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The proper action selection, initiation and execution of movement, orchestrated by the brain, is necessary for the survival of any organism. Such processes largely rely on the basal ganglia-thalamo-cortical loops. The striatum constitutes the main input nucleus of the basal ganglia and the acquisition of a behavioral repertoire has been associated with striatal plasticity. Thus, the striatum appears as a key structure for memory formation. The dorsal striatum is composed of two main anatomical-functional regions, the dorsomedial striatum (DMS) and the dorsolateral striatum (DLS), based on topographic cortical glutamatergic afferents. Two main glutamatergic inputs onto the striatum have been identified to convey striatal activity for action initiation and execution: corticostriatal (CS) and thalamostriatal (TS) inputs (mostly from the parafascicular nucleus (Pf)). The striatal-projecting neurons (the medium-sized spiny neurons, MSNs) act as coincidence detectors of cortical and thalamic activity. While extensive research addressed the contribution of CS projections, little is known about the role of TS projections. Therefore, characterizing the TS plasticity and its interactions with the CS plasticity is essential for a better understanding of the role of the striatum in procedural. In order to investigate the interaction of TS and CS plasticity at the level of a single MSN. We characterized input timing-dependent plasticity (ITDP) at CS and TS synapses in brain slices, and we explored supra- and sub-threshold regimes in ITDP protocols for the first time, as opposed to previous studies have focus only on subthreshold activities. We found that most combinations of activities induced LTP at both CS and TS synapses, with the exception of cases when supra-threshold thalamic activity preceded cortical activity. In these situations, LTD was observed, highlighting the crucial impact of synchronizing cortical and thalamic activities for the memory engram at striatal synapses. Next, we used the horizontal ladder set-up to develop a behavioral task that would involve the cortex and the Pf. To address this question, we performed electrophysiological recordings within the DLS while optogenetically activating TS and CS terminals. Therefore, we were able to record in vivo plasticity in mice engaged in procedural learning of a horizontal ladder and found CS-LTP of ChR2-evoked LFP upon learning on a rung pattern #1 (without modification of TS-evoked-LFP), whereas this plasticity was reversed upon novelty (sudden change for a rung pattern #2) to the profit of a TS-LTP. Finally, ex vivo occlusion experiment showed that CS and TS plasticity were engaged during motor learning and novelty, respectively. The ability of TS plasticity to override CS plasticity could enable flexible behavior, aiding the exit of an existing motor program in favor of a novel behavioral strategy. The results presented in this manuscript further extend our knowledge on the interplay between cortico-/thalamo-striatal plasticity and the striatal synaptic plasticity process involved in procedural memory and its reprogramming., La planification, l'initiation et l'exécution correcte des mouvements, orchestrées par le cerveau, sont nécessaires à la survie de tout organisme. De tels processus reposent sur les boucles cortex – thalamus-ganglion de la base. Le striatum constitue la principale entrée des ganglions de la base. L'acquisition d'habileté et d’automatismes cognitivo-moteurs ont été associés à la plasticité synaptique striatale. Ainsi, le striatum apparaît comme une structure clé dans l’encodage de la mémoire procédurale. Le striatum dorsal est composé de deux principales régions anatomiques-fonctionnelles, le striatum dorsomédial (DMS) et le striatum dorsolatéral (DLS), en fonction des afférences (anatomo-fonctionnelles) corticales reçues. Le striatum reçoit deux majeures entrées glutamatergiques : les entrées cortico-striatales (CS) et thalamo-striatales (TS) (principalement du noyau parafasciculaire (Pf)). Les neurones de sortie du striatum (les neurones épineux de taille moyenne, MSN) agissent comme des détecteurs de coïncidence des activités corticale et thalamique et appartiennent à deux voies trans-striatales anatomiques distinctes, la voie directe avec les D1-MSNs et la voie indirecte avec les D2-MSNs. Alors qu'un grand nombre de publications ont documenté la contribution des projections CS, le rôle des projections TS reste mal connu. Par conséquent, la caractérisation de la plasticité TS et de ses interactions avec la plasticité CS est essentielle pour une meilleure compréhension du rôle du striatum dans l'apprentissage procédural. Afin d'étudier l'interaction des plasticités TS et CS au niveau d'un MSN, nous avons caractérisé la plasticité de type input-timing-dependent plasticity (ITDP) au niveau des synapses CS et TS dans des tranches de cerveaux de souris en distinguant les D1- et D2-MSNs ; nous avons exploré pour la première fois les régimes supra- et sub-liminaires dans les paradigmes d’ITDP. Nous avons constaté que la plupart des combinaisons d'activités induisent une LTP aux synapses CS et TS, sauf lorsque l'activation supra-liminaire du Pf précède l'activité corticale. Dans ces situations, une LTD est observée dans les deux voies. Par la suite, nous avons utilisé la tâche comportementale de l’échelle horizontale pour développer une tâche qui implique le cortex et le Pf. Nous avons effectué des enregistrements électrophysiologiques dans le DLS tout en réalisant des stimulations optogénétiques des synapses TS et CS. Nous avons enregistré l’évolution des poids synaptiques CS et TS in vivo chez des souris engagées dans un apprentissage procédural sur l’échelle horizontale et nous avons constaté que le poids synaptique CS augmente lors de l'apprentissage du pattern #1 (sans modification au niveau TS), tandis que cette plasticité est inversée lorsque la souris est exposée à un changement de motif de l’échelle (changement soudain pour un pattern #2) au profit d'une augmentation du poids synaptique TS. Enfin, des expériences d'occlusion ex vivo indiquent que les plasticités CS et TS sont engagées lors de l'apprentissage procédural et de l’exposition à la nouveauté respectivement. La capacité de la plasticité TS à moduler la plasticité CS pourrait permettre un comportement flexible, en facilitant la sortie d'un programme moteur existant en faveur d'une nouvelle stratégie comportementale. Les résultats présentés dans ce manuscrit approfondissent nos connaissances sur l'interaction entre la plasticité cortico-/thalamo-striatale et les processus de plasticité synaptique striatale impliqués dans la mémoire procédurale et sa reprogrammation.

