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This research delves into idiopathic autism spectrum disorder (ASD), investigating the role of TrkB signaling pathways and BDNF regulation in the cortex. Additionally, it explores offering insights into maternal influences on mouse models. / Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by challenges in social interactions and repetitive behaviors. Prevalence of ASD is estimated to be 1 in 54 globally and is rising recently in many countries including Canada. ASD affects individuals differently, making diagnosis challenging. At present, no molecular diagnosis of ASD is available. Further, available medications only manage some symptoms of the disease and have adverse side effects in children. Therefore, there is a need for accurate molecular diagnostic tools to aid in molecular detection and treatment of ASD. To this end, a better understanding of the underlying molecular mechanisms that link ASD etiology to ASD-related behavior is crucial. While genetic factors contribute to syndromic ASD, most cases of ASD are idiopathic with unknown causes, influenced by a combination of epigenetic and environmental factors. TrkB and its downstream signaling pathways, such as Akt and Erk, are hyper-activated in syndromic ASD and hypo-activated in idiopathic cases. Therefore, drugs like rapamycin that inhibit the mTOR pathway downstream of TrkB are beneficial for syndromic ASD but not idiopathic cases. Additionally, insulin-like growth factor 1 (IGF-1), which mitigates ASD-related synaptic disruptions via Akt and Erk signaling, shows unchanged mRNA and protein levels along with its receptor in the idiopathic ASD fusiform gyrus. In ASD with either genetic or epigenetic/environmental causes, disruptions in synaptic connectivity are observed. Synaptic function is regulated by signaling pathways involving brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), as well as their downstream signaling cascades such as MAPK and Akt. The existing literature suggests that there is an association between BDNF and TrkB signaling pathways and ASD. However, a serious gap in knowledge about the precise molecular role of TrkB in ASD pathology is that our current understanding is correlational in nature and based on observational studies that lack causal experiments. This underscores the importance of further research to understand the causative role of TrkB and its related molecular events in idiopathic ASD. The present work aims to provide a deeper understanding about the causative role of molecular mechanisms underlying TrkB signaling in ASD. ASD mouse models exhibit behaviors and molecular features resembling those observed in human ASD. Therefore, these mouse models are helpful tools for studying ASD. However, understudied physiological confounding factors, such as maternal age and parity, can introduce biases and add to data variability, thus negatively impacting the reproducibility and translational value of ASD mouse models. To achieve a reliable mouse model of ASD, we conducted our first study that examines the impact of maternal age and parity on pregnancy complications, neurodevelopment, and social behavior in mice. Results demonstrate that older maternal age and prior motherhood interact to ensure a normal, steady developmental rate and provide protective effects against anxiety, social impairment, and olfactory deficits. Given the current lack of clarity regarding the causative impact of TrkB on ASD pathology, our subsequent investigation sought to establish a causal relationship between TrkB signaling and ASD. We used the TrkB agonist, LM22A-4 treatment in a validated ASD mouse model. Our results demonstrate that treatment with LM22A-4 effectively rescues the core symptoms associated with ASD (social impairment and repetitive behavior). These findings indicate that impaired TrkB signaling is responsible for ASD-like behavior of valproic acid (VPA)-exposed mice. However, unlike TrkB-related molecular events occurring in the fusiform gyrus of idiopathic ASD, TrkB isoform protein levels, BDNF species, Akt, and Erk total protein levels and activation remained unchanged in VPA-exposed cortices compared to healthy control mice. Since our VPA mouse model does not replicate human idiopathic ASD, our study cannot draw a conclusion on how disruptions in these signaling pathways may contribute to the development and manifestation of ASD symptoms. Cortex is responsible for various aspects of social behavior that are impaired in ASD. However, regulatory mechanisms that are involved in ASD upstream of cortical TrkB and BDNF are not well known. BDNF expression is highly cell-and tissue-specific and is regulated by different sets