Striatum Research Articles

Chronic silencing of subsets of cortical layer 5 pyramidal neurons has a long-term influence on the laminar distribution of parvalbumin interneurons and the perineuronal nets.

Neural networks are established throughout cortical development, which require the right ratios of glutamatergic and GABAergic neurons. Developmental disturbances in pyramidal neuron number and function can impede the development of GABAergic neurons, which can have long-lasting consequences on inhibitory networks. However, the role of deep-layer pyramidal neurons in instructing the development and distribution of GABAergic neurons is still unclear. To unravel the role of deep-layer pyramidal neuron activity in orchestrating the spatial and laminar distribution of parvalbumin neurons, we selectively manipulated subsets of layer 5 projection neurons. By deleting Snap25 selectively from Rbp4-Cre + pyramidal neurons, we abolished regulated vesicle release from subsets of cortical layer 5 projection neurons. Our findings revealed that chronically silencing subsets of layer 5 projection neurons did not change the number and distribution of parvalbumin neurons in the developing brain. However, it did have a long-term impact on the laminar distribution of parvalbumin neurons and their perineuronal nets in the adult primary motor and somatosensory cortices. The laminar positioning of parvalbumin neurons was altered in layer 4 of the primary somatosensory cortex in the adult Snap25 cKO mice. We discovered that the absence of layer 5 activity only had a transient effect on the soma morphology of striatal PV neurons during the third week of postnatal development. We also showed that the relationship between parvalbumin neurons and the perineuronal nets varied across different cortical layers and regions; therefore, their relationship is far more complex than previously described. The current study will help us better understand the bidirectional interaction between deep-layer pyramidal cells and GABAergic neurons, as well as the long-term impact of interrupting pyramidal neuron activity on inhibitory network formation.

Direct Pathway Neurons in the Mouse Ventral Striatum Are Active During Goal-Directed Action but Not Reward Consumption During Operant Conditioning

Background/Objectives: Learning is classically modeled to consist of an acquisition period followed by a mastery period when the skill no longer requires conscious control and becomes automatic. Dopamine neurons projecting to the ventral striatum (VS) produce a teaching signal that shifts from responding to rewarding or aversive events to anticipating cues, thus facilitating learning. However, the role of the dopamine-receptive neurons in the ventral striatum, particularly in encoding decision-making processes, remains less understood. Methods: Here, we introduce an operant conditioning paradigm using open-source microcontrollers to train mice in three sequential learning phases. Phase I employs classical conditioning, associating a 5 s sound cue (CS) with a sucrose–water reward. In Phase II, the CS is replaced by a lever press as the requirement for reward delivery, marking an operant conditioning stage. Phase III combines these elements, requiring mice to press the lever during the CS to obtain the reward. We recorded calcium signals from direct pathway spiny projection neurons (dSPNs) in the VS throughout the three phases of training. Results: We find that dSPNs are specifically engaged when the mouse makes a decision to perform a reward-seeking action in response to a CS but are largely inactive during actions taken outside the CS. Conclusions: These findings suggest that direct pathway neurons in the VS contribute to decision-making in learned action–outcome associations, indicating a specialized role in initiating operant behaviors.

Striatal and peripheral dopaminergic alterations related to cognitive impairment in patients with schizophrenia

Abstract Background Cognitive impairment, a major determinant of poor functioning in schizophrenia, had limited responses to existing antipsychotic drugs. The limited efficacy could be due to regional differences in the dysregulation of the dopamine system. This study investigated striatal and peripheral dopaminergic makers in schizophrenia and their relationship with cognitive impairment. Methods Thirty-three patients with schizophrenia and 36 age- and sex-matched healthy controls (HC) participated. We evaluated their cognitive performance, examined the availability of striatal dopamine transporter (DAT) using single-photon emission computed tomography with 99mTc-TRODAT, and measured plasma levels of dopaminergic precursors (phenylalanine and tyrosine) and three branched-chain amino acids (BCAA) that compete with precursors for brain uptake via ultra-performance liquid chromatography. Results Schizophrenia patients exhibited lower cognitive performance, decreased striatal DAT availability, and reduced levels of phenylalanine, tyrosine, leucine, and isoleucine, and the ratio of phenylalanine plus tyrosine to BCAA. Within the patient group, lower DAT availability in the left caudate nucleus (CN) or putamen was positively associated with attention deficits. Meanwhile, lower tyrosine levels and the ratio of phenylalanine plus tyrosine to BCAA were positively related to executive dysfunction. Among all participants, DAT availability in the right CN or putamen was positively related to memory function, and plasma phenylalanine level was positively associated with executive function. Conclusions This study supports the role of dopamine system abnormalities in cognitive impairment in schizophrenia. The distinct associations between different dopaminergic alterations and specific cognitive domain impairments suggest the potential need for multifaceted treatment approaches to target these impairments.

