Striatal Activity Research Articles

Correlations with REM sleep behavior disorder severity in isolated rapid eye movement sleep behavior disorders patients

Objectives The pathogenesis of isolated rapid eye movement sleep behavior disorders (iRBD) is poorly understood. The severity of RBD may reflect its pathogenesis. Methods We compared motor function and non-motor symptoms (NMSs) between iRBD patients and healthy volunteers. We correlated motor function, NMSs, and striatal dopaminergic activity with RBD severity using video-polysomnography. Results Twenty-one iRBD patients and 17 controls participated. The Unified Parkinson’s Disease Rating Scale part III scores were higher in patients compared to controls (p < 0.001). There was no difference in upper extremity function between patients and controls (right, p = 0.220; left, p = 0.209), but gait was slower in iRBD patients (walking time, p < 0.001; number of steps, p < 0.001). The mean value of the Korean version of the Mini-Mental State Exam and Clinical Dementia Rating were lower in patients (p = 0.006, p = 0.003, respectively). Patients with were also more depressed (p = 0.002), had decreased olfactory function (p < 0.001), reported more frequent sleep/fatigue episodes (p < 0.001), worse attention/memory capacity (p < 0.001), gastrointestinal problems (p = 0.009), urinary problems (p = 0.007), and pain (p = 0.083). Further, iRBD patients reported more frequent sleep-related disturbances (p = 0.004), but no difference in daytime sleepiness (p = 0.663). Disease severity was correlated with pain (r = 0.686, p = 0.002) and visuospatial function (r= −0.507, p = 0.038). There were no correlations between RBD severity and striatal dopaminergic activities (p > 0.09). Conclusions iRBD is a multisystem neurodegenerative disorder, and gait abnormalities may be a disease characteristic, possibly related to the akinetic-rigid phenotype of Parkinson’s disease. The correlation between pain/visuospatial dysfunction and RBD severity may be related to its pathogenesis.

Altered Ventral Striatum–Hippocampus Connectivity During Reward Processing as an Endophenotype for Psychosis

SEE CORRESPONDING ARTICLE ON PAGE 216 Ventral Striatal–Hippocampus Coupling During Reward Processing as a Stratification Biomarker for Psychotic DisordersBiological PsychiatryVol. 91Issue 2PreviewAltered ventral striatal (vST) activation to reward expectancy is a well-established intermediate phenotype for psychiatric disorders, specifically schizophrenia (SZ). Preclinical research suggests that striatal alterations are related to a reduced inhibition by the hippocampal formation, but its role in human transdiagnostic reward-network dysfunctions is not well understood. Full-Text PDF Open Access

The role of the SLC6A3 3\u2019 UTR VNTR in nicotine effects on cognitive, affective, and motor function

RationaleNicotine has been widely studied for its pro-dopaminergic effects. However, at the behavioural level, past investigations have yielded heterogeneous results concerning effects on cognitive, affective, and motor outcomes, possibly linked to individual differences at the level of genetics. A candidate polymorphism is the 40-base-pair variable number of tandem repeats polymorphism (rs28363170) in the SLC6A3 gene coding for the dopamine transporter (DAT). The polymorphism has been associated with striatal DAT availability (9R-carriers > 10R-homozygotes), and 9R-carriers have been shown to react more strongly to dopamine agonistic pharmacological challenges than 10R-homozygotes.ObjectivesIn this preregistered study, we hypothesized that 9R-carriers would be more responsive to nicotine due to genotype-related differences in DAT availability and resulting dopamine activity.MethodsN=194 non-smokers were grouped according to their genotype (9R-carriers, 10R-homozygotes) and received either 2-mg nicotine or placebo gum in a between-subject design. Spontaneous blink rate (SBR) was obtained as an indirect measure of striatal dopamine activity and smooth pursuit, stop signal, simple choice and affective processing tasks were carried out in randomized order.ResultsReaction times were decreased under nicotine compared to placebo in the simple choice and stop signal tasks, but nicotine and genotype had no effects on any of the other task outcomes. Conditional process analyses testing the mediating effect of SBR on performance and how this is affected by genotype yielded no significant results.ConclusionsOverall, we could not confirm our main hypothesis. Individual differences in nicotine response could not be explained by rs28363170 genotype.

