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

Of pride and groom: The gains and limits of studying the neuroanatomy of rodent self-grooming in translational research

International audienceIn this issue of Neuron, Xie et al. characterize a cell-specific premotor circuit, generating rhythmic orofacial forelimb movements. The authors show that neurons of the caudal part of spinal trigeminal nucleus, expressing Cerebellin-2, are necessary and sufficient for triggering forelimb movements, which form a part of rodent self-grooming

Closed-loop recruitment of striatal interneurons prevents compulsive-like grooming behaviors

International audienceCompulsive behaviors have been associated with striatal hyperactivity. Parvalbumin-positive striatal interneurons (PVIs) in the striatum play a crucial role in regulating striatal activity and suppressing prepotent inappropriate actions. To investigate the potential role of striatal PVIs in regulating compulsive behaviors, we assessed excessive self-grooming—a behavioral metric of compulsive-like behavior—in male Sapap3 knockout mice (Sapap3-KO). Continuous optogenetic activation of PVIs in striatal areas receiving input from the lateral orbitofrontal cortex reduced self-grooming events in Sapap3-KO mice to wild-type levels. Aiming to shorten the critical time window for PVI recruitment, we then provided real-time closed-loop optogenetic stimulation of striatal PVIs, using a transient power increase in the 1–4 Hz frequency band in the orbitofrontal cortex as a predictive biomarker of grooming onsets. Targeted closed-loop stimulation at grooming onsets was as effective as continuous stimulation in reducing grooming events but required 87% less stimulation time, paving the way for adaptive stimulation therapeutic protocols

Closed-loop recruitment of striatal parvalbumin interneurons prevents the onset of compulsive behaviours

ABSTRACT A prominent electrophysiological feature of compulsive behaviours is striatal hyperactivity, yet, its underlying regulatory processes still need to be characterised. Within the striatum, parvalbumin-positive interneurons (PVI) exert a powerful feed-forward inhibition essential for the regulation of striatal activity and are implied in the suppression of prepotent inappropriate actions. To investigate the potential role of striatal PVI in regulating striatal activity and compulsive behaviours, we used the Sapap3 knockout mice (Sapap3-KO), which exhibit compulsive-like self-grooming. We first showed that the number of compulsive-like events in Sapap3-KO mice was reduced to normal levels by continuous optogenetic activation of striatal PVI in the centromedial striatum. To narrow down the critical time window of striatal PVI recruitment for regulating compulsive-like grooming, we then developed a novel closed-loop optogenetic stimulation pipeline. Upon a predictive biomarker of grooming onsets, characterised by a transient power increase of 1-4 Hz frequency band in the orbitofrontal cortex, we provided real-time closed-loop stimulation of striatal PVI. This targeted closed-loop optogenetics approach reduced grooming events as efficiently as continuous recruitment of striatal PVI with a reduction of stimulation time of 87%. Together, these results demonstrated that recruitment of striatal PVI at the initiation of the compulsive events is sufficient to drastically reduce compulsive-like behaviours and pave the way for targeted closed-loop therapeutic protocols

Reduced Axon Calibre in the Associative Striatum of the Sapap3 Knockout Mouse

International audiencePathological repetitive behaviours are a common feature of various neuropsychiatric disorders, including compulsions in obsessive–compulsive disorder or tics in Gilles de la Tourette syndrome. Clinical research suggests that compulsive-like symptoms are related to associative cortico-striatal dysfunctions, and tic-like symptoms to sensorimotor cortico-striatal dysfunctions. The Sapap3 knockout mouse (Sapap3-KO), the current reference model to study such repetitive behaviours, presents both associative as well as sensorimotor cortico-striatal dysfunctions. Previous findings point to deficits in both macro-, as well as micro-circuitry, both of which can be affected by neuronal structural changes. However, to date, structural connectivity has not been analysed. Hence, in the present study, we conducted a comprehensive structural characterisation of both associative and sensorimotor striatum as well as major cortical areas connecting onto these regions. Besides a thorough immunofluorescence study on oligodendrocytes, we applied AxonDeepSeg, an open source software, to automatically segment and characterise myelin thickness and axon area. We found that axon calibre, the main contributor to changes in conduction speed, is specifically reduced in the associative striatum of the Sapap3-KO mouse; myelination per se seems unaffected in associative and sensorimotor cortico-striatal circuits

A neuroscientific approach to increase gender equality

International audienceTo the Editor-Gender inequality is prevalent in many countries and cultures, and it persists despite our awareness of it and the policies some countries have put in place to combat it. France, for example, offers significant opportunities to enable women to handle both career and personal life: it provides a social healthcare system that was ranked No. 1 by the World Health Organization in 2000, a legal framework promoting gender equality 1 , and relatively accessible and affordable childcare and scholastic infrastructure. Herein lies the paradox: despite France having a strong reputation for providing a favourable social and professional context, French women still lag behind French men in their careers. One of the main reasons gender inequality persists despite this supportive infrastructure is the perpetuation of implicit biases and gender stereotypes. These shape the way we behave, our ability to recognize unequal treatment, the willingness of disadvantaged individuals to speak up, and even the research conducted in institutions that have been raising awareness of gender inequalities in science since 2001 2,

Systemic bis-phosphinic acid derivative restores chloride transport in Cystic Fibrosis mice

International audienceMutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) are responsible for Cystic Fibrosis (CF). The most common CF-causing mutation is the deletion of the 508th aminoacid of CFTR (F508del), leading to dysregulation of the epithelial fluid transport in the airway's epithelium and the production of a thickened mucus favoring chronic bacterial colonization, sustained inflammation and ultimately respiratory failure. c407 is a bis-phosphinic acid derivative which corrects CFTR dysfunction in epithelial cells carrying the F508del mutation. This study aimed to investigate c407 in vivo activity in the F508del Cftr tm1Eur murine model of CF. Using nasal potential difference measurement, we showed that in vivo administration of c407 by topical, short-term intraperitoneal and long-term subcutaneous route significantly increased the CFTR dependent chloride (Cl −) conductance in F508del Cftr tm1Eur mice. This functional improvement was correlated with a relocalization of F508del-cftr to the apical membrane in nasal epithelial cells. Importantly, c407 long-term administration was well tolerated and in vitro ADME toxicologic studies did not evidence any obvious issue. Our data provide the first in vivo preclinical evidence of c407 efficacy and absence of toxicity after systemic administration for the treatment of Cystic Fibrosis

A Humanized Version of Foxp2 Affects Cortico-Basal Ganglia Circuits in Mice

It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting that the humanized Foxp2 allele affects basal ganglia. In the striatum, a part of the basal ganglia affected in humans with a speech deficit due to a nonfunctional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one nonfunctional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans