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Addiction-related compulsion-like behavior can be modeled in rodents with drug self-administration (SA) despite harmful consequences. Recent studies suggest that the potentiation of glutamatergic transmission at the orbitofrontal cortex (OFC) to dorsal striatum (DS) synapses drives the transition from controlled to compulsion-like SA. However, the timing of the induction of this synaptic plasticity remains elusive. Here, mice were first allowed to intravenously self-administer cocaine. When mice had to endure a risk of electrical foot shock, only a fraction persevered in cocaine SA. In these persevering mice, we recorded high A/N ratios (AMPA-R/NMDA-R: α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptor/N-methyl-D-aspartate receptor) in both types of spiny projection neurons (i.e., D1 and D2 dopamine receptor-expressing SPNs). By contrast, when we prepared slices at the end of the acquisition period, in all mice, the A/N was high in D1R- but not D2R-SPNs. These results indicate that the transition to compulsion-like cocaine SA emerges during the punishment sessions, where synapses onto D2R-SPNs are strengthened. In renouncing individuals, the cocaine-evoked strengthening in D1R-SPNs is lost. Our study thus reveals the cell-type specific sequence of the induction of plasticity that eventually may cause compulsion-like SA.

Background Activation of the mesolimbic dopamine system is positively reinforcing. After repeated activation, some individuals develop compulsive reward-seeking behavior, which is a core symptom of addiction. However, the underlying neural mechanism remains elusive. Methods We trained mice in a seek-take chain, rewarded by optogenetic dopamine neuron self-stimulation. After compulsivity was evaluated, AMPA/NMDA ratio was measured at three distinct corticostriatal pathways confirmed by retrograde labeling and anterograde synaptic connectivity. Fiber photometry method and chemogenetics were used to parse the contribution of orbitofrontal cortex afferents onto the dorsal striatum (DS) during the behavioral task. We established a causal link between DS activity and compulsivity using optogenetic inhibition. Results Mice that persevered when seeking was punished exhibited an increased AMPA/NMDA ratio selectively at orbitofrontal cortex to DS synapses. In addition, an activity peak of spiny projection neurons in the DS at the moment of signaled reward availability was detected. Chemogenetic inhibition of orbitofrontal cortex neurons curbed the activity peak and reduced punished reward seeking, as did optogenetic hyperpolarization of spiny projection neurons time-locked to the cue predicting reward availability. Conclusions Our results suggest that compulsive individuals display stronger neuronal activity in the DS during the cue predicting reward availability even when at the risk of punishment, nurturing further compulsive reward seeking.

Psychiatric disease is one of the greatest health challenges of our time. The pipeline for conceptually novel therapeutics remains low, in part because uncovering the biological mechanisms of psychiatric disease has been difficult. We asked experts researching different aspects of psychiatric disease: what do you see as the major urgent questions that need to be addressed? Where are the next frontiers, and what are the current hurdles to understanding the biological basis of psychiatric disease?

International audience; Optogenetic techniques have been developed to allow control over the activity of selected cells within a highly heterogeneous tissue, using a combination of genetic engineering and light. Optogenetics employs natural and engineered photoreceptors, mostly of microbial origin, to be genetically introduced into the cells of interest. As a result, cells that are naturally light-insensitive can be made photosensitive and addressable by illumination and precisely controllable in time and space. The selectivity of expression and subcellular targeting in the host is enabled by applying control elements such as promoters, enhancers and specific targeting sequences to the employed photoreceptor-encoding DNA. This powerful approach allows precise characterization and manipulation of cellular functions and has motivated the development of advanced optical methods for patterned photostimulation. Optogenetics has revolutionized neuroscience during the past 15 years and is primed to have a similar impact in other fields, including cardiology, cell biology and plant sciences. In this Primer, we describe the principles of optogenetics, review the most commonly used optogenetic tools, illumination approaches and scientific applications and discuss the possibilities and limitations associated with optogenetic manipulations across a wide variety of optical techniques, cells, circuits and organisms.