Novel mechanistic insights towards the repositioning of alogliptin in Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disease that impairs people's lives tremendously. The development of innovative treatment modalities for PD is a significant unmet medical need. The critical function of glucagon-like peptide-1 (GLP-1) in neurodegenerative diseases has raised impetus in investigating the repositioning of a dipeptidyl peptidase IV inhibitor, alogliptin (ALO), as an effective treatment for PD. As a result, the focus of this research was to assess the effect of ALO in a rat rotenone (ROT) model of PD. For 21 days, ROT (1.5 mg/kg) was delivered subcutaneously every other day. ALO (30 mg/kg/day), delivered by gavage for 21 days, recovered motor performance and improved motor coordination in the open-field and rotarod testing. These impacts were highlighted by restoring striatal dopamine content and correcting histological changes that occurred concurrently. The ALO molecular signaling was determined by increasing the quantity of GLP-1 and the protein expression of its downstream signaling pathway, pT172-AMPK/SIRT1/PGC-1α. Furthermore, it curbed neuroinflammation via hampering HMGB1/TLR4/NLRP3 inflammasome activation and conquered striatal microglia activation. Pre-administration of dorsomorphin reversed the neuroprotective effects. In conclusion, the promising neuroprotective effect of ALO highlights the repositioning of ALO as a prospective revolutionary candidate for combating PD.

Involvement of striatal oxido-inflammatory, nitrosative and decreased cholinergic activity in neurobehavioral alteration in adult rat model with oral co-exposure to erythrosine and tartrazine

Overuse or overconsumption of food additive or colorant cannot be ignored in our society and there are several reports of it harmful effect on the body system. This study investigated the toxicity effect of tartrazine and erythrosine (ET, 50:50) on neurobehavioral alteration, striatal oxido-nitrosative and pro-inflammatory stress and striatal acetylcholinesterase activity in experimental rat model. Rats were co-exposed to ET (2 mg/kg, 6 mg/kg and 10 mg/kg) and distilled water (control), p.o for 6 weeks. The change in neurobehavioral function (Open field test, Forced swimming test and Tail suspension test), Lipid peroxidation (Malonaldehyde, MDA), Antioxidants (Glutathione, GSH; Catalase, CAT) Nitrite, Pro-inflammatory cytokine (Tumor necrosis factor-alpha, TNF-α) and Acetylcholinesterase (AChE) activity were evaluated. Results showed significant decrease in neurobehavioral functions after co-exposure to ET. Moreover, there were significant increase in MDA and Nitrite level, significant decrease in the concentration of GSH and CAT and a significant increase TNF-α concentration and AChE activity after co-exposure to ET. Oral co-exposure to tartrazine and erythrosine induced decrease in locomotion and exploration, increase anxiety and depression-like behavior and altered the cholinergic system through upregulation of oxido-nitrosative stress, pro-inflammatory cytokine and acetylcholinesterase activity.

Dorsomedial Striatal Activity Tracks Completion of Behavioral Sequences in Rats.

For proper execution of goal-directed behaviors, individuals require both a general representation of the goal and an ability to monitor their own progress toward that goal. Here, we examine how dorsomedial striatum (DMS), a region pivotal for forming associations among stimuli, actions, and outcomes, encodes the execution of goal-directed action sequences that require self-monitoring of behavior. We trained rats to complete a sequence of at least five consecutive lever presses (without visiting the reward port) to obtain a reward and recorded the activity of individual cells in DMS while rats performed the task. We found that the pattern of DMS activity gradually changed during the execution of the sequence, permitting accurate decoding of sequence progress from neural activity at a population level. Moreover, this sequence-related activity was blunted on trials where rats did not complete a sufficient number of presses. Overall, these data suggest a link between DMS activity and the execution of behavioral sequences that require monitoring of ongoing behavior.

