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BACKGROUND: Individuals with 22q11.2 deletion syndrome (22q11DS) are at increased risk of developing psychosis and cognitive impairments, which may be related to dopaminergic and glutamatergic abnormalities. Therefore, in this exploratory study, we examined the association between dopaminergic and glutamatergic functioning in 22q11DS. Additionally, the associations between glutamatergic functioning and brain volumes in 22q11DS and healthy controls (HC), as well as those between dopaminergic and cognitive functioning in 22q11DS, were also examined. METHODS: In this cross-sectional, multimodal imaging study, glutamate, glutamine, and their combined concentration (Glx) were assessed in the anterior cingulate cortex (ACC) and striatum in 17 22q11DS patients and 20 HC using 7T proton magnetic resonance spectroscopy. Ten 22q11DS patients also underwent 18F-fallypride positron emission tomography to measure dopamine D2/3 receptor (D2/3R) availability in the ACC and striatum. Cognitive performance was assessed with the Cambridge Neuropsychological Test Automated Battery. RESULTS: No significant associations were found between ACC or striatal (1) glutamate, glutamine, or Glx concentrations and (2) D2/3R availability. In HC but not in 22q11DS patients, we found a significant relationship between ACC volume and ACC glutamate, glutamine, and Glx concentration. In addition, some aspects of cognitive functioning were significantly associated with D2/3R availability in 22q11DS. However, none of the associations remained significant after Bonferroni correction. CONCLUSIONS: Although our results did not reach statistical significance, our findings suggest an association between glutamatergic functioning and brain volume in HC but not in 22q11DS. Additionally, D2/3R availability seems to be related to cognitive functioning in 22q11DS. Studies in larger samples are needed to further elucidate our findings. ispartof: GENES vol:13 issue:9 ispartof: location:Switzerland status: published

Time is a fundamental dimension of our perception of the world and is therefore of critical importance to the organization of human behavior. A corpus of work — including recent optogenetic evidence — implicates striatal dopamine as a crucial factor influencing the perception of time. Another stream of literature implicates dopamine in reward and motivation processes. However, these two domains of research have remained largely separated, despite neurobiological overlap and the apothegmatic notion that “time flies when you’re having fun”. This article constitutes a review of the literature linking time perception and reward, including neurobiological and behavioral studies. Together, these provide compelling support for the idea that time perception and reward processing interact via a common dopaminergic mechanism.

Psychostimulants such as methylphenidate are widely used for their cognitive enhancing effects, but there is large variability in the direction and extent of these effects, and there are concerns about the potential for abuse. We tested the hypothesis that methylphenidate enhances or impairs reward/punishment-based reversal learning depending on baseline striatal dopamine levels and corticostriatal gating of reward/punishment-related representations in stimulus-specific sensory cortex. Young healthy adults were scanned with functional magnetic resonance imaging during a reward/punishment reversal learning task, after intake of methylphenidate or the selective D2/3-receptor antagonist sulpiride. Striatal dopamine synthesis capacity was indexed with [18F]DOPA positron emission tomography. Reward versus punishment learning signals were boosted to a greater degree in participants with higher dopamine synthesis capacity. By contrast, striatal and stimulus-specific sensory surprise signals were boosted in participants with lower dopamine synthesis. These results unravel the mechanisms by which methylphenidate modulates reward and attention, impacting our understanding of how it can both enhance attention and mitigate reward-related compulsivity.

Preclinical models propose that increased hippocampal activity drives subcortical dopaminergic dysfunction and leads to psychosis-like symptoms and behaviors. Here, we used multimodal neuroimaging to examine the relationship between hippocampal regional cerebral blood flow (rCBF) and striatal dopamine synthesis capacity in people at clinical high risk (CHR) for psychosis and investigated its association with subsequent clinical and functional outcomes. Ninety-five participants (67 CHR and 28 healthy controls) underwent arterial spin labeling MRI and 18F-DOPA PET imaging at baseline. CHR participants were followed up for a median of 15 months to determine functional outcomes with the global assessment of function (GAF) scale and clinical outcomes using the comprehensive assessment of at-risk mental states (CAARMS). CHR participants with poor functional outcomes (follow-up GAF n = 25) showed higher rCBF in the right hippocampus compared to CHRs with good functional outcomes (GAF ≥ 65, n = 25) (pfwe = 0.026). The relationship between rCBF in this right hippocampal region and striatal dopamine synthesis capacity was also significantly different between groups (pfwe = 0.035); the association was negative in CHR with poor outcomes (pfwe = 0.012), but non-significant in CHR with good outcomes. Furthermore, the correlation between right hippocampal rCBF and striatal dopamine function predicted a longitudinal increase in the severity of positive psychotic symptoms within the total CHR group (p = 0.041). There were no differences in rCBF, dopamine, or their associations in the total CHR group relative to controls. These findings indicate that altered interactions between the hippocampus and the subcortical dopamine system are implicated in the pathophysiology of adverse outcomes in the CHR state.