Ketamine is clinically used as an anesthetic, a fast-acting antidepressant, and recreationally used for its dissociative properties. Addictive drugs, such as cocaine, increase dopamine (DA) levels in the nucleus accumbens (NAc). This facilitates synaptic plasticity in the mesolimbic system, which causes behavioral adaptations, eventually driving the transition to compulsion1-4. The addiction liability of ketamine is a matter of much debate, also because of its complex pharmacology that among several targets includes N-methyl-d-aspartic acid (NMDA) receptor (NMDAR) antagonism5,6. Here we show that ketamine fails to induce synaptic plasticity typically observed with addictive drugs in mice despite inducing robust DA transients in the NAc. Ketamine nevertheless supported reinforcement via disinhibition of DA neurons in the ventral tegmental area (VTA). This effect was mediated by NMDAR antagonism in VTA γ-aminobutyric acid (GABA) neurons but quickly terminated by type 2 DA receptors (D2R) on DA neurons. The rapid off-kinetics of the DA transients along with the NMDARs antagonism precluded the induction of synaptic plasticity in the VTA and NAc, and failed to elicit locomotor sensitization and uncontrolled self-administration. In summary, ketamine’s dual-action leads to a unique constellation for DA-driven positive reinforcement yet low addiction liability.

Prevention of compulsive cocaine taking Over time, about 20% of chronic cocaine users lose control and become addicted. There are indications that the differential efficacy of the brain serotonin (5-HT) system may be involved in the vulnerability to drug addiction. However, the relevant circuits and underlying cellular processes remain elusive. Li et al . discovered a synaptic mechanism in mice that underlies the modulatory role of 5-HT in reducing the likelihood of transition to compulsion and eventually addiction (see the Perspective by Miyazaki and Miyazaki). Cocaine binds to 5-HT transporters to block 5-HT reuptake. The elevated extracellular 5-HT activates 5-HT 1B receptors and causes presynaptic depression of a projection from the orbitofrontal cortex to the dorsal striatum. These changes reduce the likelihood of inducing postsynaptic potentiation at these synapses, which ultimately drives compulsion. —PRS

Light-sheet microscopy is an ideal technique for imaging large cleared samples; however, the community is still lacking instruments capable of producing volumetric images of centimeter-sized cleared samples with near-isotropic resolution within minutes. Here, we introduce the mesoscale selective plane-illumination microscopy (mesoSPIM) initiative, an open-hardware project for building and operating a light sheet microscope that addresses these challenges and is compatible with any type of cleared or expanded sample (www.mesospim.org).

Addiction is a disease in which, after a period of recreational use, a subset of individuals develops compulsive use that does not stop even in light of major negative consequences. Here, we review the evidence for underlying epigenetic remodeling in brain in two settings. First, excessive dopamine signaling during drug use may modulate gene expression, altering synaptic function and circuit activity and leading over time to maladaptive behaviors in vulnerable individuals. Second, on a longer timescale, life experience can shape the epigenetic landscape in brain and thereby may contribute to an individual’s vulnerability by amplifying drug-induced changes in gene expression that drive the transition to addiction. We conclude by exploring how epigenetic mechanisms might serve as therapeutic targets for addiction treatments.

Subthalamic deep brain stimulation (DBS) for Parkinson disease (PD) currently requires laborious open-loop programming, which can mitigate the benefits of this treatment. Experimental closed-loop DBS systems are emerging that can sense the electrophysiological surrogates of PD motor signs and respond with delivery of an automatically adapted stimulation. Such biomarker-based neural interfaces constitute a major advance towards improving the outcomes of patients treated with DBS and enhancing our understanding of the pathophysiological mechanisms underlying PD. In this Perspectives article, we argue that closed-loop DBS, in addition to offering advantages in patients with PD, might extend the current indications for DBS to include selected psychiatric disorders in which the symptoms are similarly driven by pathological brain circuit activity. The success of closed-loop DBS in such settings will depend on the identification of symptom-specific biomarkers, which ideally should reflect causal mechanisms of the underlying pathology.