Inhibition of neutral sphingomyelinase 2 reduces extracellular vesicle release from neurons, oligodendrocytes, and activated microglial cells following acute brain injury

Extracellular Vesicles (EVs) are implicated in the spread of pathogenic proteinsin a growing number of neurological diseases. Given this, there is rising interest in developing inhibitors of Neutral Sphingomyelinase 2 (nSMase2), an enzyme critical in EV biogenesis. Our group recently discovered phenyl(R)‐(1‐(3‐(3,4‐dimethoxyphenyl)‐2,6‐dimethylimidazo[1,2‐b]pyridazin‐8‐yl)pyrrolidin‐3‐yl)carbamate (PDDC), the first potent, selective, orally-available, and brain-penetrable nSMase2 inhibitor, capable of dose-dependently reducing EVs release in vitro and in vivo. Herein, using multiplexed Surface Plasmon Resonance imaging (SPRi), we evaluated which brain cell-derived EVs were affected by PDDC following acute brain injury. Mice were fed PDDC-containing chow at doses which gave steady PDDC brain exposures exceeding its nSMase2 IC50. Mice were then administered an intra-striatal IL-1β injection and two hours later plasma and brain were collected. IL-1β injection significantly increased striatal nSMase2 activity which was completely normalized by PDDC. Using SPRi, we found that IL-1β-induced injury selectively increased plasma levels of CD171 + and PLP1 + EVs; this EV increase was normalized by PDDC. In contrast, GLAST1 + EVs were unchanged by IL-1β or PDDC. IL-1β injection selectively increased EVs released from activated versus non-activated microglia, indicated by the CD11b+/IB4 + ratio. The increase in EVs from CD11b + microglia was dramatically attenuated with PDDC. Taken together, our data demonstrate that following acute injury, brain nSMase2 activity is elevated. EVs released from neurons, oligodendrocytes, and activated microglial are increased in plasma and inhibition of nSMase2 with PDDC reduced these IL-1β-induced changes implicating nSMase2 inhibition as a therapeutic target for acute brain injury.

21.4 REWARD PROCESSING IN CHILDREN WITH DISRUPTIVE BEHAVIOR DISORDERS AND CALLOUS-UNEMOTIONAL TRAITS IN THE ABCD STUDY

Disrupted reward processing is implicated in the etiology of disruptive behavior disorders (DBDs) and callous-unemotional traits. However, neuroimaging investigations of reward processing underlying these phenotypes remain sparse. The authors examined neural sensitivity in response to reward anticipation and receipt among youths with DBDs, with and without callous-unemotional traits. Data were obtained from the ABCD study (mean age = 9.51 years [SD = 0.50]; 49% female). Reward-related activation during the monetary incentive delay task was examined across 16 brain regions, including the amygdala, anterior cingulate cortex (ACC), nucleus accumbens (NAcc), and orbitofrontal cortex (OFC). Latent variable modeling was used to examine network-level coactivation. The following diagnostic groups were compared: typically developing youths (N = 693) and youths with DBDs (N = 995), subdivided into those with callous-unemotional traits (DBD+CU, n = 198) and without callous-unemotional traits (DBD only, n = 276). During reward anticipation, youths in the overall DBD group (with and without callous-unemotional traits) showed decreased dorsal ACC activation compared with typically developing youths. The DBD-only group exhibited reduced ventral and dorsal striatal activity compared with the DBD+CU and typically developing groups. During reward receipt, youths with DBDs showed increased cortical (eg, OFC) and subcortical (eg, NAcc) regional activation compared with typically developing youths. The DBD+CU group demonstrated greater activation in several regions compared with those in the typically developing (eg, amygdala) and DBD-only (eg, dorsal ACC) groups. At the network level, the DBD-only group showed reduced anticipatory reward activation compared with the typically developing and DBD+CU groups, whereas youths in the DBD+CU group showed increased activation during reward receipt compared with those in the typically developing group. These findings advance our understanding of unique neuroetiologic pathways to DBDs and callous-unemotional traits.

Loneliness and the Social Brain: How Perceived Social Isolation Impairs Human Interactions.