Baseline-dependent enhancement of working memory by memantine in male rats: Involvement of NMDA receptor subunits and CaMKII signaling

N-methyl-d-aspartate (NMDA) receptors, activated by glutamate, play a crucial role in learning and memory. Memantine (MEM), a non-competitive NMDA receptor antagonist, is currently prescribed for the treatment of Alzheimer's disease or dementia, which meanwhile simultaneously promotes a need to clarify its potential pro-cognitive effects that exist in normal healthy individuals. However, the neurobehavioral mechanisms underlying the cognitive improvement by MEM in normal individuals remain to be elucidated. This study aimed to assess the effects of MEM on working memory, measured by a discrete paired-trial delay alternation task in a T-maze in normal male rats. The impacts of MEM were hypothesized to vary depending on different baseline levels of working memory performance. Neurochemical examination of the levels of calcium/calmodulin-dependent kinase 2 (CaMKII) and NMDA receptor subunits within five targeted brain regions was conducted after behavioral tests. The results showed that acute administration of MEM enhanced working memory performance, with 2.5, 5.0, and 10 mg/kg doses increasing task accuracy compared to the vehicle, particularly in low performers. Neurochemically, the protein expression of CaMKII in the amygdala and that of the glutamate (Glu) N2A subunit in the dorsal striatum were greater in the low-performance group than in the high-performance group. Additionally, the protein expression of the GluN2A subunit in the dorsal striatum was negatively associated with task performance at baseline. The expression of GluN1 and GluN2B in the nucleus accumbens was negatively associated with task performance in the retest three weeks after drug treatment. These findings underscore the baseline-dependent improvement of working memory resulting from MEM administration, with observed drug effects associated with alterations in the levels of NMDA receptor subunits in striatal subareas and CaMKII in the amygdala.

Influence of extreme light/dark cycles on monoamine levels, physiological indices, and emotional behaviors in rats

ABSTRACT Aberrant light/dark (LD) cycles are prevalent in modern society due to electric light usage, leading to mood disorders from circadian disruption or misalignment. However, research on the physiological and behavioral effects of LD variations on brain neurotransmitters is limited. We investigated the effects of extreme LD cycles on body weight (BW), core body temperature (Tcore), locomotor activity (ACT), emotional behaviors, and monoamine levels (noradrenaline [NA], dopamine [DA], and serotonin [5-HT]) in male Wistar rats that were exposed to 1 month of either long light phase (20 L:4D), long dark phase (4 L:20D), or normal (12 L:12D) LD cycles. The 20 L:4D rats exhibited blunted rhythms, with decreased amplitude and advanced/delayed acrophase in Tcore and ACT, alongside increased BW. The 4 L:20D rats showed circadian misalignment, with increased/decreased amplitude in Tcore or ACT and delayed acrophase in Tcore and ACT, also gaining BW. In the 20 L:4D group, NA and 5-HT levels decreased in the suprachiasmatic nucleus and amygdala, respectively, while the 4 L:20D group had increased DA and 5-HT levels in the caudate putamen and dorsomedial hypothalamus, respectively. Open field and social interaction tests indicated anxiety-like behaviors in both test groups. Overall, each extreme LD cycle affected Tcore, ACT amplitude, acrophase, and monoamine levels differently, inducing anxiogenic responses.

Oxytocin reduces methylphenidate-induced dorsal striatal dopamine release in male rhesus macaques.