Prescription stimulants, such as d-amphetamine or methylphenidate are used to treat suffering from attention-deficit hyperactivity disorder (ADHD). They potently release dopamine (DA) and norepinephrine (NE) and cause phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 in the striatum. Whether other brain regions are also affected remains elusive. Here, we demonstrate that d-amphetamine and methylphenidate increase phosphorylation at Ser845 (pS845-GluA1) in the membrane fraction of mouse cerebellum homogenate. We identify Bergmann glial cells as the source of pS845-GluA1 and demonstrate a requirement for intact NE release. Consequently, d-amphetamine-induced pS845-GluA1 was prevented by β1-adenoreceptor antagonist, whereas the blockade of DA D1 receptor had no effect. Together, these results indicate that NE regulates GluA1 phosphorylation in Bergmann glial cells in response to prescription stimulants., SCOPUS: ar.j, info:eu-repo/semantics/published

In a recent publication in Cell, Buffington et al. provide a fascinating example of hologenomic behavioral regulation in an autism mouse model.1 The authors report that gut bacteria from wild-type mice rescue the social deficit of Cntnap2 knockout mice.

Addiction is a disease characterized by compulsive drug seeking and consumption observed in 20-30% of users. An addicted individual will favor drug reward over natural rewards, despite major negative consequences. Mechanistic research on rodents modeling core components of the disease has identified altered synaptic transmission as the functional substrate of pathological behavior. While the initial version of a circuit model for addiction focused on early drug adaptive behaviors observed in all individuals, it fell short of accounting for the stochastic nature of the transition to compulsion. The model builds on the initial pharmacological effect common to all addictive drugs-an increase in dopamine levels in the mesolimbic system. Here, we consolidate this early model by integrating circuits underlying compulsion and negative reinforcement. We discuss the genetic and epigenetic correlates of individual vulnerability. Many recent data converge on a gain-of-function explanation for circuit remodeling, revealing blueprints for novel addiction therapies. Expected final online publication date for the Annual Review of Neuroscience, Volume 44 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Locomotor sensitization (LS) is an early behavioral adaptation to addictive drugs, driven by the increase of dopamine in the Nucleus Accumbens (NAc). However, the effect on accumbal population activity remains elusive. Here we used single cell calcium imaging to record the activity of dopamine-1-receptor (D1R) and dopamine-2-receptor (D2R) expressing spiny projection neurons (SPNs) during cocaine LS. Acute exposure to cocaine elevated D1R SPN activity and reduced D2R SPN activity, albeit with high variability between neurons. During LS, the number of D1R and D2R neurons responding in opposite directions increased. Moreover, preventing LS by inhibition of the ERK signalling pathway decreased the number of cocaine-responsive D1R SPNs, but had little effect on D2R SPNs. These results indicate that accumbal population dichotomy is dynamic and contains a subgroup of D1R SPNs that eventually drives LS. Insights into the drug-related activity dynamics provides a foundation for understanding the circuit-level addiction pathogenesis.

Locomotor sensitization (LS) is an early behavioral adaptation to addictive drugs, driven by the increase of dopamine in the Nucleus Accumbens (NAc). However, the effect on accumbal population activity remains elusive. Here, we used single-cell calcium imaging in mice to record the activity of dopamine-1-receptor (D1R) and dopamine-2-receptor (D2R) expressing spiny projection neurons (SPNs) during cocaine LS. Acute exposure to cocaine elevated D1R SPN activity and reduced D2R SPN activity, albeit with high variability between neurons. During LS, the number of D1R and D2R neurons responding in opposite directions increased. Moreover, preventing LS by inhibition of the ERK signaling pathway decreased the number of cocaine responsive D1R SPNs, but had little effect on D2R SPNs. These results indicate that accumbal population dichotomy is dynamic and contains a subgroup of D1R SPNs that eventually drives LS. Insights into the drug-related activity dynamics provides a foundation for understanding the circuit-level addiction pathogenesis.

Prescription stimulants, such as d-amphetamine or methylphenidate, are potent dopamine (DA) and norepinephrine (NE) releasers used to treat children and adults diagnosed for attention-deficit/hyperactivity disorder (ADHD). Although increased phosphorylation of the AMPA receptor subunit GluA1 at Ser845 (pS845-GluA1) in the striatum has been identified as an important cellular effector for the actions of these drugs, regulation of this posttranslational modification in the cerebellum has never been recognized. Here, we demonstrate that d-amphetamine and methylphenidate increase pS845-GluA1 in the membrane fraction in both vermis and lateral hemispheres of the mouse cerebellum. This regulation occurs selectively in Bergmann Glia Cells and requires intact norepinephrine release since the effects were abolished in mice lacking the vesicular monoamine transporter-2 selectively in NE neurons. Moreover, d-amphetamine-induced pS845-GluA1 was prevented by β1-adenoreceptor antagonist, whereas the blockade of dopamine D1 receptor had no effect. Additionally, we identified transcriptional alterations of several regulators of the cAMP/PKA pathway, which might account for the absence of pS845-GluA1 desensitization in mice repeatedly exposed to d-amphetamine or methylphenidate. Together, these results point to norepinephrine transmission as a key regulator of GluA1 phosphorylation in Bergmann Glial Cells, which may represent a new target for the treatment of ADHD.