Loneliness is a painful condition associated with increased risk for premature mortality. The formation of new, positive social relationships can alleviate feelings of loneliness, but requires rapid trustworthiness decisions during initial encounters and it is still unclear how loneliness hinders interpersonal trust. Here, a multimodal approach including behavioral, psychophysiological, hormonal, and neuroimaging measurements is used to probe a trust‐based mechanism underlying impaired social interactions in loneliness. Pre‐stratified healthy individuals with high loneliness scores (n = 42 out of a screened sample of 3678 adults) show reduced oxytocinergic and affective responsiveness to a positive conversation, report less interpersonal trust, and prefer larger social distances compared to controls (n = 40). Moreover, lonely individuals are rated as less trustworthy compared to controls and identified by the blinded confederate better than chance. During initial trust decisions, lonely individuals exhibit attenuated limbic and striatal activation and blunted functional connectivity between the anterior insula and occipitoparietal regions, which correlates with the diminished affective responsiveness to the positive social interaction. This neural response pattern is not mediated by loneliness‐associated psychological symptoms. Thus, the results indicate compromised integration of trust‐related information as a shared neurobiological component in loneliness, yielding a reciprocally reinforced trust bias in social dyads.

Effects of the Fyn kinase inhibitor saracatinib on ventral striatal activity during performance of an fMRI monetary incentive delay task in individuals family history positive or negative for alcohol use disorder. A pilot randomised trial.

Altered striatal regulation of the GluN2B subunit of N-methyl-D-aspartate (NMDA) glutamate receptors by the Fyn/Src family of protein tyrosine kinases has been implicated in animal alcohol consumption. Previously, we have described differences between individuals positive (FHP) and negative (FHN) for familial alcohol use disorder (AUD) in the ventral striatal (VS) activation associated with monetary incentive delay task (MIDT) performance during functional magnetic resonance imaging (fMRI). Here, we used AZD0530 (saracatinib), a centrally active Fyn/Src inhibitor to probe the role of Fyn/Src regulation of NMDA receptors (NMDAR) in VS activation differences between FHP and FHN individuals during fMRI MIDT performance. We studied 21 FHN and 22 FHP individuals, all without AUD. In two sessions, spaced 1 week apart, we administered 125 mg of saracatinib or placebo in a double-blind manner, prior to measuring VS signal during fMRI MIDT performance. MIDT comprises reward prospect, anticipation, and outcome phases. During the initial (prospect of reward) task phase, there was a significant group-by-condition interaction such that, relative to placebo, saracatinib reduced VS BOLD signal in FHP and increased it in FHN individuals. This study provides the first human evidence that elevated signaling in striatal protein kinase A-dependent pathways may contribute to familial AUD risk via amplifying the neural response to the prospect of reward. As Fyn kinase is responsible for NMDAR upregulation, these data are consistent with previous evidence for upregulated NMDAR function within reward circuitry in AUD risk. These findings also suggest a possible therapeutic role for Src/Fyn kinase inhibitors in AUD risk.

The Contribution of Premotor Cortico-Striatal Projections to the Execution of Serial Order Sequences.

Striatal activity is necessary to initiate and execute sequences of actions. The main excitatory input to the striatum comes from the cortex. While it is hypothesized that motor and premotor cortico-striatal projections are important to guide striatal activity during the execution of sequences of actions, technical limitations have made this challenging to address. Here, we implemented a task in mice that allows for the study of different moments to execute a serial order sequence consisting of two subsequences of actions. Using this task, we performed electrophysiological recordings in the premotor (M2) and primary motor (M1) cortices, and state-dependent optogenetic inhibitions of their cortico-striatal projections. We show that while both M2 and M1 contain activity modulations related to the execution of self-paced sequences, mainly, the premotor cortico-striatal projections contribute to the proper execution/structuring of these sequences.

Cocaine cue-induced mesocorticolimbic activation in cocaine users: Effects of personality traits, lifetime drug use, and acute stimulant ingestion.