of transcription factors in specific tissues. While NURR1, the BDNF regulator in midbrain neurons, is associated with ASD pathology, its specific role in regulation of cortical BDNF is not yet well-established. Our third study aimed to understand the role of NURR1 in regulating BDNF specifically in the cortex. We showed that in resting and depolarized neurons, when NURR1 is knocked down, BDNF mRNA levels remained unchanged, suggesting that NURR1 does not regulate BDNF in cortical neurons and highlighting the tissue-specificity of BDNF regulation. In summary, we address the understudied effects of maternal factors on mouse models, which enhances the reliability of ASD research. Further, our studies significantly enhance the understanding of ASD by elucidating the role of TrkB and its downstream signaling pathways in the behavioral aspects of the disorder. We also contribute to the knowledge of BDNF regulation in the cortex, a brain tissue with crucial roles in various aspects of social behavior. In a forward-looking approach, the results of our studies provide valuable insights into mouse modeling of idiopathic ASD and the potential role of TrkB in ASD behavioral symptoms. / Thesis / Candidate in Philosophy / Autism spectrum disorder (ASD) is a condition that is accompanied by challenges in social interaction and repetitive behaviors. ASD is a complicated condition because we do not fully understand all the details of how it works in the body. Studying ASD is important as it is the most challenging condition in children and it is becoming more common, especially in the last two decades. While scientists are developing molecular tools to improve ASD diagnosis and understand its biology, these tools are not widely used in clinics for ASD diagnosis yet. Also, the approved medications available can only help with managing some of the behavioral symptoms like self-harming behavior. Despite the pressing need to find a solution, our recent advancements have not yet brought us closer to a cure for ASD, mainly because of the complexity of the disorder. Therefore, identifying the specific ASD-related mechanisms at the molecular level that contribute to ASD-related behaviors is crucial for gaining a deeper understanding of the disease. In ASD, there are problems with how brain cells communicate with each other. This communication is controlled by certain molecules in the brain, such as brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), along with other molecules. There is evidence suggesting a link between these molecules and ASD, but we have not fully understood their precise roles because most of the current knowledge is based on observations and correlations, rather than on establishing cause-and-effect relationships. To bridge this gap, our research focused on understanding TrkB's role in ASD. We required reliable mouse models. Since we aimed to induce ASD-like behaviors in mice using an ASD-causing chemical, it was crucial to ensure they were healthy beforehand. We needed to confirm that any social deficits or repetitive behaviors were not due to other factors, such as adverse infancy experiences or impaired interactions between mother and infant. We discovered that sexually mature dams aged between 3 to 6 months, with a history of previous pregnancies and motherhood, give birth to healthier litters. These litters can serve as a more dependable source for our animal behavioral studies. Many cases of ASD in humans are caused by non-genetic factors such as environmental influences like pesticides, air pollution, and the use of certain drugs during pregnancy. In cases of human ASD triggered by non-genetic factors, there is an increase in proBDNF, the precursor of BDNF. However, this proBDNF does not efficiently convert to BDNF. With insufficient BDNF and TrkB receptors, molecules like Akt (protein kinase B, also PKB) and Erk (Extracellular Signal-Regulated Kinase), which are crucial for neuron communication, are also less active downstream. This imbalance disrupts neuron connections, leading to ASD behaviors. In our research, the ASD-causing chemical which we used is valproic acid. It is originally an anti-seizure medication. When pregnant women took valproic acid, the chance of their child having ASD increased. Scientists used this information to inject pregnant mice with valproic acid, and as a result, all the offspring showed ASD-like behaviors. We anticipated that by isolating the brains of these offspring and measuring protein levels of BDNF, TrkB, Akt, and Erk, we would observe a similar pattern to that seen in humans with non-genetic ASD cases. We focused on studying the cortex, a region of the brain responsible for regulating social behaviors in both mice and humans. Since ASD is associated with challenges in social behaviors, we isolated the cortex from mouse brains to analyze protein levels. A chemical known as LM22A-4 with a structure resembling BDNF can bind to TrkB and activate it. We expected that the offspring of pregnant dams injected with valproic acid, which led to reduced TrkB axis activation in their brains, would show improvement in ASD behavior. This anticipation stems from the understanding that LM22A-4 activates the TrkB axis, thus compensating for its reduction, which is thought to be causing ASD-like behaviors. The offspring of mothers injected with valproic acid exhibited ASD-like behaviors, unlike the control mice. Control mice were offspring of pregnant dams injected with a solution containing only the substances used to dissolve valproic acid, typically water and salt (saline). Mice prenatally exposed to valproic acid (VPA) exhibited ASD-like behaviors, but treatment with LM22A-4 helped alleviate these behaviors, promoting more typical behavior patterns. LM22A-4, by activating TrkB receptors, helped to protect the brain from harm caused by exposure to valproic acid before birth. This could mean that valproic acid-induced changes in TrkB-related molecular mechanisms are involved in social behavior difficulties and increased repetitive behaviors seen in autism. Nevertheless, the levels of TrkB, BDNF, proBDNF, Akt, and Erk in the cortex of offspring from mothers injected with valproic acid were like those in the offspring from mothers injected with the saline solution. Therefore, the BDNF and TrkB signaling pathways remained unchanged in the cortex of our valproic acid model in this study, and they differ from those observed in human idiopathic ASD. We also speculated that a protein, called NURR1 acting upstream of BDNF and TrkB might be involved in the process. NURR1 acts as a regulatory protein that binds to the BDNF, increasing the production of copies from the BDNF. We also used a small RNA that targets a specific region in the Nurr1 and inhibits its protein production We anticipated a reduction in Nurr1 levels. As NURR1 acts as an upregulator of BDNF, lower levels of Nurr1 would result in decreased BDNF production. Activating NURR1 resulted in increased BDNF mRNA levels. However, when NURR1 was reduced, BDNF mRNA levels remained unaffected. This led us to conclude that if NURR1 levels decrease, other proteins may step in to maintain BDNF mRNA levels. Therefore, in the cortex, unlike in some other brain regions, the presence of NURR1 is not essential for regulating Bdnf. In summary, before inducing ASD-like behavior in mice using valproic acid, it is crucial to ensure the health of the mice. We used sexually mature mothers with prior pregnancy experience to provide a healthy baseline. We showed valproic acid induced ASD-like behaviors in mice offspring. We also observed that LM22A-4 treatment alleviated ASD-like behaviors of offspring. In our study, we demonstrated that the levels of BDNF, TrkB, Erk, and Akt proteins in the cortex of mice exposed to valproic acid were not affected. For this reason, our mouse model does not resemble human non-genetic ASD. Finally, NURR1's role in BDNF regulation varies by brain region. Lowering NURR1 did not affect BDNF mRNA levels, suggesting compensatory mechanisms. Our findings suggest new directions for further research to better understand the roles of TrkB and BDNF in non-genetic ASD. Overall, this study provides valuable knowledge that can contribute to advancing our understanding of idiopathic ASD-related molecular mechanisms.

Contexte : De la conception à l’âge adulte, de nombreux déterminants environnementaux influencent le neurodéveloppement. Des études montrent que durant la fin de la grossesse et les premiers mois de vie, une grande quantité d’acides gras polyinsaturés (AGPI), notamment à longue chaîne (AGPI-LC), se fixe dans le tissu cérébral. Un apport optimal durant ces périodes critiques pourrait soutenir précocement le bon développement du cerveau et de ses fonctions.Objectifs : Étudier les relations entre les expositions pré- et postnatales précoces aux AGPI, et le neurodéveloppement d’enfants de 2 et 3 ans.Population : Les données utilisées étaient celles de l’étude EDEN, une cohorte mère enfant ayant recruté 2002 femmes enceintes dans les maternités de Nancy et Poitiers entre 2003 et 2006. L’alimentation maternelle pendant la grossesse a été évaluée par un questionnaire de fréquence alimentaire et une table de composition nutritionnelle. Quatre questionnaires postnatals ont permis d’évaluer la durée d’allaitement maternel, et la composition lipidique du colostrum des mères allaitantes a été analysée par chromatographie