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SYNGAP1 is a high-confidence autism spectrum disorder (ASD) risk gene, and mutations in SYNGAP1 lead to a neurodevelopmental disorder (NDD) that presents with epilepsy, ASD, motor developmental delay, and intellectual disability. SYNGAP1 codes for Ras/Rap GTP-ase activating protein SynGAP (SynGAP). SynGAP is located in the postsynaptic density of glutamatergic synapses and regulates glutamate receptor trafficking in an activity-dependent manner. In addition to forebrain glutamatergic neurons, Syngap1 is highly expressed in the striatum, although the functions of SynGAP in the striatum have not been extensively studied. Here we show that Syngap1 is expressed in both direct and indirect pathway striatal projection neurons (dSPNs and iSPNs) in mice of both sexes. In a mouse model of Syngap1 haploinsufficiency, dendritic spine density, morphology, and intrinsic excitability are altered primarily in iSPNs, but not dSPNs. At the behavioral level, SynGAP reduction alters striatal-dependent motor learning and goal-directed behavior. Several behavioral phenotypes are reproduced by iSPN-specific Syngap1 reduction and, in turn, prevented by iSPN-specific Syngap1 rescue. These results establish the importance of SynGAP to striatal neuron function and pinpoint the indirect pathway as a key circuit in the neurobiology of SYNGAP1-related NDD.

The small G-protein Ras-related C3 botulinum toxin substrate 1 (Rac1) promotes the formation of filamentous actin (F-actin). Actin is a major component of dendritic spines, and we previously found that alcohol alters actin composition and dendritic spine structure in the nucleus accumbens (NAc) and the dorsomedial striatum (DMS). To examine if Rac1 contributes to these alcohol-mediated adaptations, we measured the level of GTP-bound active Rac1 in the striatum of mice following 7 weeks of intermittent access to 20% alcohol. We found that chronic alcohol intake activates Rac1 in the DMS of male mice. In contrast, Rac1 is not activated by alcohol in the NAc and DLS of male mice or in the DMS of female mice. Similarly, closely related small G-proteins are not activated by alcohol in the DMS, and Rac1 activity is not increased in the DMS by moderate alcohol or natural reward. To determine the consequences of alcohol-dependent Rac1 activation in the DMS of male mice, we inhibited endogenous Rac1 by infecting the DMS of mice with an adeno-associated virus (AAV) expressing a dominant negative form of the small G-protein (Rac1-DN). We found that overexpression of AAV-Rac1-DN in the DMS inhibits alcohol-mediated Rac1 signaling and attenuates alcohol-mediated F-actin polymerization, which corresponded with a decrease in dendritic arborization and spine maturation. Finally, we provide evidence to suggest that Rac1 in the DMS plays a role in alcohol-associated goal-directed learning. Together, our data suggest that Rac1 in the DMS plays an important role in alcohol-dependent structural plasticity and aberrant learning.

BACKGROUND: It is well-established that parental obesity is a strong risk factor for offspring obesity. Further, a converging body of evidence now suggests that maternal weight profiles may affect the developing offsprings brain in a manner that confers future obesity risk. Here, we investigated how pre-pregnancy maternal weight status influences the reward-related striatal areas of the offsprings brain during in utero development. METHODS: We used diffusion tensor imaging to quantify the microstructure of the striatal brain regions of interest in neonates (N = 116 [66 males, 50 females], mean gestational weeks at birth [39.88], SD = 1.14; at scan [43.56], SD = 1.05). Linear regression was used to test the associations between maternal pre-pregnancy body mass index (BMI) and infant striatal mean diffusivity. RESULTS: High maternal pre-pregnancy BMI was associated with higher mean MD values in the infants left caudate nucleus. Results remained unchanged after the adjustment for covariates. CONCLUSIONS: In utero exposure to maternal adiposity might have a growth-impairing impact on the mean diffusivity of the infants left caudate nucleus. Considering the involvement of the caudate nucleus in regulating eating behavior and food-related reward processing later in life, this finding calls for further investigations to define the prognostic relevance of early-life caudate nucleus development and weight trajectories of the offspring.

