Данная работа посвящена исследованию особенностей сенсомоторного и когнитивного развития недоношенных младенцев. Недоношенность рассматривается как симптомокомплекс, который реализуется за счет многих разнообразных механизмов. На основе работ отечественных и зарубежных авторов проведен анализ наиболее часто встречающихся форм неинфекционных перинатальных патологий, в частности недоношенности. В эмпирическом исследовании с помощью однофакторного дисперсионного анализа было проведено сравнение показателей уровня развития сенсомоторных и когнитивных функций у доношенных и недоношенных младенцев в возрасте от 6 до 13 месяцев. Для реализации исследования были сформированы три группы: экспериментальная (недоношенные дети) и 2 контрольных группы (соответствующие по хронологическому и гестационному возрасту). На основе полученных данных делается вывод, что недоношенные дети демонстрируют отставание в развитии моторики при типичном развитии когнитивных функций. / This work is devoted to research of sensorimotor and cognitive development in premature infants. Prematurity is considered as a set of symptoms, which is being implemented by many mechanisms. It was analyzed the most common forms of non-infectious perinatal pathology, particularly prematurity using the works of Russian and foreign researchers. It was conducted comparison of the level of development of sensorimotor and cognitive functions in term and preterm infants aged 6 to 13 months using one-way ANOVA. Three groups were formed: experimental (premature babies), and two control groups (corresponding to chronological and gestational age). It was shown that preterm infants have delay in motor development and typical development of cognitive functions.

Human and animal studies show significant delays in neurobehavioral development in offspring after prolonged prenatal exposure to moderate and high ethanol doses resulting in high blood alcohol concentration (BECs). However, none have investigated the effects of lower ethanol doses given acutely during specific developmental time periods. Here, we sought to create a mouse model for modest and circumscribed human drinking during the 3rd and 4th weeks of pregnancy.We acutely treated mice during embryo gastrulation on gestational day (GD) 7 or neurulation on GD8 with a low or moderate ethanol dose given via gavage that resulted in BECs of 107 and 177. mg/dl, respectively. We assessed neonatal physical development (pinnae unfolding, and eye opening); weight gain from postnatal day (PD) 3-65; and neurobehavioral maturation (pivoting, walking, cliff aversion, surface righting, vertical screen grasp, and rope balance) from PD3 to 17. We used a multiple linear regression model to determine the effects of dose, sex, day of treatment and birth in animals dosed during gastrulation or neurulation, relative to their vehicle controls.We found that ethanol exposure during both time points (GD7 and GD8) resulted in some delays of physical development and significant sensorimotor delays of pivoting, walking, and thick rope balance, as well as additional significant delays in cliff aversion and surface righting after GD8 treatment. We also found that treatment with the low ethanol dose more frequently affected neurobehavioral development of the surviving pups than treatment with the moderate ethanol dose, possibly due to a loss of severely affected offspring. Finally, mice born prematurely were delayed in their physical and sensorimotor development.Importantly, we showed that brief exposure to low dose ethanol, if administered during vulnerable periods of neuroanatomical development, results in significant neurobehavioral delays in neonatal mice. We thus expand concerns about alcohol consumption during the 3rd and 4th weeks of human pregnancy to include occasional light to moderate drinking.

Yes / Born in Bradford (BiB) is a prospective multi-ethnic pregnancy and birth cohort study that was established to examine determinants of health and development during childhood and, subsequently, adult life in a deprived multi-ethnic population in the north of England. Between 2007 and 2010, the BiB cohort recruited 12,453 women who experienced 13,776 pregnancies and 13,858 births, along with 3353 of their partners. Forty five percent of the cohort are of Pakistani origin. Now that children are at primary school, the first full follow-up of the cohort is taking place. The aims of the follow-up are to investigate the determinants of children's pre-pubertal health and development, including through understanding parents' health and wellbeing, and to obtain data on exposures in childhood that might influence future health. Methods: We are employing a multi-method approach across three data collection arms (community-based family visits, school based physical assessment, and whole classroom cognitive, motor function and wellbeing measures) to follow-up over 9000 BiB children aged 7-11 years and their families between 2017 and 2021. We are collecting detailed parent and child questionnaires, cognitive and sensorimotor assessments, blood pressure, anthropometry and blood samples from parents and children. Dual x-ray absorptiometry body scans, accelerometry and urine samples are collected on subsamples. Informed consent is collected for continued routine data linkage to health, social care and education records. A range of engagement activities are being used to raise the profile of BiB and to disseminate findings. Discussion: Our multi-method approach to recruitment and assessment provides an efficient method of collecting rich data on all family members. Data collected will enhance BiB as a resource for the international research community to study the interplay between ethnicity, socioeconomic circumstances and biology in relation to cardiometabolic health, mental health, education, cognitive and sensorimotor development and wellbeing. / BiB receives core infrastructure funding from the Wellcome Trust (WT101597MA) and the National Institute for Health Research (NIHR) under its Collaboration for Applied Health Research and Care (CLAHRC) for Yorkshire and Humber and Clinical Research Network (CRN) research delivery support. Further support for genome-wide and multiple ‘omics measurements is from the UK Medical Research Council (G0600705), National Institute of Health Research (NF-SI-0611-10196), US National Institute of Health (R01 DK10324), and the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013) / ERC grant agreement no 669545. The follow-up of BiB participants, which is the focus of this paper, is funded by a joint grant from the UK Medical Research Council and UK Economic and Social Science Research Council (MR/N024397/1) and a grant from the British Heart Foundation (CS/16/4/32482.) D.A.L. works in a unit that receives UK Medical Research Council funding (MC_UU_00011/6) and is a UK National Institute of Health Research senior investigator (NF-SI-0611-10196).