Compulsion is a cardinal symptom of drug addiction (severe substance use disorder). However, compulsion is observed in only a small proportion of individuals who repeatedly seek and use addictive substances. Here, we integrate accounts of the neuropharmacological mechanisms that underlie the transition to compulsion with overarching learning theories, to outline how compulsion develops in addiction. Importantly, we emphasize the conceptual distinctions between compulsive drug-seeking behaviour and compulsive drug-taking behaviour (that is, use). In the latter, an individual cannot stop using a drug despite major negative consequences, possibly reflecting an imbalance in frontostriatal circuits that encode reward and aversion. By contrast, an individual may compulsively seek drugs (that is, persist in seeking drugs despite the negative consequences of doing so) when the neural systems that underlie habitual behaviour dominate goal-directed behavioural systems, and when executive control over this maladaptive behaviour is diminished. This distinction between different aspects of addiction may help to identify its neural substrates and new treatment strategies.

Dopamine (DA) neurons of the VTA track cues and rewards to generate a reward prediction error signal during Pavlovian conditioning. Here we explored how these neurons respond to a self-paced, operant task in freely moving mice. The animal could trigger a reward-predicting cue by remaining in a specific location of an operant box for a brief time before moving to a spout for reward collection. VTA DA neurons were identified using DAT-Cre male mice that carried an optrode with minimal impact on the behavioral task. In vivo single-unit recordings revealed transient fast spiking responses to the cue and reward in correct trials, while for incorrect ones the activity paused, reflecting positive and negative error signals of a reward prediction. In parallel, a majority of VTA DA neurons simultaneously encoded multiple actions (e.g., movement velocity, acceleration, distance to goal, and licking) in sustained slow firing modulation. Applying a GLM, we show that such multiplexed encoding of rewarding and motor variables by individual DA neurons was only apparent while the mouse was engaged in the task. Downstream targets may exploit such goal-directed multiplexing of VTA DA neurons to adjust actions to optimize the task's outcome. SIGNIFICANCE STATEMENT VTA DA neurons code for multiple functions, including the reward prediction error but also motivation and locomotion. Here we show that about half of the recorded VTA DA neurons perform multiplexing: they exploit the phasic and tonic activity modes to encode, respectively, the cue/reward responses and motor parameters, most prominently when the mouse engages in a self-paced operand task. VTA non-DA neurons, by contrast, encode motor parameters regardless of task engagement.

Activation of the mesolimbic dopamine system reinforces goal-directed behaviours. With repetitive stimulation-for example, by chronic drug abuse-the reinforcement may become compulsive and intake continues even in the face of major negative consequences. Here we gave mice the opportunity to optogenetically self-stimulate dopaminergic neurons and observed that only a fraction of mice persevered if they had to endure an electric shock. Compulsive lever pressing was associated with an activity peak in the projection terminals from the orbitofrontal cortex (OFC) to the dorsal striatum. Although brief inhibition of OFC neurons temporarily relieved compulsive reinforcement, we found that transmission from the OFC to the striatum was permanently potentiated in persevering mice. To establish causality, we potentiated these synapses in vivo in mice that stopped optogenetic self-stimulation of dopamine neurons because of punishment; this led to compulsive lever pressing, whereas depotentiation in persevering mice had the converse effect. In summary, synaptic potentiation of transmission from the OFC to the dorsal striatum drives compulsive reinforcement, a defining symptom of addiction.