The neurotransmitter acetylcholine has since long been implicated in reward learning and drug addiction. However, the role of specific cholinergic receptor subtypes on different neuronal populations remain elusive. Here, we studied the function of nicotinic acetylcholinergic alpha 7 receptors (α7 nAChRs) in cocaine and food-enforced behaviors. We found that global deletion of α7 nAChRs in mice attenuates cocaine seeking in a Pavlovian conditioned place preference paradigm and decreases operant responding to cocaine in a runway task and in self-administration, without influencing responding to palatable food. This effect can be attributed to alpha 7 receptor signaling in the striatum, as selective deletion of striatal α7 nAChRs using a viral vector approach resulted in a similar decrease in cocaine-preference as that of global deletion. To investigate which type of striatal neurons are responsible for this effect, we selectively targeted Cholinergic (ChAT-expressing) neurons and dopamine D1-receptor (D1R) expressing neurons. Mice with conditional deletion of α7 nAChRs in ChAT-neurons (α7 nAChR-ChATCre) exhibited decreased cocaine place preference and intact place preference for food, while α7 nAChR-D1RCre mice had no changes in reward learning to neither food nor cocaine. Cocaine induction of striatal immediate early gene expression of cFos, FosB, Arc and EGR2 was blocked in α7 nAChR-ChATCre mice, demonstrating the importance of α7 nAChRs on cholinergic neurons for striatal neuronal activity changes. Collectively, our findings show that α7 nAChRs on cholinergic interneurons in the striatum are pivotal for learning processes related to cocaine, but not food reward. [ABSTRACT FROM AUTHOR]

Modulating role of circRNAs and microRNAs in neurobiological changes induced by drug exposure remains unclear. We examined alterations in some circRNAs and microRNAs in the striatum after morphine dependence and withdrawal and their associations with the changes in spatial working memory performance. Male Wistar rats were used in which 10 days morphine exposure induced dependence. Withdrawal effects were assessed 30 days after stopping morphine exposure. Spatial working memory was assessed using a Y maze test on days 1 and 10 of the drug exposure and 30 days after withdrawal. The gene and protein expression were assessed after dependence and withdrawal. The results revealed that 10 days morphine exposure impaired working memory, which partially reinstated after withdrawal. After 10 days morphine exposure, significant increases in Oprm1 gene and OPRM1 protein levels were detected, which persisted even after withdrawal. The expression of circOprm1 and miR-339-3p decreased in the morphine-dependent group, but they returned to normal levels after withdrawal. The expression of Tlr4 gene and TLR4 protein levels decreased after dependence. While Tlr4 mRNA levels returned to normal after withdrawal, TLR4 protein levels remained lower than the control group. In the morphine-dependent group, both Serpini1 and circSerpini expression significantly increased, but they restored after withdrawal. Expression of miR-181b-3p, miR-181b-5p, miR-181c-3p, and miR-181c-5p decreased after dependence, but they reinstated after withdrawal. It can be concluded that circOprm1 and circSerpini via regulating the OPRM1 and TLR4 expression in the striatum are associated with the neuroadaptation underlying spatial working memory after both morphine dependence and withdrawal. [ABSTRACT FROM AUTHOR]

Background: Vascular cognitive impairment (VCI) is a significant contributor to dementia, yet the precise mechanisms underlying the cognitive decline associated with chronic cerebral hypoperfusion (CCH) remain unclear. This study investigated the molecular and epigenetic changes in the striatum, a brain region critical for motor function and cognition, following chronic hypoperfusion using a bilateral common carotid artery stenosis (BCAS) model in mice. Methods: RNA-seq was utilized to identify differentially expressed genes (DEGs) associated with hypoperfusion. In parallel, ATAC-seq was used to assess changes in chromatin accessibility within the striatum, providing insight into the epigenome and potential regulatory mechanisms. The integration of these datasets allowed us to correlate chromatin accessibility with transcriptional activity and to identify key transcription factors driving the observed gene expression changes. Results: Analysis of striatum-specific transcriptome revealed significant upregulation of immune response genes, particularly type II interferon signaling, and downregulation of neural activation pathways. Analysis of striatum-specific epigenome showed increased chromatin accessibility at promoters of immune-related genes. Integrated analysis highlighted PU.1 as a key transcription factor in upregulated pathways, while neural pathways lacked epigenetic regulation, revealing distinct molecular responses in the striatum following chronic hypoperfusion. Conclusions: Our findings indicate that upregulated pathways in the striatum following BCAS-induced CCH are driven by epigenetic changes, while downregulated pathways occur independently of these modifications. Additionally, PU.1 plays a critical role in mediating immune responses, offering a potential target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