L'être humain utilise trois systèmes sensoriels distincts pour réguler le maintien de la station debout: la somesthésie, le système vestibulaire, et le système visuel. Le rôle de la vision dans la régulation posturale demeure peu connu, notamment sa variabilité en fonction de l'âge, du type développemental, et des atteintes neurologiques. Dans notre travail, la régulation posturale induite visuellement a été évaluée chez des participants au développement et vieillissement normaux âgés de 5-85 ans, chez des individus autistes (développement atypique) âgés de 12-33 ans, ainsi que chez des enfants entre 9-18 ans ayant subi un TCC léger. À cet effet, la réactivité posturale des participants en réponse à un tunnel virtuel entièrement immersif, se mouvant à trois niveaux de vélocité, a été mesurée; des conditions contrôles, où le tunnel était statique ou absent, ont été incluses. Les résultats montrent que la réactivité (i.e. instabilité) posturale induite visuellement est plus élevée chez les jeunes enfants; ensuite, elle s'atténue pour rejoindre des valeurs adultes vers 16-19 ans et augmente de façon linéaire en fonction de l'âge après 45 ans jusqu'à redevenir élevée vers 60 ans. De plus, à la plus haute vélocité du tunnel, les plus jeunes participants autistes ont manifesté significativement moins de réactivité posturale comparativement à leurs contrôles; cette différence n'était pas présente chez des participants plus âgés (16-33 ans). Enfin, les enfants ayant subi un TCC léger, et qui étaient initialement modérément symptomatiques, ont montré un niveau plus élevé d'instabilité posturale induite visuellement que les contrôles, et ce jusqu'à 12 semaines post-trauma malgré le fait que la majorité d'entre eux (89%) n'étaient plus symptomatiques à ce stade. En somme, cela suggère la présence d'une importante période de transition dans la maturation des systèmes sous-tendant l'intégration sensorimotrice impliquée dans le contrôle postural vers l'âge de 16 ans, et d'autres changements sensorimoteurs vers l'âge de 60 ans; cette sur-dépendance visuelle pour la régulation posturale chez les enfants et les aînés pourrait guider l'aménagement d'espaces et l'élaboration d'activités ajustés à l'âge des individus. De plus, le fait que l'hypo-réactivité posturale aux informations visuelles chez les autistes dépende des caractéristiques de l'environnement visuel et de l'âge chronologique, affine notre compréhension des anomalies sensorielles propres à l'autisme. Par ailleurs, le fait que les enfants ayant subi un TCC léger montrent des anomalies posturales jusqu'à 3 mois post-trauma, malgré une diminution significative des symptômes rapportés, pourrait être relié à une altération du traitement de l'information visuelle dynamique et pourrait avoir des implications quant à la gestion clinique des patients aux prises avec un TCC léger, puisque la résolution des symptômes est actuellement le principal critère utilisé pour la prise de décision quant au retour aux activités. Enfin, les résultats obtenus chez une population à développement atypique (autisme) et une population avec atteinte neurologique dite transitoire (TCC léger), contribuent non seulement à une meilleure compréhension des mécanismes d'intégration sensorimotrice sous-tendant le contrôle postural mais pourraient aussi servir comme marqueurs sensibles et spécifiques de dysfonction chez ces populations. Mots-clés : posture, équilibre, vision, développement/vieillissement sensorimoteur, autisme, TCC léger symptomatique, réalité virtuelle. / Maintaining upright stance is essential for the accomplishment of several goal-directed behaviors, such as walking. Humans use three distinct sensory systems to regulate their posture: the somatosensory, the vestibular and the visual systems. The role of vision in postural regulation remains poorly understood, notably its variability across the life-span, developmental type and neurological insult. Hence, visually-driven postural regulation was examined in typically developing and aging participants (5-85 years-old), as well as in atypically developing individuals with autism (12-33 years-old) and in children having sustained mTBI (9-18 years-old). In order to do so, participants' postural reactivity was assessed in response to a fully immersive virtual tunnel moving at 3 different velocities; control conditions were also included wherein the tunnel was either static or absent. Results show that visually-induced postural reactivity was strongest in young children, then attenuated to become adult-like between 16-19 years of age, and started increasing again linearly with age after 45 years until becoming strong again around 60 years. Moreover, at the highest tunnel velocity, younger autistic participants showed significantly less postural reactivity compared to age-matched controls and young adults (16-33 years-old). Finally, children having sustained mTBI, who were initially moderately symptomatic, exhibited increased visually-induced instability compared to their matched controls up to 12 weeks post-injury, although most of them (89%) were no longer highly symptomatic. Altogether, this suggests the presence of an important transition period for the maturation of the systems underlying sensorimotor integration in postural control at around 16 years of age, and further sensorimotor changes after 60 years of age; this over-reliance on vision for postural regulation in childhood and late adulthood could guide the design of age-appropriate facilities/ activities. Furthermore, the fact that postural hypo-reactivity to visual information present in autism is contingent on both the visual environment and on chronological age, enhances our understanding of autism-specific sensory anomalies. Additionally, the fact that children with mTBI show balance anomalies up to 3 months post-injury, even when they are no longer highly symptomatic may be related to altered processing of dynamic visual information and could have implications for the clinical management of mTBI patients, since symptoms resolution is commonly used as a criterion for return to activities. Finally, results stemming from populations with atypical development (autism) and with so-called transient neurological insult (mild TBI) not only contribute to enhance our understanding of sensorimotor integration mechanisms underlying postural control, but could also consist of sensitive and specific markers of dysfunction in these populations. Keywords : posture, balance, vision, sensorimotor development/ aging, autism, symptomatic mTBI, virtual reality.