BACKGROUND We investigated the acute effect of short pulse widths on the therapeutic window in subthalamic nucleus deep brain stimulation in Parkinson's disease. METHODS We assessed 10 PD patients with STN-DBS at a 60-µs pulse width. We randomly and double-blindedly applied 10- to 50-µs pulse widths. The principal outcome was the therapeutic window (difference between the amplitude thresholds for visible muscle contraction and for best rigidity control). The secondary outcome was the charge per pulse (which reflects the efficiency of the stimulation) needed to control rigidity. Two-way analysis of variance and pairwise t tests were applied. RESULTS The therapeutic window widened when the pulse width shortened (r = -0.45; P

Obsessive-compulsive disorder (OCD) is a circuit disorder involving corticostriatal projections, which play a role in motor control. The Sapap3-knockout (KO) mouse is a mouse model to study OCD and recapitulates OCD-like compulsion through excessive grooming behavior, with skin lesions appearing at advanced age. Deficits in corticostriatal control provide a link to the pathophysiology of OCD. However, there remain significant gaps in the characterization of the Sapap3-KO mouse, with respect to age, specificity of synaptic dysfunction, and locomotor phenotype. We therefore investigated the corticostriatal synaptic phenotype of Sapap3-KO mice using patch-clamp slice electrophysiology, in adult mice and with projection specificity. We also analyzed grooming across age and locomotor phenotype with a novel, unsupervised machine learning technique (MoSeq). Increased grooming in Sapap3-KO mice without skin lesions was age independent. Synaptic deficits persisted in adulthood and involved the projections from the motor cortices and cingulate cortex to the dorsolateral and dorsomedial striatum. Decreased synaptic strength was evident at the input from the primary motor cortex by reduction in AMPA receptor function. Hypolocomotion, i.e., slowness of movement, was consistently observed in Sapap3-KO mice. Our findings emphasize the utility of young adult Sapap3-KO mice to investigate corticostriatal synaptic dysfunction in motor control.

Addicted individuals compulsively seek drugs. Cortico-striatal projections have been implicated in persevering to seek rewards even when punished. The temporo-spatial determinants of the activity underlying the compulsive reward seeking however remains elusive. Here we trained mice in a seek-take chain, rewarded by optogenetic dopamine neuron self-stimulation (oDASS). Mice that persevered when seeking was punished, exhibited an increased AMPA/NMDA ratio selectively at orbitofrontal cortex (OFC) to dorsal striatum (DS) synapses. In addition, an activity peak of spiny projection neurons (SPNs) in the DS at the moment of signalled reward availability was detected. Chemogenetic inhibition of OFC neurons curbed the activity peak and reduced punished reward seeking, as did optogenetic hyperpolarization of SPNs time locked to the cue predicting reward availability, establishing a causal link. Taken together, we conclude that the strengthening of OFC-DS synapses drives SPNs activity when a reward predictive cue is delivered, thus encouraging reward seeking in subsequent trials.

Overeating typically follows periods of energy deficit, but it is also sustained by highly palatable foods, even without metabolic demand. Dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) of the nucleus accumbens shell (NAcSh) project to the lateral hypothalamus (LH) to authorize feeding when inhibited. Whether plasticity at these synapses can affect food intake is unknown. Here, ex vivo electrophysiology recordings reveal that D1-MSN-to-LH inhibitory transmission is depressed in circumstances in which overeating is promoted. Endocannabinoid signaling is identified as the induction mechanism, since inhibitory plasticity and concomitant overeating were blocked or induced by CB1R antagonism or agonism, respectively. D1-MSN-to-LH projectors were largely non-overlapping with D1-MSNs targeting ventral pallidum or ventral midbrain, providing an anatomical basis for distinct circuit plasticity mechanisms. Our study reveals a critical role for plasticity at D1-MSN-to-LH synapses in adaptive feeding control, which may underlie persistent overeating of unhealthy foods, a major risk factor for developing obesity.

Subthalamic deep brain stimulation (DBS) for Parkinson disease (PD) currently requires laborious open-loop programming, which can mitigate the benefits of this treatment. Experimental closed-loop DBS systems are emerging that can sense the electrophysiological surrogates of PD motor signs and respond with delivery of an automatically adapted stimulation. Such biomarker-based neural interfaces constitute a major advance towards improving the outcomes of patients treated with DBS and enhancing our understanding of the pathophysiological mechanisms underlying PD. In this Perspectives article, we argue that closed-loop DBS, in addition to offering advantages in patients with PD, might extend the current indications for DBS to include selected psychiatric disorders in which the symptoms are similarly driven by pathological brain circuit activity. The success of closed-loop DBS in such settings will depend on the identification of symptom-specific biomarkers, which ideally should reflect causal mechanisms of the underlying pathology.

