Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance

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[superscript hum]), cortico-basal ganglia circuits are specifically affected. Here we demonstrate marked effects of this humanization of Foxp2 on learning and striatal neuroplasticity. Foxp2[superscript 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[superscript 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.Nancy Lurie Marks Family FoundationSimons Foundation (Autism Research Initiative Grant 137593)National Institutes of Health (U.S.) (Grant R01 MH060379)Wellcome Trust (London, England) (Grant 075491/Z/04)Wellcome Trust (London, England) (Grant 080971)Fondation pour la recherche medicaleMax Planck Society for the Advancement of Scienc

Rôle de la DLT cérébelleuse hétérosynaptique des fibres parallèles dans la navigation

Récemment, il a été proposé que le cervelet participe à l acquisition de fonctions cognitives telle que la navigation. Un des mécanismes de plasticité synaptique du cervelet, la Dépression synaptique à Long Terme hétérosynaptique des fibres parallèles (DLT), est déjà connu pour être impliqué dans les apprentissages moteurs. L objectif de ce travail de thèse était de déterminer si cette DLT participe également à l acquisition d une tâche de navigation. A l aide de tests de navigation développés dans l équipe, j ai étudié les performances de souris transgéniques L7-PKCI dont ce mécanisme de DLT est altéré. Dans ces tests, les souris L7-PKCI étaient déficientes dans la capacité à élaborer une trajectoire efficace pour rejoindre leur but. Ces résultats suggèrent qu un rôle essentiel du cervelet dans la navigation, et plus particulièrement de la DLT, est d adapter en permanence la sortie motrice afin d effectuer une trajectoire optimale.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Optogenetic Stimulation of Lateral Orbitofronto-Striatal Pathway Suppresses Compulsive Behaviors

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.Massachusetts Institute of Technology. Simons Center for the Social BrainEunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (NIH R37 HD028341)United States. Defense Advanced Research Projects Agency (W911NF1010059)National Institute of Mental Health (U.S.) (NIH R01 MH081201

Striatal circuits, habits, and implications for obsessive–compulsive disorder

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.Simons Initiative on Autism and the BrainUnited States. Defense Advanced Research Projects Agency (W911NF-10-1-0059)Simons Foundation. Autism Research Initiativ

A Navigation Analysis Tool (NAT) to assess spatial behavior in open-field and structured mazes

International audienceSpatial navigation calls upon mnemonic capabilities (e.g. remembering the location of a rewarding site) as well as adaptive motor control (e.g. fine tuning of the trajectory according to the ongoing sensory context). To study this complex process by means of behavioral measurements it is necessary to quantify a large set of meaningful parameters on multiple time scales (from milliseconds to several minutes), and to compare them across different paradigms. Moreover, the issue of automating the behavioral analysis is critical to cope with the consequent computational load and the sophistication of the measurements. We developed a general purpose Navigation Analysis Tool (NAT) that provides an integrated architecture consisting of a data management system (implemented in MySQL), a core analysis toolbox (in MATLAB), and a graphical user interface (in JAVA). Its extensive characterization of trajectories over time, from exploratory behavior to goal-oriented navigation with decision points using a wide range of parameters, makes NAT a powerful analysis tool. In particular, NAT supplies a new set of specific measurements assessing performances in multiple intersection mazes and allowing navigation strategies to be discriminated (e.g. in the starmaze). Its user interface enables easy use while its modular organization provides many opportunities of extension and customization. Importantly, the portability of NAT to any type of maze and environment extends its exploitation far beyond the field of spatial navigation

CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors

CalDAG-GEFI (CDGI) is a protein highly enriched in the striatum, particularly in the principal spiny projection neurons (SPNs). CDGI is strongly down-regulated in two hyperkinetic conditions related to striatal dysfunction: Huntingtons disease and levodopa-induced dyskinesia in Parkinsons disease. We demonstrate that genetic deletion of CDGI in mice disrupts dendritic, but not somatic, M1 muscarinic receptors (M1Rs) signaling in indirect pathway SPNs. Loss of CDGI reduced temporal integration of excitatory postsynaptic potentials at dendritic glutamatergic synapses and impaired the induction of activity-dependent long-term potentiation. CDGI deletion selectively increased psychostimulant-induced repetitive behaviors, disrupted sequence learning, and eliminated M1R blockade of cocaine self-administration. These findings place CDGI as a major, but previously unrecognized, mediator of cholinergic signaling in the striatum. The effects of CDGI deletion on the selfadministration of drugs of abuse and its marked alterations in hyperkinetic extrapyramidal disorders highlight CDGIs therapeutic potential.Funding Agencies: William N. &amp; Bernice E. Bumpus Foundation; Saks Kavanaugh Foundation; Simons Foundation; National Institute of Child Health and Development United States Department of Health &amp; Human Services National Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health &amp; Human Development (NICHD) [R37 HD028341]; James and Pat Poitras Research Fund; Stanley Center for Psychiatric Research at the Broad Institute; National Institute of Mental Health United States Department of Health &amp; Human Services National Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01 MH071847, F32 MH065815]; National Institute on Aging United States Department of Health &amp; Human Services National Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) [R01 AG050548]; European Community FP7 - The-matic priority HEALTH contract [222918]; Ministry of Health; JPB Foundation; National Institute on Drug Abuse United States Department of Health &amp; Human Services National Institutes of Health (NIH) - USANIH National Institute on Drug Abuse (NIDA) European Commission [R00 DA027825, R01 DA07418]</p