Oxytocin is being evaluated as potential treatment for psychostimulant use disorders. It is unknown what effect oxytocin has on dopamine signaling in response to psychostimulants in brain regions such as the striatum where oxytocin and dopamine interact to process natural rewards. We investigated the effect of oxytocin on striatal dopamine release stimulated by methylphenidate whose mechanism of action is analogous to that of cocaine. We conducted an [11C] raclopride positron emission tomography study to assess striatal dopamine release in male rhesus macaques treated with oxytocin (80 IU) [administered via the intranasal (N=5) and intravenous (N=6) routes] followed by methylphenidate/[11C] raclopride. Oxytocin delivered by both routes significantly reduced methylphenidate-stimulated dopamine release in the dorsal striatum (caudate/putamen). These effects were, in part, evidenced by a reduction in dorsal striatal [11C] raclopride binding potential (increased dopamine release) following oxytocin administration. The results provide translational and mechanistic evidence for the potential role of oxytocin as a treatment for psychostimulant use disorders.

Transcranial Magnetic Stimulation Attenuates Dyskinesias and FosB and c-Fos Expression in a Parkinson’s Disease Model

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.

Traumatic brain injury, alone or with striatal hemorrhage-like extension, transiently decreases GABA and glutamate levels along motor deficits in the rat striatum: an in vivo study

The cerebral cortex is connected to the striatum via the axons of the pyramidal glutamatergic neurons, and this pathway is intimately involved in motor function. In the striatum, glutamatergic afferents initiate the activity of GABAergic medium spiny neurons. This study addressed whether traumatic brain injury (TBI) affects GABA and glutamate extracellular levels in the dorsal striatum as an indicator of effects on the cortico-striatal pathway, in rats with motor deficits and recovered animals. Animals were assigned to a sham group, a TBI-alone group, and a TBI + striatal injury group (local injection of a FeCl2 solution to mimic hemorrhagic lesion). In the TBI-alone and TBI + striatal injury groups, motor deficits were accompanied by decreased extracellular GABA and glutamate levels in the striatum at 3 days post-injury. The TBI + striatal injury group showed higher motor deficits, which lasted 7 days longer, and GABA levels were significantly different compared to the TBI alone group. At 18 days post-injury, in recovered rats from the TBI-alone group GABA and glutamate levels returned to control levels. Alterations in extracellular GABA and glutamate levels indicate damage to the cortico-striatal pathway, underscoring the importance of studying this pathway for treatment and recovery after TBI.

GPR88 impairs the signaling of kappa opioid receptors in a heterologous system and in primary striatal neurons

The physiological role of GPR88, an orphan G protein-coupled receptor (GPCR) predominantly expressed in the striatum, remains unclear, despite its altered expression in parkinsonian animal models. GPR88 is known to interact with other GPCRs. Specifically, GPR88 expression inhibits signaling mediated by the μ-opioid receptor in cells coexpressing both receptors. The effect of GPR88 on the kappa-opioid receptor (KOR) is less understood. In this study, we examine the interaction between GPR88 and KOR, and the impact of GPR88 expression on KOR-mediated signaling in heterologous cells and primary striatal neurons. Bioluminescence resonance energy transfer and proximity ligation assays revealed an interaction between GPR88 and KOR. Functional assays showed that GPR88 antagonized the effects of U69,593, a selective KOR agonist, on forskolin-stimulated cAMP levels, β-arrestin-2 recruitment, and phosphorylation of extracellular signal-regulated kinases (ERK1/2) in HEK-293T cells coexpressing both receptors. In primary striatal neurons, GPR88 and KOR complexes were observed, with KOR activation effects enhanced when GPR88 expression was suppressed using RNA interference. These results suggest that GPR88 and KOR are coexpressed in striatal neurons, where GPR88 inhibits KOR activation. Notably, the GPR88-KOR heteromer was more prevalent in dopamine D1-receptor-containing neurons of the direct pathway of the basal ganglia. Given the roles of KORs in dopamine release, motor function regulation, and pain and reward perception, the GPR88-KOR interaction warrants further investigation in the context of neuropathic pain, Parkinson's disease, and neuropsychiatric disorders.