en phase gazeuse. Des questionnaires parentaux (2 et 3 ans) et un examen neuropsychologique (3 ans) ont permis d’évaluer plusieurs aspects du neurodéveloppement. Les analyses statistiques ont été réalisées par régressions linéaires multivariées, après ajustement sur de nombreux facteurs de confusion potentiels.Résultats : Les scores de neurodéveloppement à 2 et 3 ans des enfants allaités étaient plus élevés que ceux des enfants non allaités. Chez les enfants allaités, la durée d’allaitement maternel était associée positivement au neurodéveloppement. Le rapport n 6/n 3 dans l’alimentation maternelle en acides gras en fin de grossesse était négativement associé à plusieurs mesures du neurodéveloppement, et cette association était renforcée chez les enfants non allaités. La composition du colostrum en AGPI et en AGPI-LC reflétait amplement les apports nutritionnels en AGPI et en AGPI-LC en fin de grossesse. L’utilisation de matières grasses alimentaires était aussi associée à la composition du colostrum. Les différences de neurodéveloppement des enfants allaités ne semblait pas être expliquées par la composition du colostrum en AGPI ni en AGPI-LC, à l’exception de la teneur en acide linoléique qui était négativement associée à certaines mesures du neurodéveloppement. Dans l’ensemble, les associations avec le neurodéveloppement étaient plus fréquemment retrouvées avec les questionnaires parentaux, mais certaines évaluations par les psychologues venaient parfois conforter ces résultats.Conclusion : Associés à ceux de la littérature, ces résultats soulignent le rôle notable des AGPI durant les périodes pré- et postnatale précoce pour le neurodéveloppement de l’enfant. Le suivi des enfants de l’étude EDEN jusqu’à leur 5 ans permettra d’étudier la persistance de ces résultats. Dans une perspective de santé publique, ces travaux rappellent la nécessité de promouvoir l’allaitement maternel dans la durée et de surveiller l’équilibre des apports nutritionnels en AGPI pendant la grossesse et la période de lactation. / Context: From conception to adulthood, many environmental determinants influence neurodevelopment. Studies showed that in late pregnancy and the first months of life, a large amount of polyunsaturated fatty acids (PUFA), especially long-chain-PUFA (LCPUFA), accretes in the brain. Optimal intake during these critical periods could support the brain development and its cognitive functions.Aims: To investigate the relationships between pre- and early postnatal exposures to PUFA, and neurodevelopment of 2 and 3 years old children.Population: Data were those from the EDEN mother-child cohort study, in which 2002 pregnant women were recruited between 2003 and 2006 in the maternities of Nancy and Poitiers. Maternal food intake during pregnancy was evaluated by food frequency questionnaire combined with a food composition table. Duration of breastfeeding was assessed by 4 postnatal questionnaires. Lipids in colostrum of breastfeeding mothers were analyzed by gas chromatography. Several aspects of the cognitive and motor development were assessed by both parental questionnaires (2 and 3 y) and neuropsychological examination (3 y). Statistical analyzes were performed by multiple linear regressions, after adjusting for many potential confounders.Results: At 2 and 3 years, scores of neurodevelopment were higher among breastfed children than among never breastfed children. Among breastfed children, breastfeeding duration was positively associated with neurodevelopment. Maternal dietary n 6/n 3 ratio during late pregnancy was negatively associated with measures of neurodevelopment, and this association was reinforced among never breastfed children. Colostrum composition in PUFA and LCPUFA greatly reflected maternal intake during pregnancy. Use of oils/fats for cooking and seasoning was associated with colostrum composition. The differences of neurodevelopment of breastfed children did not seem to be explained by PUFA nor LCPUFA in colostrum, except for total linoleic acid that was negatively associated with some measures of neurodevelopment. In general, associations with neurodevelopment were more frequently found with assessments by parental questionnaires, but measures by psychologists sometimes confirmed the results.Conclusion: Combined with the literature, these results underline the importance of PUFA exposures during pre- and postnatal periods for the child neurodevelopment. Follow-up of children up to 5 years will allow to investigate whether those results persist later in childhood. From a public health perspectives, this work reiterates the need to promote breastfeeding duration and to monitor the balance of PUFA intake during pregnancy and lactation periods.

