Postnatal Tshz3 Deletion Drives Altered Corticostriatal Function and Autism Spectrum Disorder–like Behavior

International audienceBACKGROUND: Heterozygous deletion of the TSHZ3 gene, encoding for the teashirt zinc-finger homeobox family member 3 (TSHZ3) transcription factor that is highly expressed in cortical projection neurons (CPNs), has been linked to an autism spectrum disorder (ASD) syndrome. Similarly, mice with Tshz3 haploinsufficiency show ASD-like behavior, paralleled by molecular changes in CPNs and corticostriatal synaptic dysfunctions. Here, we aimed at gaining more insight into "when" and "where" TSHZ3 is required for the proper development of the brain, and its deficiency crucial for developing this ASD syndrome. METHODS: We generated and characterized a novel mouse model of conditional Tshz3 deletion, obtained by crossing Tshz3 flox/flox with CaMKIIalpha-Cre mice, in which Tshz3 is deleted in CPNs from postnatal day 2 to 3 onward. We characterized these mice by a multilevel approach combining genetics, cell biology, electrophysiology, behavioral testing, and bioinformatics. RESULTS: These conditional Tshz3 knockout mice exhibit altered cortical expression of more than 1000 genes, w50% of which have their human orthologue involved in ASD, in particular genes encoding for glutamatergic syn-apse components. Consistently, we detected electrophysiological and synaptic changes in CPNs and impaired corticostriatal transmission and plasticity. Furthermore, these mice showed strong ASD-like behavioral deficits. CONCLUSIONS: Our study reveals a crucial postnatal role of TSHZ3 in the development and functioning of the corticostriatal circuitry and provides evidence that dysfunction in these circuits might be determinant for ASD pathogenesis. Our conditional Tshz3 knockout mouse constitutes a novel ASD model, opening the possibility for an early postnatal therapeutic window for the syndrome linked to TSHZ3 haploinsufficiency

Modelling of sensory and motor loops on the scale of a musculoskeletal articulated segment

Les modèles biomécaniques éléments finis (EF) sont couramment utilisés dans de nombreux domaines. Ces modèles tendent depuis quelques années à être actifs, capable donc de générer des efforts musculaires et des mouvements. L’étape suivante consiste à rendre ces modèles réactifs, c’est-à-dire capable de réagir à une situation quelconque par des contractions musculaires et des mouvements. C’est dans cet optique que ce projet a été décomposé en 3 étapes. La première consistait à réaliser un modèle biomécanique détaillé capable de contractions musculaires et de mouvements. La seconde étape consistait à introduire des réflexes. Pour cela des modèles de capteurs sensoriels (fuseaux neuromusculaires et organes tendineux de golgi) et les réflexes associés (réflexes myotatiques et myotatiques inverses) ont ensuite été introduits au sein même du modèle. Le modèle ainsi obtenu a pu ensuite être validé grâce à une campagne expérimentale de quantification du réflexe d’étirement du tendon du biceps brachial. La dernière étape consistait à introduire des réactions de niveau supérieur, c’est-à-dire des mouvements volontaires. Pour cela une méthode de contrôle basée sur de l’apprentissage et l’optimisation a permis de générer ces mouvements et de les contrôler.En conclusion, l’introduction de boucles sensorielles et motrices de différents niveaux dans un modèle EF permet de rendre ce dernier réactif à son environnement. En effet, le modèle est ainsi capable de générer un mouvement selon des objectifs et des contraintes. Il est également capable d’adapter la contraction musculaire en fonction des évènements intervenant lors de la réalisation du mouvement.Biomechanical finite elements (FE) models are commonly used in the field of road safety, sport and medicine. These models tended in recent years to be active, i.e. able to generate muscular efforts or movements. The next step is to make these models reactive, i.e. able to react to a situation with muscle contractions and movement. It is in this context that this project was broken down into 3 steps. The first step was to create a detailed biomechanical model capable of movements and muscle contractions. The second step was to introduce reflexes. For this, physiological sensors models (neuromuscular spindles and golgi tendon organs) and the associated reflexes associated (myotatic and inverse myotatic reflexes) were then integrated into the model. The model thus obtained could then be validated thanks to an experimental campaign of characterization of the deep tendon reflex of the biceps brachial. The last step was to introduce higher-level reactions, i.e. voluntary movements. For this purpose, a control method based on learning and optimization has made it possible to generate and control these movements.In conclusion, the introduction of sensory and motor loops of different into an FE model makes the latter reactive to its environment. Indeed, the model is thus able to generate a movement according to objectives and constraints. He is also able to adapt the muscular contraction according to the events intervening during the realization of the movement