Cross-pathway integration of cAMP signals through cGMP and calcium-regulated phosphodiesterases in mouse striatal cholinergic interneurons.

Acetylcholine plays a key role in striatal function. Firing properties of striatal cholinergic interneurons depend on intracellular cAMP through the regulation of Ih currents. Yet, the dynamics of cyclic nucleotide signalling in these neurons have remained elusive. We used highly selective FRET biosensors and pharmacological compounds to analyse the functional contribution of phosphodiesterases in striatal cholinergic interneurons in mouse brain slices. PDE1A, PDE3A and PDE4 appear as the main controllers of cAMP levels in striatal cholinergic interneurons. The calcium signal elicited through NMDA or metabotropic glutamate receptors activates PDE1A, which degrades both cAMP and cGMP. Interestingly, the nitric oxide/cGMP pathway amplifies cAMP signalling via PDE3A inhibition-a mechanism hitherto unexplored in a neuronal context. The expression pattern of specific PDE enzymes in striatal cholinergic interneurons, by integrating diverse intracellular pathways, can adjust cAMP responses bidirectionally. These properties eventually allow striatal cholinergic interneurons to dynamically regulate their overall activity and modulate acetylcholine release. Remarkably, this effect is the opposite of the cGMP-induced inhibition of cAMP signals involving PDE2A in striatal medium-sized spiny neurons, which provides important insights for the understanding of signal integration in the striatum.

Modeling early phenotypes of Parkinson’s disease by age-induced midbrain-striatum assembloids

Parkinson’s disease, an aging-associated neurodegenerative disorder, is characterised by nigrostriatal pathway dysfunction caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Human in vitro models are enabling the study of the dopaminergic neurons’ loss, but not the dysregulation within the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of Parkinson’s disease. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids can develop characteristics of the nigrostriatal connectivity, with catecholamine release from the midbrain to the striatum and synapse formation between midbrain and striatal neurons. Moreover, Progerin-overexpressing assembloids acquire aging traits that lead to early neurodegenerative phenotypes. This model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of Parkinson’s disease.

Reward functioning in posttraumatic stress disorder, metabolic syndrome, and psychological resilience

BackgroundReward system dysfunction may play a role in the comorbidity of metabolic syndrome (MetS) in posttraumatic stress disorder (PTSD). Psychological resilience, through its effects on the reward system, may modulate outcomes in PTSD. Utilising a monetary incentive delay task during functional magnetic resonance imaging in a case-control study (PTSD, n = 88, trauma-exposed controls [TEC], n = 85), we aimed to investigate reward system function in relation to PTSD, MetS, and psychological resilience. MethodsUsing repeated measures analysis of variance, we assessed change in activation in the ventral striatum (VS) during reward anticipation and in the orbitofrontal cortex (OFC) during reward outcome, in relation to PTSD, MetS, and psychological resilience, controlling for possible confounders including depression severity, childhood trauma and trauma load. ResultsActivation in the VS and OFC didn't differ in relation to PTSD and MetS. When we controlled for depression severity, PTSD cases had significantly lower activation in the VS and a greater increase in activation in the OFC compared to TEC. Psychological resilience was significantly associated with decreased change in activation in the VS and increased change in activation in the OFC. We also observed a greater increase in activation during reward outcome in the OFC in those with greater childhood trauma exposure and those with exposure to fewer lifetime traumatic events. ConclusionsThe effects of depression and psychological resilience on reward system function in PTSD can be utilised towards developing interventions targeted at altering positive valence systems in PTSD.

