Dysfunctions in frontostriatal brain circuits have been implicated in neuropsychiatric disorders, including those characterized by the presence of repetitive behaviors. We developed an optogenetic approach to block repetitive, compulsive behavior in a mouse model in which deletion of the synaptic scaffolding gene, Sapap3, results in excessive grooming. With a delay-conditioning task, we identified in the mutants a selective deficit in behavioral response inhibition and found this to be associated with defective down-regulation of striatal projection neuron activity. Focused optogenetic stimulation of the lateral orbitofrontal cortex and its terminals in the striatum restored the behavioral response inhibition, restored the defective down-regulation, and compensated for impaired fast-spiking neuron striatal microcircuits. These findings raise promising potential for the design of targeted therapy for disorders involving excessive repetitive behavior.

Increasing evidence implicates abnormalities in corticostriatal circuits in the pathophysiology of obsessive-compulsive disorder (OCD) and OC-spectrum disorders. Parallels between the emergence of repetitive, compulsive behaviors and the acquisition of automated behaviors suggest that the expression of compulsions could in part involve loss of control of such habitual behaviors. The view that striatal circuit dysfunction is involved in OC-spectrum disorders is strengthened by imaging and other evidence in humans, by discovery of genes related to OCD syndromes, and by functional studies in animal models of these disorders. We highlight this growing concordance of work in genetics and neurobiology suggesting that frontostriatal circuits, and their links with basal ganglia, thalamus and brainstem, are promising candidates for therapeutic intervention in OCD.

The acquisition of language and speech is uniquely human, but how genetic changes might have adapted the nervous system to this capacity is not well understood. Two human-specific amino acid substitutions in the transcription factor forkhead box P2 (FOXP2) are outstanding mechanistic candidates, as they could have been positively selected during human evolution and as FOXP2 is the sole gene to date firmly linked to speech and language development. When these two substitutions are introduced into the endogenous Foxp2 gene of mice (Foxp2 hum ), cortico-basal ganglia circuits are specifically affected. Here we demonstrate marked effects of this humanization of Foxp2 on learning and striatal neuroplasticity. Foxp2 hum/hum mice learn stimulus-response associations faster than their WT littermates in situations in which declarative (i.e., place-based) and procedural (i.e., response-based) forms of learning could compete during transitions toward proceduralization of action sequences. Striatal districts known to be differently related to these two modes of learning are affected differently in the Foxp2 hum/hum mice, as judged by measures of dopamine levels, gene expression patterns, and synaptic plasticity, including an NMDA receptor-dependent form of long-term depression. These findings raise the possibility that the humanized Foxp2 phenotype reflects a different tuning of corticostriatal systems involved in declarative and procedural learning, a capacity potentially contributing to adapting the human brain for speech and language acquisition.T he gene encoding the transcription factor forkhead box P2 (FOXP2) is a promising candidate for investigating the evolutionary basis of human speech and language capabilities. Humans carrying only one functional copy of this transcription factor experience difficulties in learning and performing complex orofacial movements and have receptive and expressive deficits in oral and written language, whereas other cognitive skills are less affected. These speech and language deficits are associated with functional impairments in cortico-basal ganglia and corticocerebellar circuits (1). Since the time that the human and chimpanzee lineages separated, approximately 6 Mya, two amino acid substitutions have occurred in FOXP2, a higher rate of change than expected given its conservation in mammals (2, 3). Mice in which the endogenous Foxp2 gene has been "humanized" for these two amino acid changes (Foxp2 hum/hum mice) exhibit prominent neurochemical, neurophysiological, and neuroanatomical alterations in the striatum and related cortico-basal ganglia circuits (4, 5). These circuits are known to be essential for acquiring habits and other motor and cognitive behaviors (6), including vocal learning in songbirds (7) and speech and language capabilities in humans (8). However, whether learning behavior depending on these circuits is affected in Foxp2 hum/hum mice has so far not been investigated.A key functional distinction has been made between subregions of the striatum that underlie modes o...