The mammalian striatum is divided into two types of anatomical structures: the island-like, µ-opioid receptor (MOR)-rich striosome compartment and the surrounding matrix compartment. Both compartments have two types of spiny projection neurons (SPNs), dopamine receptor D1 (D1R)-expressing direct pathway SPNs (dSPNs) and dopamine receptor D2 (D2R)-expressing indirect pathway SPNs. These compartmentalized structures have distinct roles in the development of movement disorders, although the functional significance of the striosome compartment for motor control and dopamine regulation remains to be elucidated. The aim of this study was to explore the roles of striosome in locomotion and dopamine dynamics in freely moving mice. We targeted striosomal MOR-expressing neurons with male MOR-CreER mice, which express tamoxifen-inducible Cre recombinase under MOR promoter, and Cre-dependent adeno-associated virus vector. The targeted neuronal population consisted mainly of dSPNs. We found that the Gq-coupled designer receptor exclusively activated by designer drugs (DREADD)-based chemogenetic stimulation of striatal MOR-expressing neurons caused a decrease in the number of contralateral rotations and total distance traveled. Wireless fiber photometry with a genetically encoded dopamine sensor revealed that chemogenetic stimulation of striatal MOR-expressing neurons suppressed dopamine signals in the dorsal striatum of freely moving mice. Furthermore, the decrease in mean dopamine signal and the reduction of transients were associated with ipsilateral rotational shift and decrease of average speed, respectively. Thus, a subset of striosomal dSPNs inhibits contralateral rotation, locomotion, and dopamine release in contrast to the role of pan-dSPNs. Our results suggest that striatal MOR-expressing neurons have distinct roles in motor control and dopamine regulation. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is one of the major causes of severe neurological disorders and long-term dysfunction in the nervous system. Besides inducing neurodegeneration, TBI alters stem cell activity and neurogenesis within primary neurogenic niches. However, the fate of dividing cells in other brain regions remains unclear despite offering potential targets for therapeutic intervention. Here, we investigated cell division and differentiation in non-neurogenic brain regions during the acute and delayed phases of TBI-induced neurodegeneration. We subjected mice to lateral fluid percussion injury (LFPI) to model TBI and analyzed them 1 or 7 weeks later. To assess cellular proliferation and differentiation, we administered 5-ethinyl-2′-deoxyuridine (EdU) and determined the number and identity of dividing cells 2 h later using markers of neuronal precursors and astro-, micro-, and oligodendroglia. Our results demonstrated a significant proliferative response in several brain regions at one week post-injury that notably diminished by seven weeks, except in the optic tract. In addition to active astro- and microgliosis, we detected oligodendrogenesis in the striatum and optic tract. Furthermore, we observed trauma-induced neurogenesis in the striatum. These findings suggest that subcortical structures, particularly the striatum and optic tract, may possess a potential for self-repair through neuronal regeneration and axon remyelination. [ABSTRACT FROM AUTHOR]

[Display omitted] • Astrocytic Ca2+ signals in the dorsal striatum are linked to exercise-induced fatigue. • Increased astrocytic Ca2+ signaling reduces endurance. • Raised astrocytic Ca2+ signaling impairs corticostriatal long-term depression (LTD). • Decreased astrocytic Ca2+ signaling prolongs endurance and ameliorates LTD. • Astrocytic Ca2+ dynamics are associated with central fatigue and synaptic plasticity. Exercise-induced fatigue (EF) is characterized by a decline in maximal voluntary muscle force following prolonged physical activity, influenced by both peripheral and central factors. Central fatigue involves complex interactions within the central nervous system (CNS), where astrocytes play a crucial role. This study explores the impact of astrocytic calcium signals on EF. We used adeno-associated viruses (AAV) to express GCaMP7b in astrocytes of the dorsal striatum in mice, allowing us to monitor calcium dynamics. Our findings reveal that EF significantly increases the frequency of spontaneous astrocytic calcium signals. Utilizing genetic tools to either enhance or reduce astrocytic calcium signaling, we observed corresponding decreases and increases in exercise-induced fatigue time, respectively. Furthermore, modulation of astrocytic calcium signals influenced corticostriatal synaptic plasticity, with increased signals impairing and decreased signals ameliorating long-term depression (LTD). These results highlight the pivotal role of astrocytic calcium signaling in the regulation of exercise-induced fatigue and synaptic plasticity in the striatum. [ABSTRACT FROM AUTHOR]