L'être humain utilise trois systèmes sensoriels distincts pour réguler le maintien de la station debout: la somesthésie, le système vestibulaire, et le système visuel. Le rôle de la vision dans la régulation posturale demeure peu connu, notamment sa variabilité en fonction de l'âge, du type développemental, et des atteintes neurologiques. Dans notre travail, la régulation posturale induite visuellement a été évaluée chez des participants au développement et vieillissement normaux âgés de 5-85 ans, chez des individus autistes (développement atypique) âgés de 12-33 ans, ainsi que chez des enfants entre 9-18 ans ayant subi un TCC léger. À cet effet, la réactivité posturale des participants en réponse à un tunnel virtuel entièrement immersif, se mouvant à trois niveaux de vélocité, a été mesurée; des conditions contrôles, où le tunnel était statique ou absent, ont été incluses. Les résultats montrent que la réactivité (i.e. instabilité) posturale induite visuellement est plus élevée chez les jeunes enfants; ensuite, elle s'atténue pour rejoindre des valeurs adultes vers 16-19 ans et augmente de façon linéaire en fonction de l'âge après 45 ans jusqu'à redevenir élevée vers 60 ans. De plus, à la plus haute vélocité du tunnel, les plus jeunes participants autistes ont manifesté significativement moins de réactivité posturale comparativement à leurs contrôles; cette différence n'était pas présente chez des participants plus âgés (16-33 ans). Enfin, les enfants ayant subi un TCC léger, et qui étaient initialement modérément symptomatiques, ont montré un niveau plus élevé d'instabilité posturale induite visuellement que les contrôles, et ce jusqu'à 12 semaines post-trauma malgré le fait que la majorité d'entre eux (89%) n'étaient plus symptomatiques à ce stade. En somme, cela suggère la présence d'une importante période de transition dans la maturation des systèmes sous-tendant l'intégration sensorimotrice impliquée dans le contrôle postural vers l'âge de 16 ans, et d'autres changements sensorimoteurs vers l'âge de 60 ans; cette sur-dépendance visuelle pour la régulation posturale chez les enfants et les aînés pourrait guider l'aménagement d'espaces et l'élaboration d'activités ajustés à l'âge des individus. De plus, le fait que l'hypo-réactivité posturale aux informations visuelles chez les autistes dépende des caractéristiques de l'environnement visuel et de l'âge chronologique, affine notre compréhension des anomalies sensorielles propres à l'autisme. Par ailleurs, le fait que les enfants ayant subi un TCC léger montrent des anomalies posturales jusqu'à 3 mois post-trauma, malgré une diminution significative des symptômes rapportés, pourrait être relié à une altération du traitement de l'information visuelle dynamique et pourrait avoir des implications quant à la gestion clinique des patients aux prises avec un TCC léger, puisque la résolution des symptômes est actuellement le principal critère utilisé pour la prise de décision quant au retour aux activités. Enfin, les résultats obtenus chez une population à développement atypique (autisme) et une population avec atteinte neurologique dite transitoire (TCC léger), contribuent non seulement à une meilleure compréhension des mécanismes d'intégration sensorimotrice sous-tendant le contrôle postural mais pourraient aussi servir comme marqueurs sensibles et spécifiques de dysfonction chez ces populations. Mots-clés : posture, équilibre, vision, développement/vieillissement sensorimoteur, autisme, TCC léger symptomatique, réalité virtuelle. / Maintaining upright stance is essential for the accomplishment of several goal-directed behaviors, such as walking. Humans use three distinct sensory systems to regulate their posture: the somatosensory, the vestibular and the visual systems. The role of vision in postural regulation remains poorly understood, notably its variability across the life-span, developmental type and neurological insult. Hence, visually-driven postural regulation was examined in typically developing and aging participants (5-85 years-old), as well as in atypically developing individuals with autism (12-33 years-old) and in children having sustained mTBI (9-18 years-old). In order to do so, participants' postural reactivity was assessed in response to a fully immersive virtual tunnel moving at 3 different velocities; control conditions were also included wherein the tunnel was either static or absent. Results show that visually-induced postural reactivity was strongest in young children, then attenuated to become adult-like between 16-19 years of age, and started increasing again linearly with age after 45 years until becoming strong again around 60 years. Moreover, at the highest tunnel velocity, younger autistic participants showed significantly less postural reactivity compared to age-matched controls and young adults (16-33 years-old). Finally, children having sustained mTBI, who were initially moderately symptomatic, exhibited increased visually-induced instability compared to their matched controls up to 12 weeks post-injury, although most of them (89%) were no longer highly symptomatic. Altogether, this suggests the presence of an important transition period for the maturation of the systems underlying sensorimotor integration in postural control at around 16 years of age, and further sensorimotor changes after 60 years of age; this over-reliance on vision for postural regulation in childhood and late adulthood could guide the design of age-appropriate facilities/ activities. Furthermore, the fact that postural hypo-reactivity to visual information present in autism is contingent on both the visual environment and on chronological age, enhances our understanding of autism-specific sensory anomalies. Additionally, the fact that children with mTBI show balance anomalies up to 3 months post-injury, even when they are no longer highly symptomatic may be related to altered processing of dynamic visual information and could have implications for the clinical management of mTBI patients, since symptoms resolution is commonly used as a criterion for return to activities. Finally, results stemming from populations with atypical development (autism) and with so-called transient neurological insult (mild TBI) not only contribute to enhance our understanding of sensorimotor integration mechanisms underlying postural control, but could also consist of sensitive and specific markers of dysfunction in these populations. Keywords : posture, balance, vision, sensorimotor development/ aging, autism, symptomatic mTBI, virtual reality.