Anorexia nervosa (AN) typically emerges in adolescence. The cortico-striatal system (CSTS) and the default mode network (DMN) are brain circuits with a crucial development during this period. These circuits underlie cognitive functions that are impaired in AN, such as cognitive flexibility and inhibition, among others. Little is known about their involvement in adolescent AN and how weight and symptom improvement might modulate potential alterations in these circuits. Forty-seven adolescent females (30 AN, 17 healthy control) were clinically/neuropsychologically evaluated and scanned during a 3T-MRI resting-state session on two occasions, before and after a 6-month multidisciplinary treatment of the AN patients. Baseline and baseline-to-follow-up between-group differences in CSTS and DMN resting-state connectivity were evaluated, as well as their association with clinical/neuropsychological variables. Increased connectivity between the left dorsal putamen and the left precuneus was found in AN at baseline. At follow-up, body mass index and clinical symptoms had improved in the AN group. An interaction effect was found in the connectivity between the right dorsal caudate to right mid-anterior insular cortex, with lower baseline AN connectivity that improved at follow-up; this improvement was weakly associated with changes in neuropsychological (Stroop test) performance. These results support the presence of CSTS connectivity alterations in adolescents with AN, which improve with weight and symptom improvement. In addition, at the level of caudate-insula connectivity, they might be associated with inhibitory processing performance. Alterations in CSTS pathways might be involved in AN from the early stages of the disorder.

Huntington's disease (HD) is a neurological disorder characterized by motor disturbances. HD pathology is most prominent in the striatum, the central hub of the basal ganglia. The cerebral cortex is the main striatal afferent, and progressive cortico-striatal disconnection characterizes HD. We mapped striatal network dysfunction in HD mice to ultimately modulate the activity of a specific cortico-striatal circuit to ameliorate motor symptoms and recover synaptic plasticity. Multimodal MRI in vivo indicates cortico-striatal and thalamo-striatal functional network deficits and reduced glutamate/glutamine ratio in the striatum of HD mice. Moreover, optogenetically-induced glutamate release from M2 cortex terminals in the dorsolateral striatum (DLS) was undetectable in HD mice and striatal neurons show blunted electrophysiological responses. Remarkably, repeated M2-DLS optogenetic stimulation normalized motor behavior in HD mice and evoked a sustained increase of synaptic plasticity. Overall, these results reveal that selective stimulation of the M2-DLS pathway can become an effective therapeutic strategy in HD., We are very grateful to Ana Lopez (María de Maeztu Unit of Excellence, Institute of Neurosciences, University of Barcelona, MDM-2017–0729, Ministry of Science, Innovation, and Universities) and Maite Muñoz for their excellent technical support. This work has been funded by the Spanish Ministry of Sciences, Innovation and Universities through projects no. SAF2017-88076-R, RETICS de Terapia Celular, Instituto de Salud Carlos III (RD06/0010/0006), and la Marato´ de TV3. This research is part of NEUROPA. The NEUROPA Project has received funding from the European Union’s Horizon 2020 Research and Innovation Program under Grant Agreement No. 863214.