Antecedents: No hi ha gaire coneixement sobre el neurodesenvolupament de preescolars i la seva susceptibilitat enfront a factors ambientals. Objectius: Avaluar les respostes del neurodesenvolupament en nens i les seves característiques psicomètriques, i, si factors ambientals primerencs (ex., duració de la lactància materna i mares que fumen) poden influir tals respostes. Mètodes: Dues cohorts prospectives des del naixement en població general (Menorca (N=421) i Ribera d'Ebre (N=79)) van se seguides fins als 4 anys d'edat durant un període de dos anys (2001-2003). Els nens van ser avaluats per tres psicòlegs i els seus respectius mestres per les funcions neuropsicològiques (MCSA), els comportaments de dèficit d'atenció i d'hiperactivitat (TDAH-DSM-IV) i la competència social (CPSCS); junt amb l'administració (en persona) a les mares de qüestionaris generals.Resultats: Les respostes van mostrar característiques psicomètriques acceptables i els patrons neuropsicològics del TDAH eren consistents amb altres troballes sobre TDAH. La lactància materna de llarga durada estava associada amb una millora de totes les àrees comportamentals avaluades. Fumar durant l'embaràs estava associat a puntuacions cognitives més baixes.Conclusions: Avaluar el neurodesenvolupament a preescolars sans és factible i necessari per investigar efectes primerencs de factors ambientals i aplicar polítiques preventives de salut pública. / Background: Little is known about neurodevelopment among preschoolers and its susceptibility to environmental factors.Objectives: Assess neurodevelopmental outcomes and their psychometric characteristics in children; and, if early environmental factors (i.e., duration of breastfeeding and maternal smoking) influence the neurobehavioral outcomes. Methods: Two prospective population-based birth cohorts (Menorca (N=421) and Ribera d'Ebre county (N=79)) were followed up at the age of 4 years during a two year period (2001-2003). Children were assessed by three psychologists and their respective teachers for neuropsychological functions (MCSA), inattention-hyperactivity behaviors (ADHD-DSM-IV) and social behavior (CPSCS); in addition to maternal in person general questionnaires. Results: Outcomes showed acceptable psychometric characteristics and ADHD neuropsychological patterns were consistent with other ADHD findings. Long-term breastfeeding was associated with the improvement of all behavioral areas assessed. Maternal smoking during pregnancy was associated with lower cognitive scores.Conclusions: Assessing neurodevelopment in healthy preschoolers is feasible and necessary to investigate early effects of environmental factors and apply public health preventive policies.

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<p>The manifestations of early sleep disturbances on cerebrospinal fluid and their relations with early developmental competencies are understudied. Recent studies highlight cerebrospinal fluid disbursement as a potential factor associated with dysfunctions in brain development. With two studies, we explored sleep and extra-axial cerebrospinal fluid (EA-CSF) connection as a potential mechanistic pathway by which sleep dysregulation influences brain and behavior development. Specifically, we evaluated associations between (1) EA-CSF to total cerebral volume (EA-CSF/TCV) ratios, (2) parent-report of child sleep problems, and (3) social communication development in typical (Study 1) and atypical populations (Study 2). In typical infants, early sleep problems did not precede later elevated EA-CSF/TCV ratios or social-communicative competence. Elevated EA-CSF/TCV ratios were associated with impaired social communication skills, suggesting that a relationship between elevated EA-CSF/TCV ratios and social communication impairments exists regardless of neurological or sleep problems. In an atypical population with autism spectrum disorder (ASD), older children with ASD had similar EA-CSF/TCV ratios to a group of their typically developing peers. Sleep problems were negatively associated with EA-CSF/TCV ratios but positively associated with social-communicative impairments for children with ASD, highlighting the influence of sleep problems on both brain and behavioral outcomes in an atypical population. In both studies, EA-CSF volumes continue to increase during early development in the typically developing populations (but not later in the atypical sample), underlining its relevance as a marker of atypical processing. Recognizing the potential roles of EA-CSF in influencing several biosocial and behavioral aspects of development, we encourage researchers to continue to explore EA-CSF growth, especially during developmental periods of flux and transition. Future work with longitudinal data can also serve to explore sleep-related developmental changes in EA-CSF, in association with behavioral and phenotypic changes. </p>