Le contrôle postural et la perception des limites de la stabilité sont des processus complexes qui nécessitent le traitement et l’intégration d’informations sensorielles multimodales. Pendant l’enfance, le développement de la stabilité posturale s’effectue de façon non-monotonique. Plusieurs auteurs ont suggéré que ce profil non linéaire serait provoqué par une période de recalibration des systèmes sensoriels. Cette phase, nommée période de transition, est observée vers l’âge de 6-7 ans. Nous disposons toutefois de très peu d’information sur le rôle spécifique des afférences et des mécanismes d’intégration sensorielle au cours du développement postural. Les dysfonctions dans les noyaux gris centraux, telles que ceux observés dans la maladie de Parkinson, ont été associées à divers déficits dans le contrôle de la posture, dans le traitement et l’intégration sensoriel plus particulièrement, au niveau des informations proprioceptives. De plus, les limites fonctionnelles de la stabilité posturale des personnes atteintes de la maladie de Parkinson sont significativement réduites. Cependant, les connaissances concernant comment certaines pathologies des noyaux gris centraux, telles que le syndrome Gilles de la Tourette (SGT) et la maladie de Huntington (MH) affectent la capacité d’utiliser les informations sensorielles pour contrôler la posture demeurent à ce jour, incomplètes. Cette thèse porte sur le rôle des noyaux gris centraux dans les processus de traitements et d’intégration sensorielle, particulièrement les afférences proprioceptives dans le contrôle de la posture au cours du développement de l’enfant en santé, atteint du SGT et chez l’adulte atteint de la MH avec et sans symptôme clinique. Notre protocole expérimental a été testé chez ces trois populations (enfants en santé, SGT et MH). Nous avons utilisé des mesures quantitatives à partir de données issues d’une plateforme de force afin d’évaluer les ajustements posturaux dans les limites de la stabilité posturale. Les participants devaient s’incliner le plus loin possible dans quatre différentes directions (avant, arrière, droite et gauche) et maintenir l’inclinaison posturale maximale pendant 10 secondes. Afin de tester la capacité à traiter et à intégrer les informations sensorielles, la tâche expérimentale a été exécutée dans trois conditions sensorielles : 1) yeux ouverts, 2) yeux fermés et 3) yeux fermés, debout sur une mousse. Ainsi, la contribution relative de la proprioception pour le contrôle postural augmente à travers les conditions sensorielles. Dans la première étude, nous avons évalué la capacité à traiter et à intégrer les informations sensorielles avant (4 ans) et après (8-10 ans) la période de transition comparativement aux adultes. Dans la deuxième et la troisième étude, nous avons également évalué le traitement et l’intégration des informations sensorielles chez les patients atteints de désordres des noyaux gris centraux. La deuxième étude portera spécifiquement sur les adolescents atteints du SGT et la troisième, sur la MH avant et après l’apparition des symptômes cliniques. En somme, les résultats de la première étude ont démontré que la performance des enfants est affectée de façon similaire par les différentes conditions sensorielles avant et après la période de transition. Toutefois, le profil de développement des mécanismes responsables des ajustements posturaux de l’axe antéropostérieur est plus précoce comparativement à ceux de l’axe médiolatéral. Ainsi, nos résultats ne supportent pas l’hypothèse de la période de recalibration des systèmes sensoriels pendant cette période ontogénétique mais suggèrent que la période de transition peut être expliquée par la maturation précoce des mécanismes d’ajustements posturaux dans l’axe antéropostérieur. Dans l’ensemble, les résultats de nos études chez les populations atteintes de désordres des noyaux gris centraux (MH et SGT) démontrent non seulement qu’ils ont des déficits posturaux mais également que les ajustements posturaux dans les deux axes sont affectés par les conditions sensorielles. Pour la première fois, nos études démontrent des déficits globaux de traitements et d’intégration sensorielle accentués pour les signaux proprioceptifs. Ces résultats sont similaires à ceux observés dans la maladie de Parkinson. De plus, les adolescents atteints du SGT éprouvent également des troubles posturaux marqués dans la condition visuelle ce qui suggère des déficits d’intégrations visuelles et/ou multimodaux. / Postural control and the perception of the stability limits are complex mechanisms requiring the processing and integration of multimodal sensory information. During childhood, the development of postural control skills improves in a non-monotonic manner. Many researchers suggested that this non linear profile is caused by the recalibration of sensory systems. This recalibration phase, named transition period, is generally observed at 6-7 years of age. However, the exact cause of this critical turning point remains undetermined. Moreover, very little is known about the specific role of sensory information and sensorimotor mechanisms during postural development. Basal ganglia disorders such as Parkinson’s disease are associated with postural control impairments and deficits in the processing and integration of sensory information, especially in proprioception. Moreover, the limits of stability are significantly reduced in Parkinson’s disease. However, the knowledge on how other basal ganglia dysfunctions such as Gilles de la Tourette syndrome (GTS) and Huntington’s disease (HD) impact on the ability to process and integrate sensory information for postural control is still limited. In this thesis, we explored the role of basal ganglia in the processing an integration of sensory information, particularly proprioceptive signals for the postural control during the development of healthy children, in adolescents with GTS and in adults with premanifest and manifest HD. Our stability limits protocol was used to test the postural control skills of these three populations. We calculated center of pressure displacements obtained from a force plate and we investigated postural adjustments during the maximum leaning posture. The participants were asked to lean as far as possible and maintain this position during 10 seconds in different directions (forward, backward, rightward or leftward). This task simulates functional positions that frequently occur in daily life. In order to test the ability to process and integrate sensory information for postural control, the stability limits task was assessed in three sensory conditions: 1) eyes open, 2) eyes closed and 3) eyes closed while standing on foam. Thus, the relative contribution of proprioceptive signals for postural control increased across sensory conditions. In the first study, we investigated the children’s ability to process and integrate sensory information for postural control before (4 years old) and after (8 to 10 years old) the transition period compared to adults. In the second and third studies, the ability to process and integrate sensory information for postural control was assessed in participants with basal ganglia disorders, namely adolescents with GTS and adults with manifest and premanifest HD. In sum, our ontogenetic study indicated that the younger children (4 years old) were not differentially affected by sensory conditions than the older children (8 to 10 years old). Thus, our results do not support the hypothesis that an important recalibration of sensorial systems takes place during the transition period. However, the results revealed axis-dependent differences among the groups in postural control. Until the age of 10, children have a reduced ability to perform appropriate center of pressure adjustments along the mediolateral direction compared to adults. In contrast, the ability to produce precise center of pressure adjustments along the anteroposterior axis was already developed at 4 years of age, but it reached the adult level of performance after the transition period. Altogether, the assessment of participants with basal ganglia disorders indicated that they have postural adjustment impairments in both movement axes and are affected by sensory conditions. For the first time, we reported global deficits in the processing and integration of sensory information, especially in proprioception in GTS and in premanifest and manifest HD. These results are similar to those reported for Parkinson’s disease patients. Moreover, the adolescents with GTS also displayed marked postural control abnormalities in the visual condition which might be explained by either deficit in the processing of visual information and/or in multimodal sensory integration mechanisms.