Stimulant drug-paired cues can acquire the ability to activate mesocorticolimbic pathways and lead to new bouts of drug use. Studies in laboratory animals suggest that these effects are augmented by progressively greater drug use histories, impulsive personality traits, and acute drug ingestion. As a preliminary test of these hypotheses in humans, we exposed cocaine users (n = 14) and healthy volunteers (n = 10) to cocaine-related videos during two functional magnetic resonance imaging (fMRI) sessions, once following acute administration of placebo and once following d-amphetamine (0.3 mg/kg, p.o.). Across sessions, cocaine users showed larger cocaine cue-induced responses than healthy controls in the associative striatum and midbrain. Among the cocaine users, larger drug cue-induced responses during the placebo session were correlated with higher Barratt Impulsiveness Scale (BIS-11) nonplanning scores (associative striatum) and greater lifetime use of stimulant drugs (limbic, associative, and sensorimotor striatum). The administration of d-amphetamine did not augment the cue-induced activations, but, in cocaine users, drug cue-induced striatal activations were more widespread following prolonged cocaine cue exposure. Together, these effects of past and present drug use might aggravate the risk for stimulant drug use problems.

The Neural Circuitry of Reward During Sustained Threat.

Reward processing is important for understanding behavior in psychopathology. Opportunities to earn money activate the ventral striatum, as shown by the monetary incentive delay (MID) task. Anxiety conditions have been modeled by presenting shocks and startling sounds. To further investigate the co-occurrence of an anxiety condition and a rewarding stimulus, we modified the MID to include a sustained threat of scream. This study investigated neural patterns of the MID task with an uncertain threat of a startling scream. Forty-three young adults completed a functional MRI scan. The task included two conditions (scream and safe) and three cues (gain $5, gain $0, lose $5). Analyses included a whole brain, group analysis using a linear mixed-effects model and a paired t-test. The whole brain analysis revealed a main effect of cue, with increased ventral striatal activation (F2,210 = 58.8, p < 0.001) during cues to gain or lose $5. We observed a main effect of condition during cue presentation, such that bilateral insula and putamen activation was diminished (p < 0.001) in the scream versus the safe condition. A t-test of condition showed increased activation during threat blocks in the insula and putamen. A time course graph revealed that activation in the insula and putamen responded similarly to incentive but had an overall elevation during the scream condition. These results replicated expected activation in reward and in the setting of uncertain threat. Our results show that uncertain threat increases the magnitude of activation in the dorsal striatum.

Optogenetic inhibition of indirect pathway neurons in the dorsomedial striatum reduces excessive grooming in Sapap3-knockout mice.

Excessive grooming of Sapap3-KO mice has been used as a model of obsessive-compulsive disorder (OCD). Previous studies suggest that dysregulation of cortico-striatal circuits is critically important in the generation of compulsive behaviors, and it has been proposed that the alteration in the activity patterns of striatal circuitry underlies the excessive grooming observed in Sapap3-KO mice. To test this hypothesis, we used in-vivo calcium imaging of individual cells to record striatal activity in these animals and optogenetic inhibition to manipulate this activity. We identified striatal neurons that are modulated during grooming behavior and found that their proportion is significantly larger in Sapap3-KO mice compared to wild-type littermates. Inhibition of striatal cells in Sapap3-KO mice increased the number of grooming episodes observed. Remarkably, the specific inhibition of indirect pathway neurons decreased the occurrence of grooming events. Our results indicate that there is striatal neural activity related to excessive grooming engagement in Sapap3-KO mice. We also demonstrate, for the first time, that specific inhibition of striatal indirect pathway neurons reduces this compulsive phenotype, suggesting that treatments that alleviate compulsive symptoms in OCD patients may exert their effects through this specific striatal population.

Neural mapping of prepulse-induced startle reflex modulation as indices of sensory information processing in healthy and clinical populations: A systematic review.

Startle reflex is modulated when a weaker sensory stimulus (“prepulse”) precedes a startling stimulus (“pulse”). Prepulse Inhibition (PPI) is the attenuation of the startle reflex (prepulse precedes pulse by 30–500 ms), whereas Prepulse Facilitation (PPF) is the enhancement of the startle reflex (prepulse precedes pulse by 500–6000 ms). Here, we critically appraise human studies using functional neuroimaging to establish brain regions associated with PPI and PPF. Of 10 studies, nine studies revealed thalamic, striatal and frontal lobe activation during PPI in healthy groups, and activation deficits in the cortico‐striato‐pallido‐thalamic circuitry in schizophrenia (three studies) and Tourette Syndrome (two studies). One study revealed a shared network for PPI and PPF in frontal regions and cerebellum, with PPF networks recruiting superior medial gyrus and cingulate cortex. The main gaps in the literature are (i) limited PPF research and whether PPI and PPF operate on separate/shared networks, (ii) no data on sex differences in neural underpinnings of PPI and PPF, and (iii) no data on neural underpinnings of PPI and PPF in other clinical disorders.