The expression of GABAARs goes through large scale, evolutionarily conserved changes through the early postnatal period. While these changes have been well-studied in brain regions such as the hippocampus and sensory cortices, less is known about early developmental changes in other brain areas. The nucleus accumbens (NAc) is a major hub in the circuitry that mediates motivated behaviors and disruptions in NAc activity is a part of the neuropathology observed in mood and substance use disorders. Considering the importance of early developmental disruptions in the vulnerability to and etiology of these disorders, it is essential to understand normal developmental changes in the NAc as a first step to understanding how these changes might be disrupted to cause long-term pathology. Here, we aimed to address the gap in knowledge of early developmental changes in GABAAR expression in NAc neurons. We investigated the expression patterns of GABAAR α1, α2, and α4 subunits in Drd1+, Drd2+, and putative hybrid medium spiny neurons (MSNs) of the mouse NAc over a developmental window from P2 to P16. Our findings show a consistent increase in expression of all 3 GABAAR subunits in Drd1+ MSNs, accompanied by stable expression or even a decrease in expression in Drd2+ MSNs. The putative hybrid population showed a complex expression pattern, usually showing maximum expression at P9. These early developmental changes likely suggest a specific window where GABAAR expression patterns adjust to increasing glutamatergic inputs from external sources, changes in intracellular chloride concentrations, and a switch towards the mature, bistable activity patterns of MSNs from the immature, relatively excitable singular pattern. We propose that this time of dynamic changes in GABAAR expression could represent a sensitive period during which developmental insults might lead to permanent disruptions in GABAAR expression patterns. [ABSTRACT FROM AUTHOR]

ObjectiveMethodsResultsConclusionsBrain ischemia is considered an extremely potent stress factor at the cellular and molecular level which may lead to massive neuronal death. Alternatively, short brain ischemia and reperfusion (I/R) can actually stimulate neurogenesis, angiogenesis and peptidergic signaling. There is little known about the potential effect of I/R on brain expression of the novel neuropeptide; phoenixin (PNX) and its receptor GPR173.The study was carried out on adult male Wistar rats divided into seven groups: control, sham operation and 5 ischemic experimental groups across the time course of reperfusion. We examined mRNA and protein expression of GPR173 and neurogenesis markers Musashi-1, doublecortin (DCX), and Sox-2 in the striatum.GPR-173 positive cells were found only in the ischemic hemisphere, where Musashi-1, DCX and Sox-2-positive cells were also observed. Gene expression analysis also showed a significant increase of GPR-173 mRNA level in the I/R striatum in comparison with the control one. Results confirm previous findings suggesting that I/R stimulates adult neurogenesis in the striatum and affects peptidergic signaling in this structure.A very fast occurence of GPR-173 expression revealed in the striatum may potentially be exclusively related to neuroprotective neurochemical changes that occur in this region after I/R. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Slow‐acting biogenic amines, such as dopamine, are known to modulate fast neurotransmitters e.g. glutamate. In the striatum, dopamine (DA) interacts with glutamate, influencing neural excitability and promoting synaptic plasticity. The exact mechanism of such interaction is not fully understood. This study investigates, in detail, how dopamine overactivity in dopamine transporter knockout (DAT−/−) rats, alters the homeostasis of the striatal glutamate synapse from a molecular, behavioural and functional point of view.The expression, localisation, retention and electrophysiological properties of N‐methyl‐D‐aspartate (NMDA) receptors as well as dendritic spine density and morphology were investigated in the striatum of DAT−/− rats, at baseline and after treatment with the non‐competitive NMDA receptor antagonist memantine (30 mg kg−1).Dopamine overactivity dramatically reorganises the striatal glutamate synapse, redistributing NMDA receptors in the synapse as typified by reduced synaptic availability and reduced expression of NMDA scaffolding proteins, as well as by increased GluN2B‐containing NMDA receptors in the extra synapse. Such changes are accompanied by reduced spine density, suggesting dopamine‐induced structural rearrangements. These results converge into a compromised plasticity, as shown by the impaired ability to promote long‐term depression (LTD) in the striatum of DAT−/−rats. Notably, memantine counteracts hyperlocomotion, reverses spine alterations and abolishes the extrasynaptic movements of NMDA receptors in the striatum of DAT−/− rats, thus restoring functional LTD.A hyperdopaminergic condition seems to alter striatal homeostasis by increasing extrasynaptic NMDA receptors. These findings may be relevant to manipulate disorders characterised by elevated dopaminergic activity. [ABSTRACT FROM AUTHOR]