La pollution atmosphérique est omniprésente du fait de nombreuses sources émettrices de composés chimiques. Dans ce contexte, les Hydrocarbures Aromatiques Polycycliques (HAP) sont largement diffusés dans l’air et ont déjà montré des effets délétères sur la santé.Ce travail a consisté en l’évaluation de la neurotoxicité du fluorène, composé choisi comme molécule représentative de la pollution liée aux HAP, chez le rat adulte exposé par voie i.p., par voie orale ou par inhalation. Le modèle d’exposition par inhalation a ensuite été appliqué à l’étude des effets du polluant sur le développement sensori-moteur et l’activité comportementale de l’animal exposé in utero ou au cours de la lactation.Ces études ont montré que le fluorène était susceptible d’affecter le niveau d’anxiété et l’activité locomotrice du rat adulte exposé directement et indirectement au polluant, et n’avait aucun effet sur les capacités d’apprentissage. En revanche, aucune atteinte majeure de la maturation des fonctions sensori-motrices n’a été mise en évidence. L’analyse de la présence du composé et de trois de ses métabolites a par ailleurs montré que le polluant était capable de traverser la barrière hémato-encéphalique et d’être métabolisé au niveau du cerveau. Les réponses physiologiques et comportementales étant variables entre les études, les effets induits par le fluorène dépendent donc de la voie d’entrée, du niveau de contamination et du moment d’exposition.Ces résultats ont ainsi révélé chez l’animal la toxicité comportementale du fluorène à des niveaux de contamination réalistes, confirmant ainsi le risque sanitaire de l’exposition aux HAP tout au long de la vie des individus / Actually air pollution is ubiquitous due to the emission of chemical compound from many sources. In this context, Polycyclic Aromaric Hydrocarbons (PAH)related compounds are widely distributed in the air and have shown deleterious health effects.Fluorene was chosen as a representative compound of PAHs pollution. This work consisted in the evaluation of its neurotoxic effects in adult animals, exposed i.p., orally or by exposure nose-only. The inhalation model of exposure was then applied to the study of its effects on sensorimotor development and on behavioral activity of animals exposed in utero or during lactation.The results showed that fluorene is able to induce behavioral changes in adult animals exposed directly or indirectly on the level of anxiety and the locomotor activity, whereas no effect on learning and memory abilities has been observed. However, no defect on the development of motor and sensory functions was demonstrated. Furthermore, the analysis of the presence of the compound and three of its metabolites showed that the pollutant was able to cross the blood brain barrier and can be metabolized in the brain. Moreover, variations have been observed concerning behavioral and physiological responses between studies, showing that effects induced by fluorene are dependent on the way of administration, the level of contamination and the time of exposure.In conclusion, these results demonstrate in animals the behavioral toxicity of fluorene at levels of contamination corresponding to human cases of exposure, confirming so the risk of PAH exposure throughout life

Na atualidade, uma das causas importantes de lesão encefálica em neonatos é a anóxia neonatal. Este é um problema grave nos serviços de perinatologia dos hospitais em todo o mundo sendo ainda pior em países subdesenvolvidos, devido à carência de precauções e cuidados requeridos. Modelos animais de anóxia vêm sendo empregados para avaliar seus efeitos, tanto em nível neurológico, como em nível comportamental. A anóxia neonatal tem sido estudada pelo laboratório de Neurociências do Instituto de Ciências Biomédicas da Universidade de São Paulo, com modelos de estudo já desenvolvidos, adaptados e validados. Para investigar se a anóxia neonatal afeta o desenvolvimento motor somático e sensorial, ratos foram submetidos a um modelo não invasivo de anóxia global (Takada et. al., 2011). Ratos Wistar com 30 h de idade (6-8 gramas), machos e fêmeas, foram expostos por 25 minutos a gás nitrogênio 100% num fluxo de 3L/min, pressão 101.7 kPa e temperatura de 37ºC em câmara semi-hermética de policarbonato. O grupo controle foi submetido às mesmas condições porem com o ar ambiente normal. Os animais foram avaliados durante o período de aleitamento (P2 a P21) quanto a parâmetros do desenvolvimento somático; desenvolvimento ontogenético e quanto a reflexos sensório motores. Os resultados indicaram que o grupo Anoxia macho(AM) apresentou aumento no peso corporal {AM(42.25±3.62);CM(38.76±5.60);AF(40.64±5.08);CF(41.33±5.45)}e diminuição do eixo longitudinal do corpo {AM(10.15±0.27);CM(10.39±0.50);AF(9.82±0.44);CF(10.82±0.46)} em relação ao grupo Controle macho(CM) e Anoxia fêmea(AF), AF foi menor em relacao ao Controle fêmea (CF). AM apresentou maior eixo látero-lateral do crânio em relação CM e AF {AM (3.18 ±0.10); CM (3.17 ±0.13); AF(3.06 ±0.16); CF(3.00 ±0.15)} No desenvolvimento ontogenético houve retardo na abertura do canal auditivo {AM (13.79± 0.58); CM (13.75±0.83); AF(14.21±1.01); CF(13.36±0.50)} e abertura dos olhos {AM (14.00± 0.88); CM (14.64±1.28); AF(15.14±0.86); CF(13.79±0.42)} no grupo AF em relação a CF e AM, mas no grupo AM não houve diferença significante. Na erupção dos incisivos superiores {AM (10.79± 0.43); CM(11.71±1.68); AF(11.43±0.65); CF(10.07±0.27)} o grupo AM adiantou enquanto o AF atrasou em relação ao grupo controle. A avaliação dos reflexos sensóriais mostrou que a anoxia adiantou a colocação pelas vibrissas {AM (8.80± 1.21); CM (9.50±1.56); AF (9.93±1.14); CF(10.14±1.28) no AF e AM. Apenas o AM adiantou {AM (10.93± 2.09); CM(13.43±0.94); AF(10.50±0.85); CF(9.57±0.76)} no reflexo de aversão ao precipício. Nos relfexos de geotaxia negativa {AM (14.87± 1.30); CM (13.57±2.34); AF(14.57±1.40);CF (12.00±2.11)} e sobressalto ao susto {AM (14.00±0.53); CM (13.21±1.31); AF (13.29±0.61); CF (11.93±0.27)} e preensão palmar {AM (6.60±0.83); CM (4.71±0.47); AF(10.14±0.83); CF(4.71±0.47)} a anóxia provocou atraso tanto em macho quanto em fêmeas motores. Houve atraso na ontogênese da maioria dos testes de reflexos dos filhotes do grupo Anóxia. Os resultados deste estudo demonstraram que a anóxia causa danos persistentes na maioria dos parâmetros avaliados em relação aos grupos controle, e diminuição no número de neurônios do córtex sensóriomotor {M2: AM (46.84±1.72); CM (52±1.66); AF (45.55±1.80); CF (52±1.55)M1: AM (23.70±1.33); CM (41.89±1.49); AF (25.69±0.83); CF (43.88±1.46) S1HL: AM (27.93±2.69); CM (30.19±1.31); AF(23.42±2.38); CF (38.88±1.48) S1FL: AM (31.85±1.09); CM (33.88±0.48); AF(27.66±1.36); CF(32.28±1.70)}, com diferença de gênero o que evidencia a importância de que estratégias e procedimentos para minimizar os efeitos desse estímulos sejam consideradas em relação ao gênero / At present, one of the important causes of brain injury is the neonatal anoxia. This is a serious problem in the perinatology services of hospitals around the world being even worse in underdeveloped countries because of the lack of precautions and care required. Animal models of anoxia have been employed to assess their effects, both at the neurological level and at the behavioral level. Neonatal anoxia has been studied by the Neuroscience Laboratory of the Biomedical Sciences Institute of the University of São Paulo, with animal models already developed, adapted and validated. To investigate whether neonatal anoxia affects somatic and sensory motor development, rats were subjected to a non-invasive model of global anoxia (Takada et al., 2011). Male and female 30-h old (6-8 grams) Wistar rats were exposed for 25 minutes to 100% nitrogen gas in a flow of 3 L/min, pressure 101.7 kPa and temperature of 37ºC in a semi-hermetic chamber of polycarbonate. The control group was subjected to the same conditions but with normal ambient air. The animals were evaluated during the lactation period (P2 to P21) for parameters of somatic development; Ontogenetic development and for sensorimotor reflexes. The results indicated that the male Anoxia (AM) group presented increase in body weight (AM (42.25 ± 3.62), CM (38.76 ± 5.60), FA (40.64 ± 5.08), CF (41.33 ± 5.45)) and decrease in the longitudinal (10.82 ± 0.46), in relation to the male control group (CM) and the female Anoxia (AF), AF was lower in relation to the control group (AM) (10.15 ± 0.27), CM (10.39 ± 0.50), AF (9.82 ± 0.44) Female control (CF). AM increase in the cranio-lateral axis in relation to CM and AF (AM (3.18 ± 0.10); CM (3.17 ± 0.13); AF (3.06 ± 0.16); CF (3.00 ± 0.15). Concerning the ontogenetic development there was delay in opening the (13.79 ± 0.58), and the eyes {AM (14.00 ± 0.88); CM (14.64 ± 1.28), AF (15.14 ± 0.86), CF (13.79 ± 0.42)} in the AF group in relation to CF and AM, but in the AM group there was no significant difference. In the eruption of maxillary incisors (AM (10.79 ± 0.43), CM (11.71 ± 1.68), AF (11.43 ± 0.65), CF (10.07 ± 0.27), the AM group advanced while the AF delayed in control ration. The evaluation of the sensory reflexes showed that anoxia improved the placement of vibrissae (AM (8.80 ± 1.21), CM (9.50 ± 1.56), AF (9.93 ± 1.14), CF (10.14 ± 1.28) in AF and AM. Only AM advanced (AM (10.93 ± 2.09), CM (13.43 ± 0.94), AF (10.50 ± 0.85), CF (9.57 ± 0.76) in the reflex of aversion to the precipice. In negative geotaxia relays (AM (14.87 ± 1.30); CM (13.57 ± 2.34), AF (14.57 ± 1.40), CF (12.00 ± 2.11)} and startle reflex {AM (14.00 ± 0.53); CM (13.21 ± 1.31); AF (13.29 ± 0.61); CF (11.93 ± 0.27) and palmar grip (AM (6.60 ± 0.83); CM (4.71 ± 0.47), AF (10.14 ± 0.83), CF (4.71 ± 0.47)), anoxia caused delay in both male and female groups. There was a delay in the ontogenesis of most of the reflex tests of the puppies of the anoxia group. The results of this study demonstrated that anoxia causes persistent damage in most of the parameters evaluated in relation to the control groups, and a decrease in the number of sensory motor cortex neurons (M2: AM (46.84 ± 1.72), CM (52 ± 1.66), AF 1.80), CF (52 ± 1.55) M1: AM (23.70 ± 1.33), CM (41.89 ± 1.49), AF (25.69 ± 0.83), CF (43.88 ± 1.46) S1HL: AM (27.93 ± 2.69), CM (30.19 (31.88 ± 1.48), FA (27.66 ± 1.36), CF (32.28 ± 1.70), , which shows that strategies and procedures to minimize the effects of such stimuli should be considered in relation to gender

Le contrôle postural et la perception des limites de la stabilité sont des processus complexes qui nécessitent le traitement et l’intégration d’informations sensorielles multimodales. Pendant l’enfance, le développement de la stabilité posturale s’effectue de façon non-monotonique. Plusieurs auteurs ont suggéré que ce profil non linéaire serait provoqué par une période de recalibration des systèmes sensoriels. Cette phase, nommée période de transition, est observée vers l’âge de 6-7 ans. Nous disposons toutefois de très peu d’information sur le rôle spécifique des afférences et des mécanismes d’intégration sensorielle au cours du développement postural. Les dysfonctions dans les noyaux gris centraux, telles que ceux observés dans la maladie de Parkinson, ont été associées à divers déficits dans le contrôle de la posture, dans le traitement et l’intégration sensoriel plus particulièrement, au niveau des informations proprioceptives. De plus, les limites fonctionnelles de la stabilité posturale des personnes atteintes de la maladie de Parkinson sont significativement réduites. Cependant, les connaissances concernant comment certaines pathologies des noyaux gris centraux, telles que le syndrome Gilles de la Tourette (SGT) et la maladie de Huntington (MH) affectent la capacité d’utiliser les informations sensorielles pour contrôler la posture demeurent à ce jour, incomplètes. Cette thèse porte sur le rôle des noyaux gris centraux dans les processus de traitements et d’intégration sensorielle, particulièrement les afférences proprioceptives dans le contrôle de la posture au cours du développement de l’enfant en santé, atteint du SGT et chez l’adulte atteint de la MH avec et sans symptôme clinique. Notre protocole expérimental a été testé chez ces trois populations (enfants en santé, SGT et MH). Nous avons utilisé des mesures quantitatives à partir de données issues d’une plateforme de force afin d’évaluer les ajustements posturaux dans les limites de la stabilité posturale. Les participants devaient s’incliner le plus loin possible dans quatre différentes directions (avant, arrière, droite et gauche) et maintenir l’inclinaison posturale maximale pendant 10 secondes. Afin de tester la capacité à traiter et à intégrer les informations sensorielles, la tâche expérimentale a été exécutée dans trois conditions sensorielles : 1) yeux ouverts, 2) yeux fermés et 3) yeux fermés, debout sur une mousse. Ainsi, la contribution relative de la proprioception pour le contrôle postural augmente à travers les conditions sensorielles. Dans la première étude, nous avons évalué la capacité à traiter et à intégrer les informations sensorielles avant (4 ans) et après (8-10 ans) la période de transition comparativement aux adultes. Dans