The basal ganglia are a crucial component of neural networks underlying reward response and many other behaviors. Magnetoencephalography (MEG) can be used to non-invasively study the spatiotemporal dynamics of activity in neural networks. However, challenges associated with detecting deep sources has caused many to doubt the ability of MEG to detect basal ganglia signals. In this study, we employed a gambling task to assess the feasibility of using MEG to investigate basal ganglia-cortical networks during reward processing. Participants gambled to win or lose 5 or 25 cents and received unexpected high-value rewards of 50 cents at random intervals. We contrasted activity between reward conditions in the beta (15–30 Hz), gamma (30–60 Hz), and high gamma (60–150 Hz) bands. We found differences in oscillatory power in the beta and high gamma bands while contrasting the large reward condition with both the small reward and large loss conditions. Basal ganglia activity was localized to the caudate, putamen, and globus pallidum, while cortical activity appeared primarily in parietal and temporal areas. Our results show robust basal ganglia power differences in response to reward and corroborate animal literature showing beta and high gamma activation in the striatum. This experiment demonstrates that it is possible to study basal ganglia activity using MEG and reveals specific characteristics of the normal reward response that will inform future research.

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

The ability to enhance motivated performance through incentives is crucial to guide and ultimately optimise the outcome of goal-directed behaviour. It remains largely unclear how motivated behaviour and performance develops particularly across adolescence. Here, we used computational fMRI to assess how response speed and its underlying neural circuitry are modulated by reward and loss in a monetary incentive delay paradigm. We demonstrate that maturational fine-tuning of functional coupling within the cortico-striatal incentive circuitry from adolescence to adulthood facilitates the ability to enhance performance selectively for higher subjective values. Additionally, during feedback, we found developmental sex differences of striatal representations of reward prediction errors in an exploratory analysis. Our findings suggest that a reduced capacity to utilise subjective value for motivated behaviour in adolescence is rooted in immature information processing in the incentive system. This indicates that the neurocircuitry for coordination of incentivised, motivated cognitive control acts as a bottleneck for behavioural adjustments in adolescence., NeuroImage, 237, ISSN:1053-8119, ISSN:1095-9572

According to Hebbian postulate, neural circuits tune their synaptic weights depending on patterned firing of action potential on either side of the synapse. Spike-timing-dependent plasticity (STDP) is an experimental implementation of Hebbian plasticity that relies on the precise order and the millisecond timing of the paired activities in pre- and postsynaptic neurons. The striatum, the primary entrance to basal ganglia, integrates excitatory inputs from both cerebral cortex and thalamus whose activities can be concomitant or delayed. Thus, temporal coding of cortical and thalamic information via STDP paradigm may be crucial for the role of the striatum in procedural learning. Here, we explored cortico-striatal and thalamo-striatal synaptic plasticity and their interplay through STDP paradigm. The main results described here are:1. Opposing spike-timing dependent plasticity at cortical and thalamic inputs drive heterosynaptic plasticity in striatumIf the vast majority of the studies focused on cortico-striatal synaptic plasticity, much less is known about thalamo-striatal plasticity rules and their interplay with cortico-striatal plasticity. Here, we explored thalamo-striatal STDP and how thalamo-striatal and cortico-striatal synaptic plasticity interplay. a) While bidirectional and anti-Hebbian STDP was observed at cortico-striatal synapses, thalamo-striatal exhibited bidirectional and hebbian STDP...; D’après le postulat de Hebb, les circuits neuronaux ajustent et modifient durablement leurs poids synaptiques en fonction des patrons de décharges de part et d’autre de la synapse. La « spike-timing-dependent plasticity » (STDP) est une règle d’apprentissage synaptique hebbienne dépendante de la séquence temporelle précise (de l’ordre de la milliseconde) des activités appariées des neurones pré- et post-synaptiques. Le striatum, le principal noyau d’entrée des ganglions de la base, reçoit des afférences excitatrices provenant du cortex cérébral et du thalamus dont les activités peuvent être concomitantes ou décalées dans le temps. Ainsi, l’encodage temporal des informations corticales et thalamiques via la STDP pourrait être crucial pour l’implication du striatum dans l’apprentissage procédural. Nous avons exploré les plasticités synaptiques cortico- et thalamo-striatales puis leurs interactions à travers le paradigme de la STDP. Les principaux résultats sont :1. Les « spike-timing-dependent plasticity » opposées cortico-striatales et thalamo-striatales induisent des plasticités hétérosynaptiques. Si la très grande majorité des études sont consacrées à la plasticité synaptique cortico-striatale, peu ont exploré les règles de plasticité synaptique aux synapses thalamo-striatale et leurs interactions avec la plasticité cortico-striatale. Nous avons étudié la STDP thalamo-striatale et comment les plasticités synaptiques thalamo- et cortico-striatales interagissent…