Reprogrammed human lateral ganglionic eminence precursors generate striatal neurons and restore motor function in a rat model of Huntington’s disease

BackgroundHuntington’s disease (HD) is a genetic neurological disorder predominantly characterised by the progressive loss of GABAergic medium spiny neurons in the striatum resulting in motor dysfunction. One potential strategy for the treatment of HD is the development of cell replacement therapies to restore neuronal circuitry and function by the replacement of lost neurons. We propose the generation of lineage-specific human lateral ganglionic eminence precursors (hiLGEP) using direct reprogramming technology provides a novel and clinically viable cell source for cell replacement therapy for HD.MethodshiLGEPs were derived by direct reprogramming of adult human dermal fibroblasts (aHDFs) using chemically modified mRNA (cmRNA) and a defined reprogramming medium. hiLGEPs were differentiated in vitro using an optimised striatal differentiation medium. Acquisition of a striatal precursor and neural cell fate was assessed through gene expression and immunocytochemical analysis of key markers. hiLGEP-derived striatal neuron functionality in vitro was demonstrated by calcium imaging using Cal-520. To investigate the ability for hiLGEP to survive, differentiate and functionally integrate in vivo, we transplanted hiLGEPs into the striatum of quinolinic acid (QA)-lesioned rats and performed behavioural assessment using the cylinder test over the course of 14 weeks. Survival and differentiation of hiLGEPs was assessed at 8 and 14-weeks post-transplant by immunohistochemical analysis.ResultsWe demonstrate the capability to generate hiLGEPs from aHDFs using cmRNA encoding the pro-neural genes SOX2 and PAX6, combined with a reprogramming medium containing Gö6983, Y-27,632, N-2 and Activin A. hiLGEPs generated functional DARPP32 + neurons following 14 days of culture in BrainPhys™ media supplemented with dorsomorphin and Activin A. We investigated the ability for hiLGEPs to survive transplantation, differentiate to medium spiny-like striatal neurons and improve motor function in the QA lesion rat model of HD. Fourteen weeks after transplantation, we observed STEM121 + neurons co-expressing MAP2, DARPP32, GAD65/67, or GABA. Rats transplanted with hiLGEPs also demonstrated reduction in motor function impairment as determined by spontaneous exploratory forelimb use when compared to saline transplanted animals.ConclusionThis study provides proof-of-concept and demonstrates for the first time that aHDFs can be directly reprogrammed to hiLGEPs which survive transplantation, undergo neuronal differentiation to generate medium spiny-like striatal neurons, and reduce functional impairment in the QA lesion rat model of HD.

Sex and estradiol effects in the rodent dorsal striatum.

17β-Estradiol (E2) is a sex hormone that acts on many brain regions to produce changes in neuronal activity and learning. A key brain region sensitive to E2 is the dorsal striatum (also called caudate-putamen), which controls motor behaviour, goal-directed learning and habit learning. In adult rodents, oestrogen receptors (ERs) in the dorsal striatum are localized to the plasma membrane and include ERα, ERβ and G protein-coupled ER (GPER). E2, either naturally produced or exogenously applied, may influence neuronal excitability, basal synaptic transmission and long-term synaptic potentiation. These effects may be due to direct action on signalling pathways or may be due to changes in dopamine availability. In particular, estradiol influences dopamine release, dopamine receptor expression and dopamine transporter expression. We review the cellular effects that E2 has in the dorsal striatum, distinguishing between exogenously applied E2 and the oestrous cycle, as well as its influence on dorsal striatal-dependent motor and learning behaviour.

Impacts of maternal separation stress on ethanol intake and endocannabinoid system in adolescent mice

Clinical and preclinical studies suggest that early-life stress can increase the risk of developing ethanol use disorder later in life. Although the endocannabinoid (eCB) system plays a role in stress-related behaviors and ethanol consumption, it remains unclear whether the eCB system is affected in response to a combination of both factors. By using male and female adolescent C57BL/6J mice subjected to a maternal separation (MS) stress paradigm from postnatal day (PND) 1 to 14, we explored (1) the consequences of early-life stress experiences on ethanol consumption in adolescent mice and (2) how these events affect the eCB system and neuronal activation in brain regions associated with the reward system. In Experiment 1, we found that MS increased involuntary ethanol consumption specifically during the first exposure to the drug (during a 24 h-long trial on PND 28) and decreased the active/inactive nose poke ratio (discrimination index) specifically when mice were subjected to 1 h-sessions (PND 82–86) in an operant ethanol self-administration paradigm. In Experiment 2, during a two-bottle free choice paradigm, we found that MS increased mice preference for high ethanol concentrations (15 % and 20 %) but not lower ethanol concentrations (5 % and 10 %). Except for Mgll gene expression in the dorsal striatum (DS) in Experiment 2, no statistically significant effects of MS were observed regarding neuronal activation on the prefrontal cortex, DS, globus pallidus, and substantia nigra following a binge operant ethanol self-administration session (Experiment 1) or the eCB system molecules (Cnr1 and Faah gene expression) in the DS (Experiment 2).