la deuxième et la troisième étude, nous avons également évalué le traitement et l’intégration des informations sensorielles chez les patients atteints de désordres des noyaux gris centraux. La deuxième étude portera spécifiquement sur les adolescents atteints du SGT et la troisième, sur la MH avant et après l’apparition des symptômes cliniques. En somme, les résultats de la première étude ont démontré que la performance des enfants est affectée de façon similaire par les différentes conditions sensorielles avant et après la période de transition. Toutefois, le profil de développement des mécanismes responsables des ajustements posturaux de l’axe antéropostérieur est plus précoce comparativement à ceux de l’axe médiolatéral. Ainsi, nos résultats ne supportent pas l’hypothèse de la période de recalibration des systèmes sensoriels pendant cette période ontogénétique mais suggèrent que la période de transition peut être expliquée par la maturation précoce des mécanismes d’ajustements posturaux dans l’axe antéropostérieur. Dans l’ensemble, les résultats de nos études chez les populations atteintes de désordres des noyaux gris centraux (MH et SGT) démontrent non seulement qu’ils ont des déficits posturaux mais également que les ajustements posturaux dans les deux axes sont affectés par les conditions sensorielles. Pour la première fois, nos études démontrent des déficits globaux de traitements et d’intégration sensorielle accentués pour les signaux proprioceptifs. Ces résultats sont similaires à ceux observés dans la maladie de Parkinson. De plus, les adolescents atteints du SGT éprouvent également des troubles posturaux marqués dans la condition visuelle ce qui suggère des déficits d’intégrations visuelles et/ou multimodaux. / Postural control and the perception of the stability limits are complex mechanisms requiring the processing and integration of multimodal sensory information. During childhood, the development of postural control skills improves in a non-monotonic manner. Many researchers suggested that this non linear profile is caused by the recalibration of sensory systems. This recalibration phase, named transition period, is generally observed at 6-7 years of age. However, the exact cause of this critical turning point remains undetermined. Moreover, very little is known about the specific role of sensory information and sensorimotor mechanisms during postural development. Basal ganglia disorders such as Parkinson’s disease are associated with postural control impairments and deficits in the processing and integration of sensory information, especially in proprioception. Moreover, the limits of stability are significantly reduced in Parkinson’s disease. However, the knowledge on how other basal ganglia dysfunctions such as Gilles de la Tourette syndrome (GTS) and Huntington’s disease (HD) impact on the ability to process and integrate sensory information for postural control is still limited. In this thesis, we explored the role of basal ganglia in the processing an integration of sensory information, particularly proprioceptive signals for the postural control during the development of healthy children, in adolescents with GTS and in adults with premanifest and manifest HD. Our stability limits protocol was used to test the postural control skills of these three populations. We calculated center of pressure displacements obtained from a force plate and we investigated postural adjustments during the maximum leaning posture. The participants were asked to lean as far as possible and maintain this position during 10 seconds in different directions (forward, backward, rightward or leftward). This task simulates functional positions that frequently occur in daily life. In order to test the ability to process and integrate sensory information for postural control, the stability limits task was assessed in three sensory conditions: 1) eyes open, 2) eyes closed and 3) eyes closed while standing on foam. Thus, the relative contribution of proprioceptive signals for postural control increased across sensory conditions. In the first study, we investigated the children’s ability to process and integrate sensory information for postural control before (4 years old) and after (8 to 10 years old) the transition period compared to adults. In the second and third studies, the ability to process and integrate sensory information for postural control was assessed in participants with basal ganglia disorders, namely adolescents with GTS and adults with manifest and premanifest HD. In sum, our ontogenetic study indicated that the younger children (4 years old) were not differentially affected by sensory conditions than the older children (8 to 10 years old). Thus, our results do not support the hypothesis that an important recalibration of sensorial systems takes place during the transition period. However, the results revealed axis-dependent differences among the groups in postural control. Until the age of 10, children have a reduced ability to perform appropriate center of pressure adjustments along the mediolateral direction compared to adults. In contrast, the ability to produce precise center of pressure adjustments along the anteroposterior axis was already developed at 4 years of age, but it reached the adult level of performance after the transition period. Altogether, the assessment of participants with basal ganglia disorders indicated that they have postural adjustment impairments in both movement axes and are affected by sensory conditions. For the first time, we reported global deficits in the processing and integration of sensory information, especially in proprioception in GTS and in premanifest and manifest HD. These results are similar to those reported for Parkinson’s disease patients. Moreover, the adolescents with GTS also displayed marked postural control abnormalities in the visual condition which might be explained by either deficit in the processing of visual information and/or in multimodal sensory integration mechanisms.