• The transcriptome characteristics of CSDS were more focused on neuronal and synapse. • The transcriptome characteristics of FMT were more focused on inflammation. • The common transcriptome characteristics of two models was energy metabolism. • The CSDS had large more alternative splicing events than FMT. Depression is a complex disorder with multiple contributing factors, and chronic stress has previously been recognized as a major causative factor, while gut microbes have also been found to be involved in depression recently. However, gene expression in depression models with different etiologies is unclear. Here, we compared the transcriptomes of the striatum in chronic social defeat stress (CSDS) model of C57BL/6J male mice and fecal microbiota transplant (FMT) model of Kumming male mice. We found that the proportion of shared differentially expressed genes (DEGs) between the two models was only 24 %. The specific DEGs of FMT model were enriched in immune and inflammatory, and are associated with changes in vascular and ciliated ependymal cells. The specific DEGs of CSDS model were enriched in neuron and synapse. The results of network analysis suggested the expression patterns and biological function of depressive-like behaviors-related modules in the two models are different. Further, the alternative splicing events of CSDS are more than FMT. Our results suggested models of depression induced by different etiologies differ significantly in gene expression and biological function. Our study also suggested us to pay attention to the characteristics of models of depression of different etiologies and provided a more comprehensive understanding of the heterogeneity of depression. [ABSTRACT FROM AUTHOR]

Behaving as desired requires selecting the appropriate behavior and inhibiting the selection of inappropriate behavior. This inhibitory function involves multiple processes, such as reactive and proactive inhibition, instead of a single process. In this study, two male macaque monkeys were required to perform a task in which they had to sequentially select (accept) or refuse (reject) a choice. Neural activity was recorded from the anterior striatum, which is considered to be involved in behavioral inhibition, focusing on the distinction between proactive and reactive inhibitions. We identified neurons with significant activity changes during the rejection of bad objects. Cluster analysis revealed three distinct groups, of which only one showed increased activity during object rejection, suggesting its involvement in proactive inhibition. This activity pattern was consistent irrespective of the rejection method, indicating a role beyond saccadic suppression. Furthermore, minimal activity changes during the fixation task indicated that these neurons were not primarily involved in reactive inhibition. In conclusion, these findings suggest that the anterior striatum plays a crucial role in cognitive control and orchestrates goal-directed behavior through proactive inhibition, which may be critical in understanding the mechanisms of behavioral inhibition dysfunction that occur in patients with basal ganglia disease. [ABSTRACT FROM AUTHOR]

Background: L-DOPA has been considered the first-line therapy for treating Parkinson's disease (PD) via restoring striatal dopamine (DA) to normalize the activity of local spiny projection neurons (SPNs) in the direct (dSPNs) pathway and the indirect (iSPNs) pathway. While the changes in striatal acetylcholine (ACh) induced by increasing DA have been extensively discussed, their validity remains controversial. Inhibition of striatal cholinergic signaling attenuates PD motor deficits. Interestingly, enhancing striatal ACh triggers local DA release, suggesting the pro-kinetic effects of ACh in movement control. Here, we investigated the in-vivo dynamics of ACh in the dorsolateral striatum (DLS) of the 6-OHDA-lesioned mouse model after L-DOPA administration, as well as its underlying mechanism, and to explore its modulatory role and mechanism in parkinsonian symptoms. Results: Using in vivo fiber photometry recordings with genetically encoded fluorescent DA or ACh indicator, we found L-DOPA selectively decreased DLS ACh levels in parkinsonian conditions. DA inhibited ACh release via dopamine D2 receptors and dSPNs-mediated activation of type-A γ-aminobutyric acid receptors on cholinergic interneurons. Restoring DLS ACh levels during L-DOPA treatment induced additional DA release by activating nicotinic acetylcholine receptors, thereby promoting the activity of dSPNs and iSPNs. Enhancing DLS ACh facilitated L-DOPA-induced turning behavior but not dyskinesia in parkinsonian mice. Conclusions: Our results demonstrated that enhancing striatal ACh facilitated the effect of L-DOPA by modulating DA tone. It may challenge the classical hypothesis of a purely competitive interaction between dopaminergic and cholinergic neuromodulation in improving PD motor deficits. Modulating ACh levels within the dopaminergic system may improve striatal DA availability in PD patients. [ABSTRACT FROM AUTHOR]