Over the course of the past decade, tissue clearing methods have reached a high level of sophistication with a wide variety of approaches now available[1][1]. To image large cleared samples, light-sheet microscopes have proven to be ideal due to their excellent optical sectioning capability in

BACKGROUND Acute dyskinesias elicited by STN-DBS, here referred to as stimulation-induced dyskinesias, predict optimal clinical outcome in PD. However, it remains elusive whether stimulation-induced dyskinesias can guide DBS programming. OBJECTIVES Here, we characterized stimulation-induced dyskinesias clinically and anatomically. We then tested whether dyskinesia-inducing contacts could be effectively programmed using independent current source technology. METHODS We characterized stimulation-induced dyskinesias with directional and ring stimulation retrospectively in 20 patients. We then localized dyskinesia-inducing contacts by imaging coregistration and eventually programmed those contacts. RESULTS We elicited dyskinesias in half of our patients. Dyskinesia-inducing contacts were mainly directional and were all located ventrally within the dorsolateral motor STN. When these dyskinesia-inducing contacts were programmed using independent current source technology, dyskinesia disappeared and robust antibradykinetic effects were obtained. CONCLUSION We confirm that stimulation-induced dyskinesias are helpful clinical observations, which may guide programming of directional STN-DBS in PD. © 2019 International Parkinson and Movement Disorder Society.

This is safe, you can eat it Social transmission of food preference is a model for studying nonspatial memory. In mice, a signal that food is safe to eat is transmitted by its smell along with molecules in the breath of a conspecific. How the odor itself is encoded and assigned valence is poorly understood. Loureiro et al. found a monosynaptic pathway between two brain areas, the piriform cortex and the medial prefrontal cortex, that plays a central role in this process. This connection strengthens during social interaction, thereby allowing a mouse to provide a food safety message to its companion. Science , this issue p. 991

Cocaine leads to a strong euphoria, which is at the origin of its recreational use. Past the acute effects, the drug leaves traces in the brain that persist long after it has been cleared from the body. These traces eventually shape behavior such that drug use may become compulsive, and addiction develops. Here, we discuss cocaine-evoked synaptic plasticity of glutamatergic transmission onto dopamine (DA) neurons of the ventral tegmental area (VTA) as one of the earliest traces after a first injection of cocaine. We review the literature that has examined the induction requirements, as well as the expression mechanism of this form of plasticity, and ask the question about its functional significance.

Most Mage family members code for antigens on melanoma tumor cells. Maged1 is the black sheep, promiscuously found in normal adult cells, including neurons of the basal ganglia and prefrontal cortex. In this issue of EMBO reports , De Backer et al [1] propose an unexpected role for Maged1 . Acute effects of cocaine, such as enhanced locomotion and reinforcement, are gone in mice in which the gene is deleted. In a painstaking combinatorial approach comparing several conditional gene knockout (KO) mouse lines, the authors parse the relevant neural circuits.

The dopamine (DA) hypothesis posits the increase of mesolimbic dopamine levels as a defining commonality of addictive drugs, initially causing reinforcement, eventually leading to compulsive consumption. While much experimental evidence from psychostimulants supports this hypothesis, it has been challenged for opioid reinforcement. Here, we use genetically encoded DA and calcium indicators as well as cFos to reveal that heroin activates DA neurons located in the medial part of the VTA, preferentially projecting to the medial shell of the nucleus accumbens (NAc). Chemogenetic and optogenetic manipulations of VTA DA or GABA neurons establish a causal link to heroin reinforcement. Inhibition of DA neurons blocked heroin self-administration, while heroin inhibited optogenetic self-stimulation of DA neurons. Likewise, heroin occluded the self-inhibition of VTA GABA neurons. Together, these experiments support a model of disinhibition of a subset of VTA DA neurons in opioid reinforcement.