Fentanyl exposure alters rat CB1 receptor expression in the insula, nucleus accumbens and substantia nigra

Prolonged periods of opioid use have been shown to cause neuroadaptations in the brain’s reward circuitry, contributing to addictive behaviors and drug dependence. Recently, considerable focus has been placed on the role of the endocannabinoid system (ECS) and its CB receptors in opioid-driven behaviors. However, opioid-induced neuroadaptations to the ECS remain understudied. In this study, we systematically assessed CB1 receptor (CB1R) protein expression within the cortico-mesolimbic-basal ganglia circuit in rats following chronic fentanyl exposure. Male and female Long Evans rats were administered increasing daily doses of fentanyl or saline for 14 days. During naloxone-precipitated withdrawal, fentanyl-treated rats exhibited significantly higher withdrawal symptoms than saline-treated controls. Using Western Blotting, we demonstrated that the fentanyl-treated rats had significantly higher CB1R expression in the insula and significantly lower CB1R expression in the nucleus accumbens and substantia nigra compared to saline-treated rats. No significant differences in CB1R expression were detected between saline and fentanyl-treated rats in the prefrontal cortex, dorsal striatum, medial septum, hypothalamus, amygdala, hippocampus, ventral tegmental area, periaqueductal gray area, pedunculopontine tegmentum, and laterodorsal tegmentum (LDT). These findings suggest that chronic fentanyl exposure leads to region-specific neuroadaptations of CB1R protein expression in motivation- and addiction-associated brain regions.

Connectivity-Based Real-Time Functional Magnetic Resonance Imaging Neurofeedback in Nicotine Users: Mechanistic and Clinical Effects of Regulating a Meta-Analytically Defined Target Network in a Double-Blind Controlled Trial.

One of the fundamental questions in real-time functional magnetic resonance imaging neurofeedback (rt-fMRI NF) investigations is the definition of a suitable neural target for training. Previously, we applied a meta-analytical approach to define a network-level target for connectivity-based rt-fMRI NF in substance use disorders. The analysis yielded consistent connectivity alterations between the insula and anterior cingulate cortex (ACC) as well as the dorsal striatum and the ACC. In the current investigation, we addressed the feasibility of regulating this network and its functional relevance using connectivity-based neurofeedback. In a double-blind, sham-controlled design, 60 nicotine users were randomly assigned to the experimental or sham control group for one NF training session. The preregistered primary outcome was defined as improved inhibitory control performance after regulation of the target network compared to sham control. Secondary outcomes were (1) neurofeedback-specific changes in functional connectivity of the target network; (2) changes in smoking behavior and impulsivity measures; and (3) changes in resting-state connectivity profiles. Our results indicated no differences in behavioral measures after receiving feedback from the target network compared to the sham feedback. Target network connectivity was increased during regulation blocks compared to rest blocks, however, the experimental and sham groups could regulate to a similar degree. Accordingly, the observed activation patterns may be related to the mental strategies used during regulation attempts irrespective of the group assignment. We discuss several crucial factors regarding the efficacy of a single-session connectivity-based neurofeedback for the target network. This includes high fluctuation in the connectivity values of the target network that may impact controllability of the signal. To our knowledge, this investigation is the first randomized, double-blind controlled real-time fMRI study in nicotine users. This raises the question of whether previously observed effects in nicotine users are specific to the neurofeedback signal or reflect more general self-regulation attempts.

Rapid modulation of striatal cholinergic interneurons and dopamine release by satellite astrocytes.