Withania somnifera ameliorates nandrolone-decanoate-induced brain damage in rats by inhibiting cell death, prodynorphin mRNA expression and acetylcholinesterase activity

The misuse of anabolic-androgenic steroids by athletes and non-athletes causes harmful effects on the central nervous system. In Ayurvedic medicine, Withania somnifera (WS) as an herbal drug has been reported for several functions including adaptogenic, anticonvulsant, cytoprotective and antioxidant. The present study investigated the neuroprotective functions of WS (100, 200 and 400 mg/kg body weight) in nandrolone decanoate (ND)-induced (16 mg/kg body weight) brain injury in male Wistar rats. ND was injected intramuscularly twice weekly for 4 weeks. The water emulsion of WS root powder was administered orally once daily for 30 days to ND-treated rats. At the end of the experiment, anxiety-like behaviour was assessed in rats using the elevated plus maze. Haematoxylin-and-eosin-stained coronal sections of the parietal cortex and hippocampus of ND rats showed severe alterations in brain histology compared with control rats. Acetylcholinesterase (AChE) activity in the striatum and prodynorphin gene expression in the hippocampus was significantly elevated in the ND group compared with the control group. Treating ND induced rats with various doses of WS significantly reversed the brain damage, anxiety behaviour, increased striatal AChE activity and reduced prodynorphin gene expression in the hippocampus. In conclusion, WS extract can be used as a neuroprotective agent to reduce the effects of anabolic steroids.

Prefrontal and striatal dopamine D2/D3 receptors correlate with fMRI BOLD activation during stopping

D2-like dopamine receptors in animals and humans have been shown to be linked to impulsive behaviors that are highly relevant for several psychiatric disorders. Here, we investigate the relationship between the fronto-striatal D2/D3 dopamine receptor availability and response inhibition in a selected population of healthy OPRM1 G-allele carriers. Twenty-two participants successively underwent blood-oxygen level dependent functional magnetic resonance imaging (fMRI) while performing a stop-signal task and a separate positron emission tomography (PET) scan. Striatal and extrastriatal D2/D3 dopamine receptor availability was measured using the radiotracer [18F]fallypride. Caudate D2/D3 dopamine receptor availability positively correlated with stopping-related fronto-striatal fMRI activation. In addition, right prefrontal D2/D3 dopamine receptor availability correlated positively with stopping-related striatal fMRI BOLD signal. Our study partially replicates previous findings on correlations between striatal D2/D3 dopamine receptor availability and response inhibition in a population selected for its genetic determination of dopamine response to alcohol and as a modulator of impulse control via the endogenous opioid system. We confirm the important role of D2/D3 dopamine receptor availability in the fronto-striatal neural circuit for response inhibition. Moreover, we extend previous findings suggesting that dopamine receptor availability in the right inferior frontal cortex, a crucial region of the stopping network, is also strongly associated with stopping-related striatal fMRI activity in healthy OPRM1 G-allele carriers.

Brain activations associated with anticipation and delivery of monetary reward: A systematic review and meta-analysis of fMRI studies.