Implementation of reflex loops in a biomechanical finite element model

In the field of biomechanics, the offer of models which are more and more realistic requires to integrate a physiological response, in particular, the controlled muscle bracing and the reflexes. The following work aims to suggest a unique methodology which couples together a sensory and motor loop with a finite element model. Our method is applied to the study of the oscillation of the elbow in the case of a biceps brachial stretch reflex. The results obtained are promising in the purpose of the development of reactive human body models

Real-Time Analysis of the Dynamic Foot Function: A Machine Learning and Finite Element Approach

International audienceAbstract Finite element analysis (FEA) has been widely used to study foot biomechanics and pathological functions or effects of therapeutic solutions. However, development and analysis of such foot modeling is complex and time-consuming. The purpose of this study was therefore to propose a method coupling a FE foot model with a model order reduction (MOR) technique to provide real-time analysis of the dynamic foot function. A generic and parametric FE foot model was developed and dynamically validated during stance phase of gait. Based on a design of experiment of 30 FE simulations including four parameters related to foot function, the MOR method was employed to create a prediction model of the center of pressure (COP) path that was validated with four more random simulations. The four predicted COP paths were obtained with a 3% root-mean-square-error (RMSE) in less than 1 s. The time-dependent analysis demonstrated that the subtalar joint position and the midtarsal joint laxity are the most influential factors on the foot functions. These results provide additionally insight into the use of MOR technique to significantly improve speed and power of the FE analysis of the foot function and may support the development of real-time decision support tools based on this method

Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors

We previously linked TSHZ3 haploinsufficiency to autism spectrum disorder (ASD) and showed that embryonic or postnatal Tshz3 deletion in mice results in behavioral traits relevant to the two core domains of ASD, namely social interaction deficits and repetitive behaviors. Here, we provide evidence that cortical projection neurons (CPNs) and striatal cholinergic interneurons (SCINs) are two main and complementary players in the TSHZ3-linked ASD syndrome. We show that in the cerebral cortex, TSHZ3 is expressed in CPNs and in a proportion of GABA interneurons, while not in cholinergic interneurons or glial cells. TSHZ3-expressing cells, which are predominantly SCINs in the striatum, represent a low proportion of neurons in the ascending cholinergic projection system. We then characterized two new conditional knockout (cKO) models generated by crossing Tshz3 flox/flox with Emx1-Cre ( Emx1-cKO ) or Chat-Cre ( Chat-cKO ) mice to decipher the respective role of CPNs and SCINs. Emx1-cKO mice show altered excitatory synaptic transmission onto CPNs and plasticity at corticostriatal synapses, with neither cortical neuron loss nor impaired layer distribution. These animals present social interaction deficits but no repetitive patterns of behavior. Chat-cKO mice exhibit no loss of SCINs but changes in the electrophysiological properties of these interneurons, associated with repetitive patterns of behavior without social interaction deficits. Therefore, dysfunction in either CPNs or SCINs segregates with a distinct ASD behavioral trait. These findings provide novel insights onto the implication of the corticostriatal circuitry in ASD by revealing an unexpected neuronal dichotomy in the biological background of the two core behavioral domains of this disorder

Cellular and behavioral outcomes of dorsal striatonigral neuron ablation: new insights into striatal functions

International audienceThe striatum is the input structure of the basal ganglia network that contains heterogeneous neuronal populations, including two populations of projecting neurons called the medium spiny neurons (MSNs), and different types of interneurons. We developed a transgenic mouse model enabling inducible ablation of the striatonigral MSNs constituting the direct pathway by expressing the human diphtheria toxin (DT) receptor under the control of the Slc35d3 gene promoter, a gene enriched in striatonigral MSNs. DT injection into the striatum triggered selective elimination of the majority of striatonigral MSNs. DT-mediated ablation of striatonigral MSNs caused selective loss of cholinergic interneurons in the dorsal striatum but not in the ventral striatum (nucleus accumbens), suggesting a region-specific critical role of the direct pathway in striatal cholinergic neuron homeostasis. Mice with DT injection into the dorsal striatum showed altered basal and cocaine-induced locomotion and dramatic reduction of L-DOPA-induced dyskinesia in the parkinsonian condition. In addition, these mice exhibited reduced anxiety, revealing a role of the dorsal striatum in the modulation of behaviors involving an emotional component, behaviors generally associated with limbic structures. Altogether, these results highlight the implication of the direct striatonigral pathway in the regulation of heterogeneous functions from cell survival to regulation of motor and emotion-associated behaviors