Astrocytes are increasingly appreciated to possess underestimated and important roles in modulating neuronal circuits. Astrocytes in striatum can regulate dopamine transmission by governing the extracellular tone of axonal neuromodulators, including GABA and adenosine. However, here we reveal that striatal astrocytes occupy a cell type-specific anatomical and functional relationship with cholinergic interneurons (ChIs), through which they rapidly excite ChIs and govern dopamine release via nicotinic acetylcholine receptors on subsecond timescales. We identify that ChI somata are in unexpectedly close proximity to astrocyte somata, in mouse and human, forming a "soma-to-soma" satellite-like configuration not typically observed for other striatal neurons. We find that transient depolarization of astrocytes in mouse striatum reversibly regulates ChI excitability by decreasing extracellular calcium. These findings reveal a privileged satellite astrocyte-interneuron interaction for striatal ChIs operating on subsecond timescales via regulation of extracellular calcium dynamics to shape downstream striatal circuit activity and dopamine signaling.

Effects of chronodisruption and alcohol consumption on gene expression in reward-related brain areas in female rats.

Circadian dysfunction caused by exposure to aberrant light-dark conditions is associated with abnormal alcohol consumption in humans and animal models. Changes in drinking behavior have been linked to alterations in clock gene expression in reward-related brain areas, which could be attributed to either the effect of chronodisruption or alcohol. To date, however, the combinatory effect of circadian disruption and alcohol on brain functions is less understood. Moreover, despite known sex differences in alcohol drinking behavior, most research has been carried out on male subjects only, and therefore implications for females remain unclear. To address this gap, adult female rats housed under an 11 h/11 h light-dark cycle (LD22) or standard light conditions (LD24, 12 h/12 h light-dark) were given access to an intermittent alcohol drinking protocol (IA20%) to assess the impact on gene expression in brain areas implicated in alcohol consumption and reward: the prefrontal cortex (PFC), nucleus accumbens (NAc), and dorsal striatum (DS). mRNA expression of core clock genes (Bmal1, Clock, Per2), sex hormone receptors (ERβ, PR), glutamate receptors (mGluR5, GluN2B), a calcium-activated channel (Kcnn2), and an inflammatory cytokine (TNF-α) were measured at two-time points relative to the locomotor activity cycle. Housing under LD22 did not affect alcohol intake but significantly disrupted circadian activity rhythms and reduced locomotion. Significant changes in the expression of Bmal1, ERβ, and TNF-α were primarily related to the aberrant light conditions, whereas changes in Per2 and PR expression were associated with the effect of alcohol. Collectively, these results indicate that disruption of circadian rhythms and/or intermittent alcohol exposure have distinct effects on gene expression in the female brain, which may have implications for the regulation of alcohol drinking, addiction, and, ultimately, brain health.

Regulator of G protein signalling 14 (RGS14) protein expression profile in the adult mouse brain.

Regulator of G protein signalling 14 (RGS14) is a multifunctional signalling protein that serves as a natural suppressor of synaptic plasticity in the mouse brain. Our previous studies showed that RGS14 is highly expressed in postsynaptic dendrites and spines of pyramidal neurons in hippocampal area CA2 of the developing mouse brain. However, our more recent work with monkey brain shows that RGS14 is found in multiple neuron populations throughout hippocampal area CA1 and CA2, caudate nucleus, putamen, globus pallidus, substantia nigra and amygdala. In the mouse brain, we also have observed RGS14 protein in discrete limbic regions linked to reward behaviour and addiction, including the central amygdala and the nucleus accumbens, but a comprehensive mapping of RGS14 protein expression in the adult mouse brain is lacking. Here, we report that RGS14 is more broadly expressed in mouse brain than previously known. Intense RGS14 staining is observed in specific neuron populations of the hippocampal formation, amygdala, septum, bed nucleus of stria terminalis and ventral striatum/nucleus accumbens. RGS14 is also observed in axon fibre tracts including the dorsal fornix, fimbria, stria terminalis and the ventrohippocampal commissure. Moderate RGS14 staining is observed in various other adjacent regions not previously reported. These findings show that RGS14 is expressed in brain regions that govern aspects of core cognitive functions such as sensory perception, emotion, memory, motivation and execution of actions and suggest that RGS14 may serve to suppress plasticity and filter inputs in these brain regions to set the overall tone on experience-to-action processes.