Background Idiopathic normal pressure hydrocephalus can present with parkinsonism. However, abnormalities of the striatal dopamine reuptake transporter are unclear. Objectives To explore presence and features of striatal dopaminergic deficit in subjects with idiopathic normal pressure hydrocephalus as compared to Parkinson's disease (PD) patients and healthy controls. Methods We investigated 50 subjects with idiopathic normal pressure hydrocephalus, 25 with PD, and 40 healthy controls. All participants underwent [123 I]-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane and single-photon emission computed tomography to quantify the striatal dopamine reuptake transporter binding. All subjects with idiopathic normal pressure hydrocephalus underwent a levodopa (l-dopa) challenge test and magnetic resonance imaging to evaluate ventriculomegaly and white matter changes. Gait, cognition, balance, and continence were assessed with the Idiopathic Normal Pressure Hydrocephalus Rating Scale, and parkinsonism with the motor section of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale. All patients completed a 2-year follow-up. Results A total of 62% of patients with idiopathic normal pressure hydrocephalus featured a reduced striatal dopamine reuptake transporter binding, which correlated with the severity of parkinsonism but not with features of ventriculomegaly or white matter changes. Unlike PD, this dopaminergic deficit in idiopathic normal pressure hydrocephalus was more symmetric and prominent in the caudate nucleus. Conclusions Subjects with idiopathic normal pressure hydrocephalus can present a reduction of striatal dopamine reuptake transporter binding, which is consistent with the severity of parkinsonism and qualitatively differs from that found in PD patients. Longitudinal interventional studies are needed to prove a role for striatal dopamine reuptake transporter deficit in the pathophysiology of idiopathic normal pressure hydrocephalus. © 2020 International Parkinson and Movement Disorder Society.

OBJECTIVE: To determine whether striatal dopamine (DA) release is affected by food ingestion and whether the DA response to high-calorie food images is greater in the fasted than fed state in people with obesity. METHODS: Striatal DA release was evaluated in 10 people with obesity and prediabetes after participants consumed a meal to satiation and after they fasted overnight, and in response to viewing images of high-calorie compared with low-calorie foods after consuming a meal to satiation or fasting overnight, by using positron emission tomography with [(11)C]raclopride injection. RESULTS: Striatal DA D2/D3 receptor availability was not different during fasted and fed conditions. Viewing images of high-calorie foods induced striatal DA release relative to viewing images of low-calorie foods (p

The striatal dopamine system has long been studied in the context of reward learning, motivation, and movement. Given the prominent role dopamine plays in a variety of adaptive behavioral states, as well as diseases like addiction, it is essential to understand the full complexity of dopamine neurons and the striatal systems they target. A growing number of studies are uncovering details of the heterogeneity in dopamine neuron subpopulations. Here, we review that work to synthesize current understanding of dopamine system heterogeneity across three levels: anatomical organization, functions in behavior, and modes of action, wherein we focus on signaling profiles and local mechanisms for modulation of dopamine release. Together, these studies reveal new and emerging dimensions of the striatal dopamine system, informing its contribution to dynamic motivational and decision-making processes.

Rationale: We constantly need to decide not only which actions to perform, but also how vigorously to perform them. In agreement with an earlier theoretical model, it has been shown that a significant portion of the variance in our action vigor can be explained by the average rate of rewards received for that action. Moreover, this invigorating effect of average reward rate was shown to vary with within-subject changes in dopamine, both in human individuals and experimental rodents. Objectives: Here, we assessed whether individual differences in the effect of average reward rate on vigor are related to individual variation in a stable measure of striatal dopamine function in healthy, unmedicated participants. Methods: Forty-four participants performed a discrimination task to test the effect of average reward rate on response times to index vigor and completed an [18F]-DOPA PET scan to index striatal dopamine synthesis capacity. Results: We did not find an interaction between dopamine synthesis capacity and average reward rate across the entire group. However, a post hoc analysis revealed that participants with higher striatal dopamine synthesis capacity, particularly in the nucleus accumbens, exhibited a stronger invigorating effect of average reward rate among the 30 slowest participants. Conclusions: Our findings provide converging evidence for a role of striatal dopamine in average reward rate signaling, thereby extending the current literature on the mechanistic link between average reward rate, vigor, and dopamine.

The striatum is critical for making decisions based on predictions of future reward. These predictions can be updated by brief pulses of dopamine, encoding reward prediction errors. However, it is unclear how this mechanism handles the need to generate predictions over multiple time horizons: from seconds or less (if singing a song) to potentially hours or more (if hunting for food). Here we monitor and model dopamine pulses across distinct striatal subregions, and find that these reflect predictions over distinct temporal scales. Dopamine dynamics systematically accelerated from ventral to dorsal-medial to dorsal-lateral striatum, in the tempo of their spontaneous fluctuations, their integration of prior rewards, and their discounting of future rewards. In this way parallel striatal circuits can achieve a more comprehensive set of value computations, to guide a broad range of reward-related behaviors.

Brain dopamine signaling is essential for the motivation to eat, and obesity is associated with altered dopaminergic signaling and increased food craving. We used molecular neuroimaging to explore whether striatal dopamine transporter (DAT) availability is associated with craving as measured with the General Food Craving Questionnaire-Trait (G-FCQ-T). We here show that humans with obesity (n = 34) experienced significantly more craving for food compared with lean subjects (n = 32), but food craving did not correlate significantly with striatal DAT availability as assessed with 123I-FP-CIT single-photon emission computed tomography. We conclude that food craving is increased in obesity, but the scores for food craving are not related to changes in striatal DAT availability.

Addiction is a complex disease that impacts millions of people around the world. Clinically, addiction is formalized as substance use disorder (SUD), with three primary symptom categories: exaggerated substance use, social or lifestyle impairment, and risky substance use. Considerable efforts have been made to model features of these criteria in non-human animal research subjects, for insight into the underlying neurobiological mechanisms. Here we review evidence from rodent models of SUD-inspired criteria, focusing on the role of the striatal dopamine system. We identify distinct mesostriatal and nigrostriatal dopamine circuit functions in behavioral outcomes that are relevant to addictions and SUDs. This work suggests that striatal dopamine is essential for not only positive symptom features of SUDs, such as elevated intake and craving, but also for impairments in decision making that underlie compulsive behavior, reduced sociality, and risk taking. Understanding the functional heterogeneity of the dopamine system and related networks can offer insight into this complex symptomatology and may lead to more targeted treatments.