According to Hebbian postulate, neural circuits tune their synaptic weights depending on patterned firing of action potential on either side of the synapse. Spike-timing-dependent plasticity (STDP) is an experimental implementation of Hebbian plasticity that relies on the precise order and the millisecond timing of the paired activities in pre- and postsynaptic neurons. The striatum, the primary entrance to basal ganglia, integrates excitatory inputs from both cerebral cortex and thalamus whose activities can be concomitant or delayed. Thus, temporal coding of cortical and thalamic information via STDP paradigm may be crucial for the role of the striatum in procedural learning. Here, we explored cortico-striatal and thalamo-striatal synaptic plasticity and their interplay through STDP paradigm. The main results described here are:1. Opposing spike-timing dependent plasticity at cortical and thalamic inputs drive heterosynaptic plasticity in striatumIf the vast majority of the studies focused on cortico-striatal synaptic plasticity, much less is known about thalamo-striatal plasticity rules and their interplay with cortico-striatal plasticity. Here, we explored thalamo-striatal STDP and how thalamo-striatal and cortico-striatal synaptic plasticity interplay. a) While bidirectional and anti-Hebbian STDP was observed at cortico-striatal synapses, thalamo-striatal exhibited bidirectional and hebbian STDP..., D’après le postulat de Hebb, les circuits neuronaux ajustent et modifient durablement leurs poids synaptiques en fonction des patrons de décharges de part et d’autre de la synapse. La « spike-timing-dependent plasticity » (STDP) est une règle d’apprentissage synaptique hebbienne dépendante de la séquence temporelle précise (de l’ordre de la milliseconde) des activités appariées des neurones pré- et post-synaptiques. Le striatum, le principal noyau d’entrée des ganglions de la base, reçoit des afférences excitatrices provenant du cortex cérébral et du thalamus dont les activités peuvent être concomitantes ou décalées dans le temps. Ainsi, l’encodage temporal des informations corticales et thalamiques via la STDP pourrait être crucial pour l’implication du striatum dans l’apprentissage procédural. Nous avons exploré les plasticités synaptiques cortico- et thalamo-striatales puis leurs interactions à travers le paradigme de la STDP. Les principaux résultats sont :1. Les « spike-timing-dependent plasticity » opposées cortico-striatales et thalamo-striatales induisent des plasticités hétérosynaptiques. Si la très grande majorité des études sont consacrées à la plasticité synaptique cortico-striatale, peu ont exploré les règles de plasticité synaptique aux synapses thalamo-striatale et leurs interactions avec la plasticité cortico-striatale. Nous avons étudié la STDP thalamo-striatale et comment les plasticités synaptiques thalamo- et cortico-striatales interagissent…