Thèse de doctorat présentée en vue de l'obtention du doctorat en psychologie (Ph.D). / L'enfance et l'adolescence sont des périodes uniques de la vie où les changements neuronaux favorisent l'établissement de réseaux cérébraux matures et le développement des capacités intellectuelles. Le langage est un domaine cognitif qui est, non seulement essentiel pour la communication interhumaine, mais qui contribue également au développement de nombreuse capacités et prédit de manière significative la réussite académique. Les régions cérébrales frontotemporales sont des régions clés du réseau langagier du cerveau. Il a été démontré que les neuropathologies telles que l'épilepsie des lobes frontal et temporal (ELF et ELT) interfèrent avec le développement des réseaux cérébraux du langage et provoquent des circuits cérébraux aberrants. Les patrons exacts de réorganisation des réseaux cérébraux fonctionnels ne sont toutefois, pas entièrement compris et l'association avec le profil neuropsychologique reste spéculative. Par conséquent, l'objectif principal de cette thèse est d'accroître la compréhension des altérations du réseau langagier et d'améliorer les connaissances de l'association de l'architecture du réseau et des capacités cognitives chez les enfants et les adolescents avec ELF ou ELT. La présente thèse est composée de trois articles scientifiques, les deux premiers présentant des travaux méthodologiques qui ont permis d'optimiser les méthodes appliquées dans le troisième article, l'étude empirique principale menée auprès d'enfants avec ELF et ELT. Le premier article présente le bilan neuropsychologique pédiatrique comme un outil important pour estimer les capacités cognitives et dresser un profil cognitif avec ses forces et ses faiblesses. Dans le deuxième article, l'analyse factorielle parallèle (PARAFAC) est présentée et validée comme une nouvelle technique employée pour corriger les artefacts de mouvement qui contaminent le signal hémodynamique évalué par la spectroscopie fonctionnelle proche infrarouge (fNIRS). Une meilleure qualité du signal permet une interprétation fiable de la réponse cérébrale en plis de déduire des métriques d'organisation du réseau cérébral. Le troisième article consiste en une étude empirique, où le traitement cérébral du langage, est comparé entre des enfants avec ELF et ELT, et des pairs neuroptypiques. Les schémas de connectivité fonctionnelle indiquent que le groupe de patients présente moins de connexions intra-hémisphériques dans l'hémisphère gauche et entre les hémisphères, et des connexions accrues dans l'hémisphère droit par rapport au groupe témoin. Les mesures de l'architecture du réseau révèlent en outre une efficacité de traitement local plus élevée dans l'hémisphère droit chez les enfants atteints de ELF et ELT par rapport aux enfants en bonne santé. L'architecture du réseau local de l'hémisphère gauche et la capacité intellectuelle globale dans le groupe de patients sont négativement liées, tandis que dans le groupe contrôle, aucune association de ce type n'est identifiable. Ces résultats suggèrent que la réorganisation du réseau de langage chez les enfants avec ELF ou ELT semble dans certains cas soutenir un meilleur résultat cognitif, soit lorsque l'efficacité du traitement local dans l'hémisphère gauche est diminuée. Au contraire, une plus grande efficacité de traitement local semble être une caractéristique d'un réseau de langage cérébral associé à de moins bonnes capacités cognitives. Les travaux de recherche de cette thèse de doctorat fournissent des lignes directrices pour l'utilisation de l'évaluation neuropsychologique pédiatrique, à la fois dans un contexte clinique et scientifique. L'introduction de PARAFAC pour corriger les artefacts de mouvement dans le signal fNIRS est un ajout important au pipeline de prétraitement qui permet d'augmenter la qualité du signal pour une analyse ultérieure. De futurs projets pourront s'appuyer sur cette validation initiale et étendre l'utilisation de PARAFAC pour les analyses du signal fNIRS. Sur cette base méthodologique solide, le travail empirique confirme l'incidence accrue de circuits cérébraux aberrants liés au traitement du langage chez les enfants atteints de ELF et de ELT, et soutient en outre l'efficacité du réseau local en tant que déterminant clé de l'impact de la plasticité cérébrale précoce sur les capacités cognitives. Afin de mieux comprendre les altérations du réseau en réponse aux neuropathologies et leur impact, des études avec des échantillons plus grands et de différents groupes d'âge, devraient étudier plus spécifiquement le rôle des facteurs cliniques (e.g., le type d'épilepsie, la latéralisation de l'épilepsie, le contrôle des crises, etc.) et aborder leurs influences sur le développement. À long terme, cela augmentera le pronostic des phénotypes cliniques chez les patients pédiatriques atteints de ELF et de ELT, et offrira des opportunités d'interventions précoces pour soutenir un développement typique. / Childhood and adolescence are unique periods in life where neuronal changes support the establishment of mature brain networks and the development of intellectual capacities. Language is one cognitive domain that is not only an essential part of inter-human communication but also contributes to the development of other capacities and significantly influences academic achievement. Frontotemporal brain areas are key regions of the brain's language network. Neuropathologies such as frontal and temporal lobe epilepsies (FLE and TLE) have been shown to interfere with developing brain language networks and cause aberrant cerebral circuits. The exact patterns of functional brain network reorganization are not fully understood and the association with the neuropsychological profile remains speculative. Therefore, the main objective of this thesis was to increase comprehension