Behavioral flexibility is key to survival in a dynamic environment. While flexible, goal-directed behaviors are initially dependent on dorsomedial striatum, they become dependent on lateral striatum with extended training as behaviors become inflexible. Similarly, dopamine release shifts from ventromedial to lateral striatum across learning, and impairment of lateral dopamine release disrupts habitual, inflexible responding. This raises the possibility that lateral dopamine release is a causative mechanism in establishing inflexible behaviors late in training, though this has not been directly tested. Here, we utilized optogenetics to activate dopamine terminals in dorsal medial (DMS), dorsal lateral (DLS), and ventral (NAc) striatum in DATcre mice to determine how specific dopamine subpopulations impact behavioral flexibility. Mice performed a reversal task in which they self-stimulated DMS, DLS, or NAc dopamine terminals by pressing one of two levers before action-outcome lever contingencies were reversed. Consistent with presumed ventromedial/lateral striatal function, we found that mice self-stimulating ventromedial dopamine terminals rapidly reversed lever preference following contingency reversal, while mice self-stimulating dopamine terminals in DLS showed impaired reversal learning. These impairments were characterized by more regressive errors and reliance on lose-stay strategies following reversal, suggesting reward insensitivity and overreliance on previously learned actions. This study supports a model of striatal function in which dorsomedial dopamine facilitates goal-directed responding, and dorsolateral dopamine release is a key mechanism in supporting the transition toward inflexible behaviors.

BACKGROUND: The Parkinson’s Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson’s disease, healthy controls, and carriers of the most common Parkinson’s disease-related genetic mutations, which aims to define biomarkers of Parkinson’s disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson’s disease that correlate with reduced DAT binding. METHODS: This cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual’s age. We used t tests, χ(2) tests, and Fisher’s exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number . FINDINGS: Between Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p

A leading hypothesis for schizophrenia and related psychotic disorders proposes that cortical brain disruption leads to subcortical dopaminergic dysfunction, which underlies psychosis in the majority of patients who respond to treatment. Although supported by preclinical findings that prefrontal cortical lesions lead to striatal dopamine dysregulation, the relationship between prefrontal structural volume and striatal dopamine function has not been tested in people with psychosis. We therefore investigated the in vivo relationship between striatal dopamine synthesis capacity and prefrontal grey matter volume in treatment-responsive patients with psychosis, and compared them to treatment non-responsive patients, where dopaminergic mechanisms are not thought to be central. Forty patients with psychosis across two independent cohorts underwent 18F-DOPA PET scans to measure dopamine synthesis capacity (indexed as the influx rate constant Kicer) and structural 3T MRI. The PET, but not MR, data have been reported previously. Structural images were processed using DARTEL-VBM. GLM analyses were performed in SPM12 to test the relationship between prefrontal grey matter volume and striatal Kicer. Treatment responders showed a negative correlation between prefrontal grey matter and striatal dopamine synthesis capacity, but this was not evident in treatment non-responders. Specifically, we found an interaction between treatment response, whole striatal dopamine synthesis capacity and grey matter volume in left (pFWE corr. = 0.017) and right (pFWE corr. = 0.042) prefrontal cortex. We replicated the finding in right prefrontal cortex in the independent sample (pFWE corr. = 0.031). The summary effect size was 0.82. Our findings are consistent with the long-standing hypothesis of dysregulation of the striatal dopaminergic system being related to prefrontal cortex pathology in schizophrenia, but critically also extend the hypothesis to indicate it can be applied to treatment-responsive schizophrenia only. This suggests that different mechanisms underlie the pathophysiology of treatment-responsive and treatment-resistant schizophrenia.

Learning to avoid aversive outcomes is an adaptive strategy to limit one’s future exposure to stressful events. However, there is considerable variance in active avoidance learning across a population. The mesolimbic dopamine system contributes to behaviors elicited by aversive stimuli, although it is unclear if the heterogeneity in active avoidance learning is explained by differences in dopamine transmission. Furthermore, it is not known how dopamine signals evolve throughout active avoidance learning. To address these questions, we performed voltammetry recordings of dopamine release in the ventral medial striatum throughout training on inescapable footshock and signaled active avoidance tasks. This approach revealed differences in the pattern of dopamine signaling during the aversive cue and the safety period that corresponded to subsequent task performance. Dopamine transmission throughout the footshock bout did not predict performance but rather was modulated by the prior stress exposure. Additionally, we demonstrate that dopamine encodes a safety prediction error signal, which illustrates that ventral medial striatal dopamine release conveys a learning signal during both appetitive and aversive conditions.

Decades of research suggest that the mesocortical dopamine system exerts powerful control over mPFC physiology and function. Indeed, dopamine signaling in the medial prefrontal cortex (mPFC) is implicated in a vast array of processes, including working memory, stimulus discrimination, stress responses, and emotional and behavioral control. Consequently, even slight perturbations within this delicate system result in profound disruptions of mPFC-mediated processes. Many neuropsychiatric disorders are associated with dysregulation of mesocortical dopamine, including schizophrenia, depression, attention deficit hyperactivity disorder, post-traumatic stress disorder, among others. Here, we review the anatomy and functions of the mesocortical dopamine system. In contrast to the canonical role of striatal dopamine in reward-related functions, recent work has revealed that mesocortical dopamine fine-tunes distinct efferent projection populations in a manner that biases subsequent behavior towards responding to stimuli associated with potentially aversive outcomes. We propose a framework wherein dopamine can serve as a signal for switching mPFC states by orchestrating how information is routed to the rest of the brain.