International audience; Two core symptoms characterize Attention Deficit Hyperactivity Disorder (ADHD) subtypes: inattentiveness and hyperactivity–impulsivity. While previous brain imaging research investigated ADHD as if it was a homogenous condition, its two core symptoms may originate from different brain mechanisms. We, therefore, hypothesized that the functional connectivity of cortico-striatal and attentional networks would be different between ADHD subtypes. We studied 165 children (mean age 10.93 years; age range, 7–17 year old) diagnosed as having ADHD based on their revised Conner's rating scale score and 170 typical developing individuals (mean age 11.46 years; age range, 7–17 year old) using resting state functional fMRI. Groups were matched for age, IQ and head motion during the MRI acquisition. We fractionated the ADHD group into predominantly inattentive, hyperactive–impulsive and combined subtypes based on their revised Conner's rating scale score. We then analyzed differences in resting state functional connectivity of the cortico-striatal and attentional networks between these subtypes. We found a double dissociation of functional connectivity in the cortico-striatal and ventral attentional networks, reflecting the subtypes of the ADHD participants. Particularly, the hyperactive–impulsive subtype was associated with increased connectivity in cortico-striatal network, whereas the inattentive subtype was associated with increased connectivity in the right ventral attention network. Our study demonstrated for the first time a right lateralized, double dissociation between specific networks associated with hyperactivity–impulsivity and inattentiveness in ADHD children, providing a biological basis for exploring symptom dimensions and revealing potential targets for more personalized treatments.

La maladie de Parkinson (MP) est la deuxième maladie neurodégénérative la plus commune. Les symptômes principalement observés chez les patients atteints de la MP sont la rigidité, les tremblements, la bradykinésie et une instabilité posturale. Leur sévérité est souvent asymétrique. La cause principale de ces symptômes moteurs est la dégénérescence du circuit dopaminergique nigro-striatal qui mène à un débalancement d’activité du circuit cortico-striatal. Ce débalancement de circuits est le point essentiel de cette thèse. Dans les protocoles de recherche décrits ici, des patients atteints de la MP (avant et après une dose de levodopa) et des participants contrôles sains ont effectué des mouvements auto-initiés ou en réponse à des stimulis externes pendant que l’on mesurait leur activité cérébrale en imagerie par résonance magnétique fonctionnelle (IRMf). Dans cette thèse, nous abordons et mettons en évidence quatre (4) points principaux. En première partie (chapitre 2), nous présentons un recensement de la littérature sur les cicruits cortico-striataux et cortico-cérébelleux dans la MP. En utilisant des méthodes de neuroimagerie, des changements d’activité cérébrale et cérébelleuse ont été observés chez les patients atteints de la MP comparés aux participants sains. Même si les augmentations d’activité du cervelet ont souvent été attribuées à des mécanismes compensatoires, nos résultats suggèrent qu’elles sont plus probablement liées aux changements pathophysiologiques de la MP et à la perturbation du circuit cortico-cérébelleux. En général, nous suggérons (1) que le circuit cortico-cérébelleux est perturbé chez les patients atteints de la MP, et que les changements d’activité du cervelet sont liés à la pathophysiologie de la MP plutôt qu’à des mécanismes compensatoires. En deuxième partie (chapitre 3), nous discutons des effets de la levodopa sur les hausses et baisses d’activité observés chez les patients atteints de la MP, ainsi que sur l’activité du putamen pendant les mouvements d’origine interne et externe. De nombreuses études en neuroimagerie ont montré une baisse d’activité (hypo-activité) préfrontale liée à la déplétion de dopamine. En revanche, l’utilisation de tâches cognitives a montré des augmentations d’activité (hyper-activité) corticale chez les patients atteints de la MP comparés aux participants sains. Nous avons suggéré précédemment que ces hypo- et hyper-activités des régions préfrontales dépendent de l’implication du striatum. Dans cette thèse nous suggérons de plus (2) que la levodopa ne rétablit pas ces hyper-activations, mais plutôt qu’elles sont liées à la perturbation du circuit méso-cortical, et aussi possiblement associées à l’administration de médication dopaminergique à long terme. Nous montrons aussi (3) que la levodopa a un effet non-spécifique à la tâche sur l’activité du circuit cortico-striatal moteur, et qu’elle n’a pas d’effet sur l’activité du circuit cortico-striatal cognitif. Nous montrons enfin (chapitre 4) que la levodopa a un effet asymétrique sur les mouvements de la main droite et gauche. À peu près 50% des patients atteints de la MP démontrent une asymétrie des symptômes moteurs, et ceci persiste à travers la durée de la maladie. Nos résultats suggèrent (4) que la levodopa pourrait avoir un plus grand effet sur les patrons d’activations des mouvements de la main la plus affectée., Parkinson’s disease (PD) is the second most common neurodegenerative disease, mainly manifested by tremor, rigidity, bradykinesia and postural instability, and often an asymmetry of symptom severity of the left and right sides of the body. The depletion of dopamine of the nigrostriatal pathway is the primary cause of the motor symptoms observed in patients with PD, leading to an imbalance in basal-ganglia prefrontal circuits. In the protocols described here, patients with PD before and after levodopa administration and healthy participants performed self-initiated (SI) and externally triggered (ET) movements with the left and right hand during functional magnetic resonance imaging (fMRI). In the chapters of this thesis, we argue and provide evidence for four main points. The first portion (chapter 2) provides a literature review on cortico-striatal and cortico-cerebellar circuit disruption in PD. Using neuroimaging techniques, changes in cerebral and cerebellar activity have been observed in patients with PD compared with healthy participants. Although increases in activity in the cerebellum have often been interpreted as compensatory mechanisms, we provide evidence that they are more likely to be related to pathophysiological changes of the disease, and the disruption of the cortico- cerebellar circuit. In general, we argue (1) is that activity in the cerebellum is linked to the pathophysiology of PD. In the second section (chapter 3) we discuss the effect of levodopa on the patterns of cortical hypo- and hyper-activity in PD, as well as the activity of the putamen in SI and ET movements. Many studies have shown cortical hypo-activity in relation to nigrostriatal dopamine depletion. In contrast, some cognitive studies have also identified increases in cortical activity in patients with PD as compared with healthy control participants. We have previously suggested that cortical hypo- and hyper-activations depend on striatal recruitment. In this thesis, we further show that hyper-activations in the prefrontal cortex are not reestablished with levodopa administration. We suggest (2) that they are rather associated with mesocortical dopamine circuit dysfunction, and perhaps linked with long- term dopaminergic medication administration. Furthermore, we show (3) that levodopa has a non-task specific effect on the motor cortico-striatal loop, but does not affect the cognitive cortico-striatal circuit. Finally (chapter 4), we show that the effect of levodopa on movements of the left and right hands is not symmetrical. Previous studies have shown that in about 50% of patients, one side of the body is more severely affected, and this asymmetry persists throughout the duration of the disease. Our results suggest (4) that levodopa may have stronger effects on the cerebral hemodynamic patterns related to the movements of the more affected hand than on those of the less affected hand.