Na atualidade, uma das causas importantes de lesão encefálica em neonatos é a anóxia neonatal. Este é um problema grave nos serviços de perinatologia dos hospitais em todo o mundo sendo ainda pior em países subdesenvolvidos, devido à carência de precauções e cuidados requeridos. Modelos animais de anóxia vêm sendo empregados para avaliar seus efeitos, tanto em nível neurológico, como em nível comportamental. A anóxia neonatal tem sido estudada pelo laboratório de Neurociências do Instituto de Ciências Biomédicas da Universidade de São Paulo, com modelos de estudo já desenvolvidos, adaptados e validados. Para investigar se a anóxia neonatal afeta o desenvolvimento motor somático e sensorial, ratos foram submetidos a um modelo não invasivo de anóxia global (Takada et. al., 2011). Ratos Wistar com 30 h de idade (6-8 gramas), machos e fêmeas, foram expostos por 25 minutos a gás nitrogênio 100% num fluxo de 3L/min, pressão 101.7 kPa e temperatura de 37ºC em câmara semi-hermética de policarbonato. O grupo controle foi submetido às mesmas condições porem com o ar ambiente normal. Os animais foram avaliados durante o período de aleitamento (P2 a P21) quanto a parâmetros do desenvolvimento somático; desenvolvimento ontogenético e quanto a reflexos sensório motores. Os resultados indicaram que o grupo Anoxia macho(AM) apresentou aumento no peso corporal {AM(42.25±3.62);CM(38.76±5.60);AF(40.64±5.08);CF(41.33±5.45)}e diminuição do eixo longitudinal do corpo {AM(10.15±0.27);CM(10.39±0.50);AF(9.82±0.44);CF(10.82±0.46)} em relação ao grupo Controle macho(CM) e Anoxia fêmea(AF), AF foi menor em relacao ao Controle fêmea (CF). AM apresentou maior eixo látero-lateral do crânio em relação CM e AF {AM (3.18 ±0.10); CM (3.17 ±0.13); AF(3.06 ±0.16); CF(3.00 ±0.15)} No desenvolvimento ontogenético houve retardo na abertura do canal auditivo {AM (13.79± 0.58); CM (13.75±0.83); AF(14.21±1.01); CF(13.36±0.50)} e abertura dos olhos {AM (14.00± 0.88); CM (14.64±1.28); AF(15.14±0.86); CF(13.79±0.42)} no grupo AF em relação a CF e AM, mas no grupo AM não houve diferença significante. Na erupção dos incisivos superiores {AM (10.79± 0.43); CM(11.71±1.68); AF(11.43±0.65); CF(10.07±0.27)} o grupo AM adiantou enquanto o AF atrasou em relação ao grupo controle. A avaliação dos reflexos sensóriais mostrou que a anoxia adiantou a colocação pelas vibrissas {AM (8.80± 1.21); CM (9.50±1.56); AF (9.93±1.14); CF(10.14±1.28) no AF e AM. Apenas o AM adiantou {AM (10.93± 2.09); CM(13.43±0.94); AF(10.50±0.85); CF(9.57±0.76)} no reflexo de aversão ao precipício. Nos relfexos de geotaxia negativa {AM (14.87± 1.30); CM (13.57±2.34); AF(14.57±1.40);CF (12.00±2.11)} e sobressalto ao susto {AM (14.00±0.53); CM (13.21±1.31); AF (13.29±0.61); CF (11.93±0.27)} e preensão palmar {AM (6.60±0.83); CM (4.71±0.47); AF(10.14±0.83); CF(4.71±0.47)} a anóxia provocou atraso tanto em macho quanto em fêmeas motores. Houve atraso na ontogênese da maioria dos testes de reflexos dos filhotes do grupo Anóxia. Os resultados deste estudo demonstraram que a anóxia causa danos persistentes na maioria dos parâmetros avaliados em relação aos grupos controle, e diminuição no número de neurônios do córtex sensóriomotor {M2: AM (46.84±1.72); CM (52±1.66); AF (45.55±1.80); CF (52±1.55)M1: AM (23.70±1.33); CM (41.89±1.49); AF (25.69±0.83); CF (43.88±1.46) S1HL: AM (27.93±2.69); CM (30.19±1.31); AF(23.42±2.38); CF (38.88±1.48) S1FL: AM (31.85±1.09); CM (33.88±0.48); AF(27.66±1.36); CF(32.28±1.70)}, com diferença de gênero o que evidencia a importância de que estratégias e procedimentos para minimizar os efeitos desse estímulos sejam consideradas em relação ao gênero / At present, one of the important causes of brain injury is the neonatal anoxia. This is a serious problem in the perinatology services of hospitals around the world being even worse in underdeveloped countries because of the lack of precautions and care required. Animal models of anoxia have been employed to assess their effects, both at the neurological level and at the behavioral level. Neonatal anoxia has been studied by the Neuroscience Laboratory of the Biomedical Sciences Institute of the University of São Paulo, with animal models already developed, adapted and validated. To investigate whether neonatal anoxia affects somatic and sensory motor development, rats were subjected to a non-invasive model of global anoxia (Takada et al., 2011). Male and female 30-h old (6-8 grams) Wistar rats were exposed for 25 minutes to 100% nitrogen gas in a flow of 3 L/min, pressure 101.7 kPa and temperature of 37ºC in a semi-hermetic chamber of polycarbonate. The control group was subjected to the same conditions but with normal ambient air. The animals were evaluated during the lactation period (P2 to P21) for parameters of somatic development; Ontogenetic development and for sensorimotor reflexes. The results indicated that the male Anoxia (AM) group presented increase in body weight (AM (42.25 ± 3.62), CM (38.76 ± 5.60), FA (40.64 ± 5.08), CF (41.33 ± 5.45)) and decrease in the longitudinal (10.82 ± 0.46), in relation to the male control group (CM) and the female Anoxia (AF), AF was lower in relation to the control group (AM) (10.15 ± 0.27), CM (10.39 ± 0.50), AF (9.82 ± 0.44) Female control (CF). AM increase in the cranio-lateral axis in relation to CM and AF (AM (3.18 ± 0.10); CM (3.17 ± 0.13); AF (3.06 ± 0.16); CF (3.00 ± 0.15). Concerning the ontogenetic development there was delay in opening the (13.79 ± 0.58), and the eyes {AM (14.00 ± 0.88); CM (14.64 ± 1.28), AF (15.14 ± 0.86), CF (13.79 ± 0.42)} in the AF group in relation to CF and AM, but in the AM group there was no significant difference. In the eruption of maxillary incisors (AM (10.79 ± 0.43), CM (11.71 ± 1.68), AF (11.43 ± 0.65), CF (10.07 ± 0.27), the AM group advanced while the AF delayed in control ration. The evaluation of the sensory reflexes showed that anoxia improved the placement of vibrissae (AM (8.80 ± 1.21), CM (9.50 ± 1.56), AF (9.93 ± 1.14), CF (10.14 ± 1.28) in AF and AM. Only AM advanced (AM (10.93 ± 2.09), CM (13.43 ± 0.94), AF (10.50 ± 0.85), CF (9.57 ± 0.76) in the reflex of aversion to the precipice. In negative geotaxia relays (AM (14.87 ± 1.30); CM (13.57 ± 2.34), AF (14.57 ± 1.40), CF (12.00 ± 2.11)} and startle reflex {AM (14.00 ± 0.53); CM (13.21 ± 1.31); AF (13.29 ± 0.61); CF (11.93 ± 0.27) and palmar grip (AM (6.60 ± 0.83); CM (4.71 ± 0.47), AF (10.14 ± 0.83), CF (4.71 ± 0.47)), anoxia caused delay in both male and female groups. There was a delay in the ontogenesis of most of the reflex tests of the puppies of the anoxia group. The results of this study demonstrated that anoxia causes persistent damage in most of the parameters evaluated in relation to the control groups, and a decrease in the number of sensory motor cortex neurons (M2: AM (46.84 ± 1.72), CM (52 ± 1.66), AF 1.80), CF (52 ± 1.55) M1: AM (23.70 ± 1.33), CM (41.89 ± 1.49), AF (25.69 ± 0.83), CF (43.88 ± 1.46) S1HL: AM (27.93 ± 2.69), CM (30.19 (31.88 ± 1.48), FA (27.66 ± 1.36), CF (32.28 ± 1.70), , which shows that strategies and procedures to minimize the effects of such stimuli should be considered in relation to gender