetic profiles and return to a long lasting elevated dopamine state, termed the dopamine hang-up. All features of these responses are modeled with high correlation using first-order modeling as well as our recently published restricted diffusion model of evoked dopamine overflow. We also report that functionally distinct subregions of the dorsal striatum express selective dopamine kinetic diversity.