Schizophrenia (SCH) is a chronic and serious mental illness which puts an enormous burden on the individual, families, and society. It is well established that altered dopamine signaling and excitatory‐inhibitory imbalance contributes to the symptoms of schizophrenia. Recent neuroimaging and histological studies suggest that the striatum is a key area involved in SCH, however, our knowledge of how specific cell neuronal subtypes of certain subcortical structures may be impaired is incomplete. To this date, no detailed investigation of the putamen has ever been published regarding neuroanatomical changes in SCH. Here we tested whether the density of calretinin immunopositive (CR+) neurons and DARPP32+ neurons is altered in the putamen of patients with SCH. We used immunohistochemistry to reveal CR+ and DARPP32+ neurons in six samples from patients with SCH and six age‐ and gender‐matched control subjects. In line with previous studies, we detected small, medium, and large CR+ neurons. The density of small CR+ neurons was significantly lower in SCH (p = 0.0076). Medium and large CR+ and DARPP32+ neuronal density was not significantly different between groups. The present study substantiates previous results showing significantly lower density of small CR+ interneurons in the caudate nucleus in samples from patients with schizophrenia, highlighting the involvement of the striatum in the disorder. Our results warrant further studies focusing on the role of CR+ interneurons in the regulation of information processing in the fronto‐striatal networks, evidently key structures in schizophrenia. [ABSTRACT FROM AUTHOR]

Background/Objectives: Antipsychotic medicines are used to treat several psychological disorders and some symptoms caused by dementia and schizophrenia. Haloperidol (Hal) is a typical antipsychotic usually used to treat psychosis; however, its use causes motor or extrapyramidal symptoms (EPS) such as catalepsy. Hal blocks the function of presynaptic D2 receptors on cholinergic interneurons, leading to the release of acetylcholine (ACh), which is hydrolyzed by the enzyme acetylcholinesterase (AChE). Methods: This study was designed to investigate the Hal-inhibitory effects on AChE activity in regions representative of the cholinergic system of mice and potential associations between cataleptic effects generated by Hal using therapeutic doses and their inhibitory effects on AChE. Results: The distribution of the AChE activity in the different regions of the brain followed the order striatum > hippocampus > (prefrontal cortex/hypothalamus/ cerebellum) > brainstem > septo-hippocampal system. In ex vivo assays, Hal inhibited AChE activity obtained from homogenate tissue of the striatum, hippocampus, and septo-hippocampal system in a concentration-dependent manner. The inhibitory concentration of 50% of enzyme activity (IC50) indicated that the septo-hippocampal system required a higher concentration of Hal (IC50 = 202.5 µmol·L−1) to inhibit AChE activity compared to the striatum (IC50 = 162.5 µmol·L−1) and hippocampus (IC50 = 145 µmol·L−1). In in vivo assays, male Swiss mice treated with concentrations of Hal higher than 0.1 mg·kg−1 induced cataleptic effects. Positive correlations with Spearman's correlation were observed only between the lack of cataleptic effect and the decreased AChE activity of the hippocampus in the mice treated with 0.01 mg·kg−1 of Hal but not in the striatum and septo-hippocampal system. Conclusions: Our results suggest that Hal could increase cholinergic effects via AChE inhibition, in addition to its dopamine antagonist effect, as an alternative approach to the treatment of behavioral disturbances associated with dementia. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive, neurodegenerative disease characterized by motor dysfunction and dopamine deficits. The MitoPark (MP) mouse model of PD recapitulates several facets of Parkinson's disease, including gradual development of motor deficits, which enables the study of potential therapeutic interventions. One therapeutic strategy involves decreasing the mitochondrial metabolic load by inducing ketosis and providing an alternative energy source for neurons, leading to decreased neuronal oxidative stress. Thus, we hypothesized that administration of a ketone ester–enriched diet (KEED) would improve motor and dopamine release deficits in MP mice. Motor function (rotarod and open field tests), dopamine release (fast‐scan cyclic voltammetry), tissue dopamine levels (gas chromatography–mass spectrometry) and dopamine neurons and axons (immunofluorescence) were assessed in MP, and control mice fed either the standard or a KEED. When started on the ketone diet before motor dysfunction onset, MP mice had improved motor function relative to standard diet (SD) MP mice. While the KEED did not preserve dopamine neurons or striatal dopamine axons, dopamine release in ketone diet MP mice was greater than SD MP mice but less than control mice. In a follow‐up experiment, we began the ketone diet after motor dysfunction onset and observed a modest preservation of motor function in ketone diet MP mice relative to SD MP mice. The improvement in motor dysfunction indicates that a KEED or ketone supplement may have a beneficial effect on delaying motor deficit progression in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Cognitive flexibility, the capacity to adapt behaviour to changes in the environment, is impaired in a range of brain disorders, including schizophrenia and Parkinson's disease. Putative neural substrates of cognitive flexibility include mesencephalic pathways to the ventral striatum (VS) and dorsomedial striatum (DMS), hypothesized to encode learning signals needed to maximize rewarded outcomes during decision‐making. However, it is unclear whether mesencephalic projections to the ventral and dorsal striatum are distinct in their contribution to flexible reward‐related learning. Here, rats acquired a two‐choice spatial probabilistic reversal learning (PRL) task, reinforced on an 80%|20% basis (correct|incorrect responses) that assessed the flexibility of behaviour to repeated reversals of response‐outcome contingencies. We report that optogenetic stimulation of projections from the ventral tegmental area (VTA) to the nucleus accumbens shell (NAcS) in the VS significantly impaired reversal learning when optical stimulation was temporally aligned with negative feedback (i.e., reward omission). VTA → NAcS stimulation during other phases of the behavioural task was without significant effect. Optogenetic stimulation of projection neurons from the substantia nigra (SN) to the DMS, aligned either with reward receipt or omission or prior to making a choice, had no significant effect on reversal learning. These findings are consistent with the notion that increased activity in the VTA → NAcS pathway disrupts behavioural flexibility by impairing learning from negative reinforcement. [ABSTRACT FROM AUTHOR]