Summary Striatal dopamine and smartphone behavior have both been linked with behavioral variability. Here, we leverage day-to-day logs of natural, unconstrained smartphone behavior and establish a correlation between a measure of smartphone social activity previously linked with behavioral variability and a measure of striatal dopamine synthesis capacity using [18F]-DOPA PET in (N = 22) healthy adult humans. Specifically, we find that a higher proportion of social app interactions correlates with lower dopamine synthesis capacity in the bilateral putamen. Permutation tests and penalized regressions provide evidence that this link between dopamine synthesis capacity and social versus non-social smartphone interactions is specific. These observations provide a key empirical grounding for current speculations about dopamine's role in digital social behavior., Graphical abstract, Highlights • Putamen dopamine synthesis capacity correlates with smartphone social app use. • The correlation parallels a prior link between social app use and motor variability. • It is selective to social app use, controlling for multiple smartphone use factors., Behavioral neuroscience; Biological sciences; Neuroscience

How to model hallucinations in mice There has not been enough progress in our understanding of the basic mechanisms underlying psychosis. Studying psychotic disorders in animal models is difficult because the diagnosis relies on self-reported symptoms that can only be assessed in humans. Schmack et al. developed a paradigm to probe and rigorously measure experimentally controlled hallucinations in rodents (see the Perspective by Matamales). Using dopamine-sensor measurements and circuit and pharmacological manipulations, they demonstrated a brain circuit link between excessive dopamine and hallucination-like experience. This could potentially be useful as a translational model of common psychotic symptoms described in various psychiatric disorders. It may also help in the development of new therapeutic approaches based on anatomically selective modulation of dopamine function. Science , this issue p. eabf4740 ; see also p. 33

Vigor reflects how motivated one is to respond to a stimulus. We previously showed that humans are more vigorous when more reward is available on average, and that this relationship is modulated by the dopamine precursor levodopa. Dopamine signalling and probabilistic reward learning degrade with age, so the relationship between vigor and reward should change with age. We test this and assess whether the relationship between vigor and reward correlates with D1 dopamine receptor availability measured using Positron Emission Tomography. We measured response times of 30 older and 30 younger subjects during an oddball discrimination task where rewards varied systematically between trial. Reward rate had a similar impact on the vigor of both groups. We observed a weak positive association across subjects between ventral striatal dopamine receptor availability and effect of average reward rate on response time, which was in the opposite direction to our prediction. Overall, the effect of reward on response vigor is similar between younger and older humans and is weakly sensitive to dopamine D1 receptor availability.

Two students of Jean-Martin Charcot, Paul Blocq and Georges Marinesco, presented a case of hemi-parkinsonism to the Societe de Biologie on 27 May 1893. A tuberculoma was found at post-mortem in the cerebral peduncle contralateral to the side of the body affected by Parkinson's disease. A year later, in one of his lessons, Edouard Brissaud suggested that damage to the substantia nigra caused by the granuloma might have been responsible for the physical signs. This article provides brief biographical accounts of both Blocq and Marinesco and a detailed review of their seminal paper before going on to discuss how the substantia nigra was eventually established as the most consistent pathological substrate for Parkinson's disease and its role in the dopamine miracle which led to striatal dopamine replacement therapy in 1967.

The striatum is the primary input structure of the basal ganglia, which participates in motivational and goal-directed behaviors (Pisani et al., 2007). In physiological conditions, local cholinergic interneurons (ChIs) and dopaminergic afferents modulate basal ganglia output through striatal projection neurons, also called medium spiny neurons (MSNs). In general, the release of the neurotransmitters dopamine (DA) and acetylcholine (ACh) elicits contradictory effects on MSNs, which express their corresponding DA receptors (DARs) and muscarinic acetylcholine receptors (mAChRs), respectively (Ztaou and Amalric, 2019). Recently, we discovered a novel receptor-receptor interaction (i.e., heteromerization) between the dopamine D2 receptor (D2R) and the muscarinic acetylcholine M1 receptor (M1R), both expressed at striatopallidal MSNs (Crans et al., 2020). The putative striatal D2R-M1R complex coordinates a sophisticated interplay between the dopaminergic and cholinergic neurotransmission systems. Fuxe et al. (2012) foresaw that the existence of this heteromer within the striatum would mechanistically justify the use of anticholinergics in Parkinson's disease (PD) treatment, thus opening up the development of novel pharmacotherapeutic strategies for PD management. As a proof of concept, we demonstrated that an M1R-selective antagonist (i.e., VU0255035, 10 mg/kg, i.p.) potentiated the antiparkinsonian-like efficacy of an ineffective D2R-selective agonist dose (i.e., sumanirole, 3 mg/kg, i.p.) in a rodent model of experimental Parkinsonism (Crans et al., 2020). Overall, the novel D2R-M1R heteromer could serve as a specific drug target to alleviate motor deficits in PD, whereas it may avoid major adverse effects associated with traditional pharmacotherapies.