Visual object recognition occurs easily despite differences in position, size, and rotation of the object, but the neural mechanisms responsible for this invariance are not known. We have found a set of transforms that achieve invariance in a neurally plausible way. We find that a transform based on local spatial frequency analysis of oriented segments and on logarithmic mapping, when applied twice in an iterative fashion, produces an output image that is unique to the object and that remains constant as the input image is shifted, scaled, or rotated.

Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric condition estimated to afflict 1-3% of the world population. The estimated financial impact in the treatment and management of OCD is in the billions of dollars annually in the US alone. At present there is a marked lack of evidence on the specific causes of OCD. Current hypotheses largely focus on the serotonin (5-HT) system on the basis of the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in alleviating symptoms of patients with OCD, yet a considerable fraction of patients are non-responsive or minimally responsive to these agents. Despite this fact, SSRIs have remained the primary pharmacological treatment avenue for OCD. In recent years, multiple lines of evidence have implicated glutamatergic synaptic dysfunction within the cortico-striatal-thalamo-cortical (CSTC) brain circuit in the etiology of OCD and related disorders, thereby prompting intensified effort in the development and evaluation of agents that modulate glutamatergic neurotransmission for the treatment of OCD. With this in mind, here we review the following topics with respect to synaptic dysfunction and the neural circuitry underlying OCD: (1) evidence supporting the critical involvement of the CSTC circuit, (2) genetic studies supporting the involvement of glutamatergic dysfunction, (3) insights from genetic animal models of OCD, and (4) preliminary findings with glutamatergic neurotransmission-modulating agents in the treatment of OCD. Given the putative mechanistic overlap between OCD and the broader OC-spectrum of disorders, unraveling the synaptic basis of OCD has potential to translate into more effective treatments for an array of poorly understood human disorders.