Background/Objectives: Dopamine replacement therapy for Parkinson's disease (PD) may lead to disabling incontrollable movements known as L-DOPA-induced dyskinesias. Transcranial magnetic stimulation (TMS) has been applied as non-invasive therapy to ameliorate motor symptoms and dyskinesias in PD treatment. Recent studies have shown that TMS-induced motor effects might be related to dopaminergic system modulation. However, the mechanisms underlying these effects of TMS are not fully understood. Objectives: To assess the expression of FosB and c-Fos in dopamine-D1 receptor-containing cells of dyskinetic rats and to analyze the effect of TMS on dyskinetic behavior and its histological marker (FosB). Methods: We investigated the outcome of TMS on cellular activation, using c-Fos immunoreactivity, on D1 receptor-positive (D1R+) cells into the motor cortex and striatum of dyskinetic (n = 14) and intact rats (n = 14). Additionally, we evaluated the effect of TMS on the dyskinesia global score and its molecular marker, FosB, in the striatum (n = 67). Results: TMS reduces c-Fos expression in D1R+cells into the motor cortex and striatum. Moreover, TMS treatment attenuated dyskinesias, along with a low stratal FosB expression. Conclusions: The current study shows that TMS depressed FosB and c-Fos expression in D1R+ cells of the dorsal striatum and motor cortex, in accordance with previous evidence of its capacity to modulate the dopaminergic system, thus suggesting a mechanism by which TMS may mitigate dyskinesias. Additionally, our observations highlight the potential therapeutic effect of TMS on dyskinesias in a PD model. [ABSTRACT FROM AUTHOR]

Circuit influences on the midbrain dopamine system are crucial to adaptive behavior and cognition. Recent developments in the study of neuropeptide systems have enabled high‐resolution investigations of the intersection of neuromodulatory signals with basal ganglia circuitry, identifying the nociceptin/orphanin FQ (N/OFQ) endogenous opioid peptide system as a prospective regulator of striatal dopamine signaling. Using a prepronociceptin‐Cre reporter mouse line, we characterized highly selective striosomal patterning of Pnoc mRNA expression in mouse dorsal striatum, reflecting the early developmental expression of Pnoc. In the ventral striatum, Pnoc expression in the nucleus accumbens core was grouped in clusters akin to the distribution found in striosomes. We found that PnoctdTomato reporter cells largely comprise a population of dopamine receptor D1 (Drd1) expressing medium spiny projection neurons localized in dorsal striosomes, known to be unique among striatal projection neurons for their direct innervation of midbrain dopamine neurons. These findings provide a new understanding of the intersection of the N/OFQ system among basal ganglia circuits with particular implications for developmental regulation or wiring of striato‐nigral circuits. [ABSTRACT FROM AUTHOR]