of language network alterations and enhance the knowledge on the association of network topology and cognitive capacities in children and adolescents with FLE or TLE. This thesis consists of three scientific articles, with the first two presenting methodological work that allowed for the optimization of the methods applied in the third article, which is the main empirical study conducted on children with FLE and TLE. The first article presents the pediatric neuropsychological assessment as a valuable tool to estimate cognitive capacities and draw a cognitive profile with strengths and weaknesses. In the second article, parallel factor analysis (PARAFAC) is presented and validated as a novel technique to correct motion artifacts that contaminate the hemodynamic signal assessed with functional near-infrared spectroscopy (fNIRS). A better signal quality is the basis for a reliable interpretation of the cerebral response and derive metrics of brain network organization. The third article consists of an empirical study where cerebral language processing is compared between children with FLE and TLE, and neuroptypical peers. Patterns of functional connectivity indicate that the patient group demonstrates fewer intra-hemispheric connections in the left hemisphere and between hemispheres, and increased connections within the right hemisphere as compared to the control group. Metrics of network architecture further reveal a higher local processing efficiency within the right hemisphere in children with FLE and TLE compared to healthy peers. Local network architecture of the left hemisphere and the overall intellectual capacity in the patient group is negatively related, while in the control group no such association is identifiable. These findings suggest that language network reorganization in children with FLE or TLE in some cases seems to support a better cognitive outcome, namely when local processing efficiency in the left hemisphere is decreased. On the contrary, a higher local processing efficiency seems to be a characteristic of a brain language network that goes along with worse cognitive capacities. The research work of this doctoral thesis provides guidelines for the use of pediatric neuropsychological assessment both in a clinical and scientific context. The introduction of PARAFAC to correct motion artifact in the fNIRS signal is an important add-on to the preprocessing pipeline that allows to increase signal quality for subsequent analysis. Future projects will be able to build on this initial validation and extend PARAFAC's use for fNIRS analysis. On this solid methodological foundation, the empirical work confirms the increased incidence of aberrant brain circuits related to language processing in children with FLE and TLE, and further supports local network efficiency as a key determinant of the impact of early brain plasticity on cognitive capacities. In order to further understand network alterations in response to neuropathologies and their impact, studies with larger samples sizes and different age groups should further investigate the specific role of clinical factors (e.g., epilepsy type, epilepsy lateralization, seizure control, etc.) and address developmental influences. Ultimately, this will increase prognosis of clinical phenotypes in pediatric patients with FLE and TLE, and offer opportunities for early interventions to support a healthy development.

Neurotrophins and their receptors are key molecules in the development of thenervous system. Neurotrophin-3 binds preferentially to its high-affinity receptorNTRK3, which exists in two major isoforms in humans, the full-length kinaseactiveform (150 kDa) and a truncated non-catalytic form (50 kDa). The twovariants show different 3'UTR regions, indicating that they might be differentiallyregulated at the post-transcriptional level. In this work we explore howmicroRNAs take part in the regulation of full-length and truncated NTRK3,demonstrating that the two isoforms are targeted by different sets of microRNAs.We analyze the physiological consequences of the overexpression of some of theregulating microRNAs in human neuroblastoma cells. Finally, we providepreliminary evidence for a possible involvement of miR-124 - a microRNA with noputative target site in either NTRK3 isoform - in the control of the alternativespicing of NTRK3 through the downregulation of the splicing repressor PTBP1. / Las neurotrofinas y sus receptores constituyen una familia de factores crucialespara el desarrollo del sistema nervioso. La neurotrofina 3 ejerce su funciónprincipalmente a través de una unión de gran afinidad al receptor NTRK3, del cualse conocen dos isoformas principales, una larga de 150KDa con actividad de tipotirosina kinasa y una truncada de 50KDa sin dicha actividad. Estas dos isoformasno comparten la misma región 3'UTR, lo que sugiere la existencia de unaregulación postranscripcional diferente. En el presente trabajo se ha exploradocomo los microRNAs intervienen en la regulación de NTRK3, demostrando que lasdos isoformas son reguladas por diferentes miRNAs. Se han analizado lasconsecuencias fisiológicas de la sobrexpresión de dichos microRNAs utilizandocélulas de neuroblastoma. Finalmente, se ha estudiado la posible implicación delmicroRNA miR-124 en el control del splicing alternativo de NTRK3 a través de laregulación de represor de splicing PTBP1.