BackgroundMethylphenidate (MPH) is the first-line pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). MPH binds to the dopamine (DA) transporter (DAT), which has high density in the striatum. Assessments of the striatal dopamine transporter by single positron emission computed tomography (SPECT) in childhood and adolescent patients are rare but can provide insight in how effects of MPH affect DAT availability. The aim of our within-subject study was to investigate the effect of MPH on DAT availability and how responsivity to MPH in DAT availability is linked to clinical symptoms and cognitive functioning.MethodsThirteen adolescent male patients (9-16 years) with diagnosis of ADHD according to DSM-IV and long-term stimulant medication (for at least 6 months) with MPH were assessed twice within 7 days using SPECT after application of I-123-ß-CIT to examine DAT binding potential (DAT BP). SPECT measures took place in on and off-MPH status balanced for order across participants. A virtual-reality continuous-performance test was performed at each time point. Further clinical symptoms were assessed for baseline off-MPH.ResultsOn-MPH status was associated with a highly significant decrease (−27,6%) of striatal DAT BP as compared to off-MPH (t=4.93, pConclusionOur findings corroborate previous reports from mainly adult samples that MPH reduces striatal DAT BP availability and suggest higher off-MPH DAT BP, likely reflecting low baseline DA levels, as a marker of symptom severity. More speculatively, regional specific responsivity of DAT BP to MPH may reflect treatment response with respect to cognitive functioning. However, implications from this small patient sample should be treated with caution and warrant replication.

Vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex that mediates the retrograde transport of cargo proteins from endosomes to the trans-Golgi network. Mutations such as D620N in the VPS35 gene have been identified in patients with autosomal dominant Parkinson's disease (PD). However, it remains poorly understood whether and how VPS35 deficiency or mutation contributes to PD pathogenesis; specifically, the studies that have examined VPS35 thus far have differed in results and methodologies. We generated a VPS35 D620N mouse model using a Rosa26-based transgene expression platform to allow expression in a spatial manner, so as to better address these discrepancies. Here, aged (20-months-old) mice were first subjected to behavioral tests. Subsequently, DAB staining analysis of substantia nigra (SN) dopaminergic neurons with the marker for tyrosine hydroxylase (TH) was performed. Next, HPLC was used to determine dopamine levels, along with levels of its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum. Western blotting was also performed to study the levels of key proteins associated with PD. Lastly, autoradiography (ARG) evaluation of [3H]FE-PE2I binding to the striatal dopamine transporter DAT was carried out. We found that VPS35 D620N Tg mice displayed a significantly higher dopamine level than NTg counterparts. All results were then compared with that of current VPS35 studies to shed light on the disease pathogenesis. Our model allows future studies to explicitly control spatial expression of the transgene which would generate a more reliable PD phenotype. National Medical Research Council (NMRC) Published version This research was supported by the Open Fund-Large Collaborative Grant [OFLCG18May-0026]; and Open Fund-Individual Research Grant [NMRC/OFIRG/0074/2018] administered by the Singapore Ministry of Health’s National Medical Research Council.

Habits are inflexible behaviors that can be maladaptive in diseases including drug addiction. The striatum is integral to habit formation, and interspersed throughout the striatum are patches, or striosomes, which are characterized by unique gene expression relative to the surrounding matrix. Recent work has indicated that patches are necessary for habit formation, but how patches contribute to habits remains partially understood. Here, using optogenetics, we modulated striatal patches in Sepw1-NP67 mice during habit formation. We find that patch activation during operant training impairs habit formation, and conversely, that acute patch stimulation after reward devaluation can drive habitual reward seeking. Patch stimulation invigorates general locomotion but is not inherently rewarding. Finally, we use fast-scan cyclic voltammetry to demonstrate that patch stimulation suppresses dopamine release in dorsal striatum in vivo. Overall, this work provides novel insight into the role of the patch compartment in habit formation, and potential interactions with dopamine signaling.

Low-threshold spiking interneurons (LTSIs) in the dorsomedial striatum are potent modulators of goal-directed learning. Here, we uncover a novel function for LTSIs in locally and directly gating striatal dopamine, using in vitro fast scan cyclic voltammetry as well as in vivo GRAB-DA sensor imaging and pharmacology during operant learning. We demonstrate that LTSIs, acting via GABAB signaling, attenuate dopamine release, thereby serving as local coordinators of striatal plasticity.

αSynuclein aggregation at the synapse is an early event in Parkinson’s disease and is associated with impaired striatal synaptic function and dopaminergic neuronal death. The cysteine string protein (CSPα) and αsynuclein have partially overlapping roles in maintaining synaptic function and mutations in each cause neurodegenerative diseases. CSPα is a member of the DNAJ/HSP40 family of co-chaperones and like αsynuclein, chaperones the SNARE complex assembly and neurotransmitter release. αSynuclein can rescue neurodegeneration in CSPαKO mice. However, whether αsynuclein aggregation alters CSPα expression and function is unknown. Here we show that αsynuclein aggregation at the synapse induces a decrease in synaptic CSPα and a reduction in the complexes that CSPα forms with HSC70 and STGa. We further show that viral delivery of CSPα rescues in vitro the impaired vesicle recycling in PC12 cells with αsynuclein aggregates and in vivo reduces synaptic αsynuclein aggregates restoring normal dopamine release in 1-120hαsyn mice. These novel findings reveal a mechanism by which αsynuclein aggregation alters CSPα at the synapse, and show that CSPα rescues αsynuclein aggregation-related phenotype in 1-120hαsyn mice similar to the effect of αsynuclein in CSPαKO mice. These results implicate CSPα as a potential therapeutic target for the treatment of early-stage PD.

Midbrain dopamine neurons play key roles in decision-making by regulating reward valuation and actions. These roles are thought to depend on dopamine neurons innervating striatum. In addition to actions and rewards, however, efficient decisions often involve consideration of uncertain sensory signals. The functions of striatal dopamine during sensory decisions remains unknown. We trained mice in a task that probed decisions based on sensory evidence and reward value, and recorded the activity of striatal dopamine axons. Dopamine axons in ventral striatum (VS) responded to bilateral stimuli and trial outcomes, encoding prediction errors that scaled with decision confidence and reward value. By contrast, dopamine axons in dorsal striatum (DS) responded to contralateral stimuli and contralateral actions. Thus, during sensory decisions, striatal dopamine signals are anatomically organized. VS dopamine resembles prediction errors suitable for reward maximization under sensory uncertainty whereas DS dopamine encodes specific combinations of stimuli and actions in a lateralized fashion.