While multiple studies have examined the brain functional correlates of reward, meta-analyses have either focused on studies using the monetary incentive delay (MID) task, or have adopted a broad strategy, combining data from studies using both monetary and non-monetary reward, as probed using a wide range of tasks. To meta-analyze fMRI studies that used monetary reward and in which there was a definable cue-reward contingency. Studies were limited to those using monetary reward in order to avoid potential heterogeneity from use of other rewards, especially social rewards. Studies using gambling or delay discounting tasks were excluded on the grounds that reward anticipation is not easily quantifiable. English-language fMRI studies (i) that reported fMRI findings on healthy adults; (ii) that used monetary reward; and (iii) in which a cue that was predictive of reward was compared to a no win (or lesser win) condition. Only voxel-based studies were included; those where brain coverage was incomplete were excluded. Ovid, Medline and PsycInfo, from 2000 to 2020, plus checking of review articles and meta-analyses. Data were pooled using Seed-based d Mapping with Permutation of Subject Images (SDM-PSI). Heterogeneity among studies was examined using the I2 statistic. Publication bias was examined using funnel plots and statistical examination of asymmetries. Moderator variables including whether the task was pre-learnt, sex distribution, amount of money won and width of smoothing kernel were examined. Pooled data from 45 studies of reward anticipation revealed activations in the ventral striatum, the middle cingulate cortex/supplementary motor area and the insula. Pooled data from 28 studies of reward delivery again revealed ventral striatal activation, plus cortical activations in the anterior and posterior cingulate cortex. There was relatively little evidence of publication bias. Among moderating variables, only whether the task was pre-learnt exerted an influence. According to this meta-analysis monetary reward anticipation and delivery both activate the ventral but not the dorsal striatum, and are associated with different patterns of cortical activation.

Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning.

SUMMARYTuberous sclerosis complex (TSC) is a neurodevelopmental disorder that often presents with psychiatric conditions, including autism spectrum disorder (ASD). ASD is characterized by restricted, repetitive, and inflexible behaviors, which may result from abnormal activity in striatal circuits that mediate motor learning and action selection. To test whether altered striatal activity contributes to aberrant motor behaviors in the context of TSC, we conditionally deleted Tsc1 from direct or indirect pathway striatal projection neurons (dSPNs or iSPNs, respectively). We find that dSPN-specific loss of Tsc1 impairs endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses and strongly enhances corticostriatal synaptic drive, which is not observed in iSPNs. dSPN-Tsc1 KO, but not iSPN-Tsc1 KO, mice show enhanced motor learning, a phenotype observed in several mouse models of ASD. These findings demonstrate that dSPNs are particularly sensitive to Tsc1 loss and suggest that enhanced corticostriatal activation may contribute to altered motor behaviors in TSC.

Ventral Striatal–Hippocampus Coupling During Reward Processing as a Stratification Biomarker for Psychotic Disorders

BackgroundAltered ventral striatal (vST) activation to reward expectancy is a well-established intermediate phenotype for psychiatric disorders, specifically schizophrenia (SZ). Preclinical research suggests that striatal alterations are related to a reduced inhibition by the hippocampal formation, but its role in human transdiagnostic reward-network dysfunctions is not well understood. MethodsWe performed functional magnetic resonance imaging during reward processing in 728 individuals including healthy control subjects (n = 396), patients (SZ: n = 46; bipolar disorder: n = 45; major depressive disorder: n = 60), and unaffected first-degree relatives (SZ: n = 46; bipolar disorder: n = 50; major depressive disorder: n = 85). We assessed disorder-specific differences in functional vST-hippocampus coupling and transdiagnostic associations with dimensional measures of positive, negative, and cognitive symptoms. We also probed the genetic underpinning using polygenic risk scores for SZ in a subset of healthy participants (n = 295). ResultsFunctional vST-hippocampus coupling was 1) reduced in patients with SZ and bipolar disorder (pFWE < .05, small-volume corrected [SVC]); 2) associated transdiagnostically to dimensional measures of positive (pFWE = .01, SVC) and cognitive (pFWE = .02, SVC), but not negative, (pFWE > .05, SVC) symptoms; and 3) reduced in first-degree relatives of patients with SZ (pFWE = .017, SVC) and linked to the genetic risk for SZ in healthy participants (p = .035). ConclusionsWe provide evidence that reduced vST-hippocampus coupling during reward processing is an endophenotype for SZ linked to positive and cognitive symptoms, supporting current preclinical models of the emergence of psychosis. Moreover, our data indicate that vST-hippocampus coupling is familial and linked to polygenic scores for SZ, supporting the use of this measure as an intermediate phenotype for psychotic disorders.