The coupling of GABA(B) receptors to G-protein-gated inwardly rectifying potassium (GIRK) channels constitutes an important inhibitory pathway in the brain. Here, we examined the mechanism underlying desensitization of agonist-evoked currents carried by homomeric GIRK2 channels expressed in HEK-293T cells. The canonical GABA(B) receptor agonist baclofen produced GIRK2 currents that decayed by 57.3+/-1.4% after 60 s of stimulation, and then deactivated rapidly (time constant of 3.90+/-0.21 s) upon removal of agonist. Surface labeling studies revealed that GABA(B) receptors, in contrast to micro opioid receptors (MOR), did not internalize with a sustained stimulation for 10 min, excluding receptor redistribution as the primary mechanism for desensitization. Furthermore, heterologous desensitization was observed between GABA(B) receptors and MOR, implicating downstream proteins, such G-proteins or the GIRK channel. To investigate the G-protein turnover cycle, the non-hydrolyzable GTP analogue (GTPgammaS) was included in the intracellular solution and found to attenuate desensitization to 38.3+/-2.0%. The extent of desensitization was also reduced (45.3+/-1.3%) by coexpressing a mutant form of the Galphaq G-protein subunit that has been designed to sequester endogenous RGS proteins. Finally, reconstitution of GABA(B) receptors with Galphao G-proteins rendered insensitive to RGS resulted in significantly less desensitization (28.5+/-3.2%). Taken together, our results demonstrate that endogenous levels of RGS proteins effectively enhance GABA(B) receptor-dependent desensitization of GIRK currents.

Unlike most basal ganglia disorders, which usually progress slowly and relentlessly, a number of movement disorders may develop as acute or subacute conditions. Their occurrence commonly prompts patients to rush into the emergency room. A proper diagnosis is not always straightforward and requires a detailed analysis of the movement disorder phenomenology and a thorough medication screening, as many of these acute situations may be iatrogenic and drug-related. An accurate identification of the problem may enable an effective management and an appropriate therapy. This article is an overview of three distinct movement disorder emergencies, namely acute dystonia, acute chorea, and acute complications that can be observed in Parkinson's disease. Each topic is illustrated with a case report.Contrairement à la plupart des affections des ganglions de la base, qui évoluent généralement sur un mode lentement progressif, certains mouvements anormaux peuvent se développer sur un mode aigu ou subaigu, amenant les patients à consulter en urgence. Le diagnostic est souvent délicat. Il repose sur une analyse détaillée de la phénoménologie et une anamnèse médicamenteuse fouillée, dans la mesure où ces situations sont volontiers iatrogènes. Une identification correcte du problème permet souvent une thérapeutique efficace. Le présent article propose une mise au point de trois problématiques de ce type, à savoir la dystonie aiguë, la chorée aiguë et les complications aiguës que l’on peut observer dans la maladie de Parkinson. Chaque sujet est illustré par un cas clinique.

Advanced Parkinson's disease (PD) is characterized by severe motor and non-motor complications that negatively impact on patients' autonomy and health-related quality of life. In early disease, the therapeutic strategy consists of gradual increase in dopaminergic treatment and levodopa dose fragmentation. In more advanced stages, this approach becomes insufficient and three therapeutic options can be considered: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, and continuous levodopa/carbidopa intestinal gel infusion.La maladie de Parkinson (MP) avancée est caractérisée par la présence de complications motrices et non motrices qui ont un impact significatif sur l’autonomie et la qualité de vie des patients. La stratégie thérapeutique consiste à fractionner le traitement dopaminergique, à recourir aux formes à libération prolongée, et aux inhibiteurs des enzymes de dégradation de la dopamine. Lorsque ces mesures sont insuffisantes, trois options thérapeutiques plus invasives peuvent être envisagées : la stimulation cérébrale profonde, la perfusion sous-cutanée continue d’apomorphine et l’administration intrajéjunale de gel de lévodopa/carbidopa. L’objectif de cet article est de décrire les indications, bénéfices et effets secondaires potentiels de ces traitements dits « complexes ».

Summary Hippocampal neurons activated during encoding drive the recall of contextual fear memory. Little is known about how such ensembles emerge during acquisition and eventually form the cellular engram. Manipulating the activity of granule cells (GCs) of the dentate gyrus (DG) we reveal a mechanism of lateral inhibition that modulates the size of the cellular engram. GCs engage somatostatin positive interneurons that inhibit the dendrites of surrounding GCs. Our findings reveal a microcircuit within the DG that controls the size of the cellular engram and the stability of contextual fear memory.