Journeys to novel and familiar destinations employ different navigational strategies. The first drive to a new restaurant relies on map-based planning, but after repeated trips the drive is automatic and guided by local environmental cues1,2. Ventral striatal dopamine rises during navigation toward goals and reflects the spatial proximity and value of goals3, but the impact of experience, the neural mechanisms, and the functional significance of dopamine ramps are unknown4,5. Here, we used fiber photometry6–8 to record the evolution of activity in midbrain dopamine neurons as mice learned a variety of reward-seeking tasks, starting recordings before training had commenced and continuing daily for weeks. When mice navigated through space toward a goal, robust ramping activity in dopamine neurons appeared immediately – after the first rewarded trial on the first training day in completely naïve animals. In this task spatial cues were available to guide behavior, and although ramps were strong at first, they gradually faded away as training progressed. If instead mice learned to run a fixed distance on a stationary wheel for reward, a task that required an internal model of progress toward the goal, strong dopamine ramps persisted indefinitely. In a passive task in which a visible cue and reward moved together toward the mouse, ramps appeared and then faded over several days, but in an otherwise identical task with a stationary cue and reward ramps never appeared. Our findings provide strong evidence that ramping activity in midbrain dopamine neurons reflects the use of a cognitive map9,10 – an internal model of the distance already covered and the remaining distance until the goal is reached. We hypothesize that dopamine ramps may be used to reinforce locations on the way to newly-discovered rewards in order to build a graded ventral striatal value landscape for guiding routine spatial behavior.

Background Dopamine transporter (DAT) imaging may enable clinicians to discriminate idiopathic normal pressure hydrocephalus (iNPH) from other parkinsonian disorders. However, a specific pattern of dopaminergic loss in DAT imaging of iNPH patients remains to be further elucidated. Methods In this preliminary study, 11 patients with iNPH in our hospital between March 2017 and February 2019 were finally enrolled. A diagnosis of iNPH was made according to the two established criteria. For visual analysis of DAT imaging, a striatum was divided into five domains. A semi-quantitative visual assessment was performed with a consensus between a nuclear medicine specialist and an experienced neurologist who were blinded to the clinical diagnosis. Results Striatal dopaminergic deficits were abnormal in 90.9% (10/11) of patients with iNPH. The degree of dopaminergic reduction was mild and heterogeneous. However, a tendency of preferential striatal DAT loss in the caudate nucleus (90.9%, 10/11) than in the putamen (72.7%, 8/11) was observed, whereas ventral portion (9.1%, 1/11) was relatively preserved. Conclusion Striatal dopaminergic depletion might be mild and heterogeneous in patients with iNPH. These dopaminergic deficits were more common in the caudate nucleus than in the putamen, suggesting a pattern different from other degenerative parkinsonian disorders.

To investigate whether the patterns of striatal dopamine depletion could provide prognostic information on the clinical profiles of early-stage Parkinson disease (PD).Approximately 634 patients with drug-naive PD who underwent F-FP-CIT PET scans were followed up for at least 2 years. After quantifying dopamine transporter (DAT) availability in each striatal subregion, the patterns of striatal dopamine depletion of each patient were assessed based on (1) the degree of dopamine loss in the other striatal subregions compared to the posterior putamen (inter-subregional ratio [ISR]) and (2) the interhemispheric asymmetry of dopamine loss in the posterior putamen (asymmetry index [AI]). According to their patterns, we assessed the longitudinal changes in L-dopa-equivalent doses and L-dopa-induced dyskinesia (LID)-free times using the linear mixed model and Cox regression model, respectively.There was no significant correlation between the ISR and AI values (Pearson correlation coefficient, 0.150). The linear mixed model showed that higher AI values were associated with slower longitudinal increases in L-dopa-equivalent dose across time (P = 0.003), whereas ISR values were not (P = 0.154). The Cox regression model demonstrated that higher ISR values were associated with early development of LID (hazard ratio, 1.693; P = 0.010), whereas AI values were not (P = 0.269).The present study demonstrated that the pattern of anterior-to-posterior gradient and right-to-left asymmetry of striatal DAT availability predicted the development of LID and increasing doses of dopaminergic medications.

Creative problem solving involves search processes, and it is known to be hard to motivate. Reward cues have been found to enhance performance across a range of tasks, even when cues are presented subliminally, without being consciously detected. It is uncertain whether motivational processes, such as reward, can influence problem solving. We tested the effect of supraliminal and subliminal reward on participant performance on problem solving that can be solved by deliberate analysis or by insight. Forty-one participants attempted to solve 100 compound remote associate problems. At the beginning of each problem, a potential reward cue (1 or 25 cents) was displayed, either subliminally (17 ms) or supraliminally (100 ms). Participants earned the displayed reward if they solved the problem correctly. Results showed that the higher subliminal reward increased the percentage of problems solved correctly overall. Second, we explored if subliminal rewards preferentially influenced solutions that were achieved via a sudden insight (mostly processed below awareness) or via a deliberate analysis. Participants solved more problems via insight following high subliminal reward when compared with low subliminal reward, and compared with high supraliminal reward, with no corresponding effect on analytic solving. Striatal dopamine (DA) is thought to influence motivation, reinforce behavior, and facilitate cognition. We speculate that subliminal rewards activate the striatal DA system, enhancing the kinds of automatic integrative processes that lead to more creative strategies for problem solving, without increasing the selectivity of attention, which could impede insight.