L7-PKCI transgenic mice, having a specific lack of parallel fiber-Purkinje cell LTD, were tested with two different mazes to dissociate the relative importance of declarative and procedural components of spatial navigation. Our data bring evidence for a deficit of L7-PKCI mice in the acquisition of an adapted goal-oriented behavior, i.e. in the procedural component of the task. This finding supports the hypothesis that cerebellar LTD may subserve a general sensory-motor adaptation process shared by motor and spatial learning functions.3 Spatial navigation offers a suitable framework to study the ability of animals to adapt their behavior to a specific context, defined here as the combination of the multimodal information sensed by the animal and its internal state at a specific time.Spatial navigation requires at least two complementary processes: (i) the elaboration of a spatial representation of the environment (declarative component), enabling the animal to encode the spatio-temporal relationships among environmental cues or events; (ii) the acquisition of a motor behavior adapted to the context in which navigation takes place (procedural component), permitting the execution of optimal (direct) trajectories toward rewarding locations 1 . Several types of cerebellar animal models have been tested in spatial navigation tasks 2 (Supplementary Note). The consensus that emerged from these studies points toward a role of the cerebellum in mediating the procedural component of the spatial navigation function. We focused on the cellular mechanisms subserving the contribution of the cerebellum in spatial learning. Our working hypothesis is that cerebellar Long-Term synaptic Depression (LTD), occurring at the parallel fiber-Purkinje cell (PF-PC) synapses and required for the acquisition of classical conditioning tasks 3 , may also be necessary for the acquisition of efficient trajectories toward a spatial goal through a basic and common process of sensory-motor adaptation.We (synaptic transmission and plasticity), known to be essential for navigation tasks, appeared also to be conserved in L7-PKCI mice (Supplementary Fig. 1).In order to dissociate the relative importance of the declarative and procedural components of navigation, we adopted two different behavioral paradigms: the Morris water maze (MWM) and a new task called the Starmaze (Fig. 1). In both cases, the animal has to find a fixed hidden platform from random departure locations, which requires the declarative capability of learning a spatial representation of the environment. Yet, in contrast to the MWM task, the Starmaze allows the animal to 4 only swim within alleys guiding its movements. This helps to execute goal-directed trajectories effectively, and reduces the procedural demand of the task.To compare the navigation performances of L7-PKCI mice (n = 14) and their control littermates (n = 15) when solving the hidden-platform version of the MWM, we first used three standard parameters: (i) The mean escape latency, measuring the time employed by ...

Obsessive-compulsive disorder (OCD) is a mental disorder featuring obsessions (intrusive thoughts) and compulsions (repetitive behaviors performed in the context of rigid rituals). There is strong evidence for a neurobiological basis of this disorder, involving limbic cortical regions and related basal ganglion areas. However, more research is needed to lift the veil on the precise nature of that involvement and the way it drives the clinical expression of OCD. Altered cognitive functions may underlie the symptoms and thus draw a link between the clinical expression of the disorder and its neurobiological etiology. Our extensive review demonstrates that OCD patients do present a broad range of neuropsychological dysfunctions across all cognitive domains (memory, attention, flexibility, inhibition, verbal fluency, planning, decision-making), but some methodological issues temper this observation. Thus, future research should have a more integrative approach to cognitive functioning, gathering contributions of both experimental psychology and more fundamental neurosciences.

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Learning a new goal-directed behavioral task often requires the improvement of at least two processes, including an enhanced stimulusresponse association and an optimization of the execution of the motor response. The cerebellum has recently been shown to play a role in acquiring goal-directed behavior, but it is unclear to what extent it contributes to a change in the stimulus-response association and/or the optimization of the execution of the motor response. We therefore designed the stimulus-dependent water Y-maze conditioning task, which allows discrimination between both processes, and we subsequently subjected Purkinje cell-specific mutant mice to this new task. The mouse mutants L7-PKCi, which suffer from impaired PKC-dependent processes such as parallel fiber to Purkinje cell long-term depression (PF-PC LTD), were able to acquire the stimulus-response association, but exhibited a reduced optimization of their motor performance. These data show that PF-PC LTD is not required for learning a stimulus-response association, but they do suggest that a PKC-dependent process in cerebellar Purkinje cells is required for optimization of motor responses.

Head direction cells, which are functionally coupled to 'place' cells of the hippocampus, a structure critically involved in spatial cognition, are likely neural substrates for the sense of direction. Here we studied the mechanism by which head direction cells are principally anchored to background visual cues [M.B. Zugaro et al. (2001) J. Neurosci., 21, RC154,1-5]. Anterodorsal thalamic head direction cells were recorded while the rat foraged on a small elevated platform in a 3-m diameter cylindrical enclosure. A large card was placed in the background, near the curtain, and a smaller card was placed in the foreground, near the platform. The cards were identically marked, proportionally dimensioned, subtended the same visual angles from the central vantage point and separated by 90 degrees. The rat was then disoriented in darkness, the cards were rotated by 90 degrees in opposite directions about the center and the rat was returned. Preferred directions followed either the background card, foreground card or midpoint between the two cards. In continuous lighting, preferred directions shifted to follow the background cue in most cases (30 of the 53 experiments, Batschelet V-test, P < 0.01). Stroboscopic illumination, which perturbs dynamic visual signals (e.g. motion parallax), blocked this selectivity. Head direction cells remained equally anchored to the background card, foreground card or configuration of the two cards (Watson test, P > 0.1). This shows that dynamic visual signals are critical in distinguishing typically more stable background cues which govern spatial neuronal responses and orientation behaviors.