This scientific commentary refers to ‘Reduced striatal dopamine synthesis capacity in patients with schizophrenia during remission of positive symptoms’, by Avram et al. (doi:10.1093/brain/awz093).

Background: Positron Emission Tomography (PET) findings suggest that increased striatal dopamine neurotransmission may underlie Obsessive-Compulsive Disorder (OCD) in adults This is untested in pediatric OCD since PET is overly invasive and untenable for pediatric research Thus, we used neuromelanin-sensitive MRI (NM-MRI) to assess nigrostriatal dopamine transmission in children with OCD and predict response to cognitive behavioral therapy (CBT) Methods: NM-MRI data was collected from 35 children on a GE 3T scanner with a 64-channel head coil Those with OCD received manualized CBT before being re-scanned after 16-10 weeks Following stringent QC procedures, 10 scans were excluded, leaving baseline and follow-up data from 15 children with OCD (9 7±1 7 years) and 10 matched controls (10 0 ± 1 8 years) Data were preprocessed with in house procedures (Wengler et al, Neuroimage, 2020) Linear regression analyses assessed group differences in dopamine signal and associations with CBT response Results: Group differences in NM-MRI signal were detected in the VTA with greater signal in the OCD compared to HC group (t(14 45)=-2 13, p= 05) NM-MRI signal did not correlate significantly with baseline OC symptoms, but predicted better CBT response in the OCD group (p= 04), as measured by change in symptoms pre-post CBT Conclusions: These new findings suggest alterations in the mesocortical dopaminergic system in pediatric OCD, stemming from the VTA Dopaminergic hyperactivity may contribute to the reward processing deficits noted in OCD and mark CBT response in pediatric patients Data collection has resumed (post COVID-19) and we anticipate increasing the sample size before the SOBP meeting in April Supported By: NIMH R01MH115024-01A1 Keywords: Pediatric Obsessive-Compulsive Disorder, Neuromelanin-Sensitive MRI, Precision Psychiatry, Dopamine, Cognitive Behavioral Therapy

Social defeat in rodents putatively can model hypohedonia. The present studies examined models for assessing hypohedonia-like behavior and tested the hypotheses that 1) individual differences in baseline reward sensitivity predict vulnerability, and 2) defeat elicits changes in pharmacological measures of striatal dopaminergic function. Male Wistar rats (n=142) received repeated defeat (3 “triad” blocks of 3 defeats) or control handling. To determine whether defeat influenced consumption of SuperSac (glucose-saccharin) over an isocaloric, less preferred, glucose solution, a 2-choice paradigm was used. To determine repeated defeat effects on the reinforcing efficacy of SuperSac, a progressive-ratio schedule of reinforcement was used. Amphetamine-induced locomotor activity (0.08 mg/kg, s.c.) was determined as a measure sensitive to striatal dopaminergic function. Defeat reduced SuperSac consumption during the first two triads—an effect seen in the third triad only in defeated rats with High vs. Low baseline SuperSac intake. The characteristic escalation in PR breakpoint for SuperSac normally seen in controls was absent in defeated rats, leading to a significant difference by the third triad. Defeat-induced blunting of the escalation in PR performance was greater in rats with High antecedent PR breakpoints and persisted 2.5 weeks post-defeat. Repeated defeat also blunted amphetamine-induced locomotion 13 days post-defeat. Thus, hypohedonic-like effects of social defeat were detected and accompanied by persistently attenuated striatal dopamine function. Early effects were seen for consumption of differentially-palatable solutions, and persistent effects were seen for the “breakpoint” motivational measure. The results implicate initial reward sensitivity as a risk factor for stress-induced hypohedonia.

Striatal dopamine (DA) plays a central role in reward-related learning and behavioral adaptation to changing environments. Recent studies suggest that rather than being broadcast as a uniform signal throughout the entire region, DA release dynamics diverge between different striatal regions. In a previous study, we showed that phasic DA release patterns in the ventromedial striatum (VMS) rapidly adapt during reversal learning. However, it is unknown how DA dynamics in the dorsolateral striatum (DLS) are modulated during such adaptive behavior. Here, we used fast-scan cyclic voltammetry to measure phasic DA release in the DLS during spatial reversal learning. In the DLS, we observed minor DA release after the onset of a visual cue signaling reward availability, followed by more pronounced DA release during more proximal reward cues (e.g., lever extension) and execution of the operant response (i.e., lever press), both in rewarded and non-rewarded trials. These release dynamics (minor DA after onset of the predictive visual cue, prominent DA during the operant response) did not change significantly during or following a reversal of response-reward contingencies. Notably, the DA increase to the lever press did not reflect a general signal related to the initiation of any motivated motor response, as we did not observe DA release when rats initiated nose pokes into the food receptacle during inter-trial intervals. This suggests that DA release in the DLS occurs selectively during the initiation and execution of a learned operant response. Together with our previous results obtained in the VMS, these findings reveal distinct phasic DA release patterns during adaptation of established behavior in DLS and VMS. The VMS DA signal, which is highly sensitive to reversal of response-reward contingences, may provide a teaching signal to guide reward-related learning and facilitate behavioral adaptation, whereas DLS DA may reflect a 'response execution signal' largely independent of outcome, that may be involved in initiation and energizing of operant behavior.

Fast-scan cyclic voltammetry (FSCV) has been used for over 20 years to study rapid neurotransmission in awake and behaving animals. These experiments were first carried out with carbon-fiber microelectrodes (CFMs) encased in borosilicate glass, which can be inserted into the brain through micromanipulators and guide cannulas. More recently, chronically implantable CFMs constructed with small diameter fused-silica have been introduced. These electrodes can be affixed in the brain with minimal tissue response, which permits longitudinal measurements of neurotransmission in single recording locations during behavior. Both electrode designs have been used to make novel discoveries in the fields of neurobiology, behavioral neuroscience, and psychopharmacology. The purpose of this Review is to address important considerations for the use of FSCV to study neurotransmitters in awake and behaving animals, with a focus on measurements of striatal dopamine. Common issues concerning experimental design, data collection, and calibration are addressed. When necessary, differences between the two methodologies (acute vs chronic recordings) are discussed. The topics raised in this Review are particularly important as the field moves beyond dopamine toward new neurochemicals and brain regions., Graphical abstract

Is altered dopamine transmission a pre-existing vulnerability trait for addiction? Preliminary support for this hypothesis has been provided by recent neuroimaging studies. While most effects remain to be replicated, there is now evidence that, compared to healthy controls, people at familial risk for substance use disorders exhibit both increases and decreases in striatal dopamine function. The following review assesses the strength of this evidence, considers explanations for discrepant results, and discusses potential implications for understanding pathways to addiction.

In schizophrenia, among the most consistent brain changes are both aberrant dopamine function in the dorsal striatum and aberrant intrinsic functional connectivity (iFC) between distinct cortical networks and thalamic nuclei; however, it is unknown whether these changes are pathophysiologically related. Such a relationship is expected because cortico-thalamic-connectivity is modulated by striatal dopamine within topographically distinct, parallel but interacting cortico-basal-ganglia-thalamic circuits. We hypothesized: (1) Within-circuits, aberrant striatal dopamine contributes to aberrant cortico-thalamic-iFC, specifically, associative-striatum dopamine contributes to salience-network-thalamic-iFC, and sensorimotor-striatum dopamine to auditory-sensorimotor-network-thalamic-iFC. (2) Due to between-circuits interactions following an anterior-to-posterior gradient, salience-network-centered-system changes contribute to auditory-sensorimotor-network-centered-system changes. To test these hypotheses, 19 patients with schizophrenia during symptomatic remission of positive symptoms and 19 age- and sex-comparable controls underwent simultaneous fluorodihydroxyphenyl-L-alanine positron emission tomography (18F-DOPA-PET) and resting-state functional magnetic resonance imaging (rs-fMRI). The influx constant kicerbased on18F-DOPA-PET was used to measure dopamine synthesis capacity (DSC), indicating striatal dopamine function; correlation coefficients between rs-fMRI time-series of cortical networks and thalamic regions-of-interest were used to measure iFC. In the salience-network(SAL)-centered-system, patients had reduced associative-striatum-DSC, which correlated positively with SAL-mediodorsal-thalamus-iFC and mediated the reduction of SAL-thalamic-iFC in patients. In the auditory-sensorimotor-network(ASM)-centered-system, patients had reduced sensorimotor-striatum-DSC, which correlated positively with ASM-ventrolateral-thalamus-iFC, but did not mediate increased ASM-thalamic-iFC in patients. Finally, aberrant DSC and iFC of the SAL-centered-system mediated corresponding changes in the ASM-centered-system. Results demonstrate that cortico-thalamic-dysconnectivity links with aberrant striatal dopamine in schizophrenia - in a topographically distinct way, with an anterior-to-posterior gradient, and primary changes in the SAL-centered system.

Rapid phasic activity of midbrain dopamine neurons are thought to signal reward prediction errors (RPEs), resembling temporal difference errors used in machine learning. Recent studies describing slowly increasing dopamine signals have instead proposed that they represent state values and arise independently from somatic spiking activity. Here, we developed novel experimental paradigms using virtual reality that disambiguate RPEs from values. We examined the dopamine circuit activity at various stages including somatic spiking, axonal calcium signals, and striatal dopamine concentrations. Our results demonstrate that ramping dopamine signals are consistent with RPEs rather than value, and this ramping is observed at all the stages examined. We further show that ramping dopamine signals can be driven by a dynamic stimulus that indicates a gradual approach to a reward. We provide a unified computational understanding of rapid phasic and slowly ramping dopamine signals: dopamine neurons perform a derivative-like computation over values on a moment-by-moment basis.

3,4-Methylenedioxypyrovalerone (MDPV) is a selective catecholamine reuptake inhibitor abused for its psychostimulant properties. This study examined if MDPV administration alters impulsive choice measured by delay discounting in rats. Three groups of rats were tested in daily delay discounting sessions to determine the effects of acute cocaine (1.0-30.0 mg/kg), MDPV (0.1-3.0 mg/kg), or saline on mean adjusted delay (MAD). Dose-dependent decreases in MAD were elicited only by acute MDPV, which also suppressed operant responding at the highest dose. Next, rats received post-session injections (30.0 mg/kg cocaine, 3.0 mg/kg MDPV, or saline) every other day for a total of 10 injections. MAD increased during saline treatment, did not change during cocaine treatment, and was reduced during MDPV treatment. In dose-effect re-determinations, no acute drug effects on MAD were observed, but compared to the initial dose-effect determination, MDPV suppressed operant responding in more animals, with zero animals completing trials at the highest dose. All saline and MDPV-treated subjects were sacrificed, and striatal and cortical dopamine levels were quantified by HPLC. These studies indicate that administration of MDPV may increase impulsive choice acutely and persistently. These proimpulsive effects are possibly mediated by increases in striatal dopamine turnover.