Des études récentes ont démontré une augmentation de la prévalence de l’infertilité au Canada ainsi qu’une augmentation fulgurante de l’utilisation de la procréation assistée. Le Québec s’est doté en 2010 d’un programme de financement de la procréation assistée visant un accès universel ainsi que la protection de la santé des mères et des enfants. Les diverses parties prenantes attribuent un certain nombre de lacunes à ce programme, incluant l’absence de mesures de prévention et de promotion de la santé visant à réduire la prévalence de l’infertilité. En effet, une proportion significative de cas d’infertilité découle de facteurs modifiables et relatifs aux modes de vie tels que le tabagisme, les infections transmises sexuellement et par le sang, les problèmes de poids, les toxines environnementales et l’âge. De plus, l’âge maternel avancé ainsi que l’usage de la procréation assistée comportent des risques pour la santé des mères et des enfants au sujet desquels la population ne possède pas une connaissance suffisante. Des approches en amont ont été proposées par diverses organisations et dans divers pays, toutefois, peu ont été adoptées. Force est de constater que ces initiatives représentent de grands défis au point de vue de l’acceptabilité sociale, en raison de la nature sensible du sujet et d’une grande valorisation sociale de l’autonomie reproductive. L’éthique des communications en santé permet d’identifier ces défis qui touchent l’usage de tactiques persuasives, le risque de stigmatisation et l’attribution indue d’une responsabilité. Si leur élaboration tient compte de ces enjeux, les campagnes de communications en santé ont le potentiel d’informer adéquatement la population afin de favoriser l’autonomie et la santé reproductive des individus, sans causer de dommage iatrogénique. L’éthique de l’ « empowerment », qui requiert l’attribution d’une responsabilité individuelle de nature prospective, l’apport de ressources concrètes et l’implication des communautés, permet d’identifier les besoins en termes de solutions législatives favorisant des contextes socioéconomiques qui soutiennent la santé reproductive et l’autonomie reproductive. / Recent studies have demonstrated an increased prevalence of infertility in Canada and a tremendous growth in assisted reproductive technologies use. In 2010, the Quebec government launched a public funding program for assisted reproductive technologies, which aims to provide equitable access and to protect the health of mothers and children. Various stakeholders have identified a number of shortcomings to this program, including the absence of prevention and health promotion measures aimed towards reducing the prevalence of infertility. Indeed, a significant proportion of infertility cases is attributable to modifiable and lifestyle related factors such as smoking, sexually transmitted infections, weight problems, environmental toxins and age. In addition, both advanced maternal age and assisted reproductive technologies utilization pose risks to the health of mothers and children, about which the population is not adequately informed. Preventative approaches have been proposed by many organizations in various countries but few have been implemented. A reason for this might be that these initiatives represent major challenges in terms of social acceptability, due to the sensitive nature of the subject and the strong social respect for reproductive autonomy. Health communication ethics highlights these issues such as the use of persuasive tactics, the risk of stigmatization, and undue attribution of responsibility. If designed effectively with these challenges in mind, health communication campaigns for infertility prevention have the potential to adequately inform the public, thus fostering reproductive autonomy and health, without causing iatrogenic damage. The ‘ethics of empowerment’, with its requirements for assigning only prospective individual responsibility, providing concrete resources and involving communities in social change, helps in identifying the needs for policy solutions that address the social context in order to enhance reproductive health and reproductive autonomy.

Des études récentes ont démontré une augmentation de la prévalence de l’infertilité au Canada ainsi qu’une augmentation fulgurante de l’utilisation de la procréation assistée. Le Québec s’est doté en 2010 d’un programme de financement de la procréation assistée visant un accès universel ainsi que la protection de la santé des mères et des enfants. Les diverses parties prenantes attribuent un certain nombre de lacunes à ce programme, incluant l’absence de mesures de prévention et de promotion de la santé visant à réduire la prévalence de l’infertilité. En effet, une proportion significative de cas d’infertilité découle de facteurs modifiables et relatifs aux modes de vie tels que le tabagisme, les infections transmises sexuellement et par le sang, les problèmes de poids, les toxines environnementales et l’âge. De plus, l’âge maternel avancé ainsi que l’usage de la procréation assistée comportent des risques pour la santé des mères et des enfants au sujet desquels la population ne possède pas une connaissance suffisante. Des approches en amont ont été proposées par diverses organisations et dans divers pays, toutefois, peu ont été adoptées. Force est de constater que ces initiatives représentent de grands défis au point de vue de l’acceptabilité sociale, en raison de la nature sensible du sujet et d’une grande valorisation sociale de l’autonomie reproductive. L’éthique des communications en santé permet d’identifier ces défis qui touchent l’usage de tactiques persuasives, le risque de stigmatisation et l’attribution indue d’une responsabilité. Si leur élaboration tient compte de ces enjeux, les campagnes de communications en santé ont le potentiel d’informer adéquatement la population afin de favoriser l’autonomie et la santé reproductive des individus, sans causer de dommage iatrogénique. L’éthique de l’ « empowerment », qui requiert l’attribution d’une responsabilité individuelle de nature prospective, l’apport de ressources concrètes et l’implication des communautés, permet d’identifier les besoins en termes de solutions législatives favorisant des contextes socioéconomiques qui soutiennent la santé reproductive et l’autonomie reproductive. / Recent studies have demonstrated an increased prevalence of infertility in Canada and a tremendous growth in assisted reproductive technologies use. In 2010, the Quebec government launched a public funding program for assisted reproductive technologies, which aims to provide equitable access and to protect the health of mothers and children. Various stakeholders have identified a number of shortcomings to this program, including the absence of prevention and health promotion measures aimed towards reducing the prevalence of infertility. Indeed, a significant proportion of infertility cases is attributable to modifiable and lifestyle related factors such as smoking, sexually transmitted infections, weight problems, environmental toxins and age. In addition, both advanced maternal age and assisted reproductive technologies utilization pose risks to the health of mothers and children, about which the population is not adequately informed. Preventative approaches have been proposed by many organizations in various countries but few have been implemented. A reason for this might be that these initiatives represent major challenges in terms of social acceptability, due to the sensitive nature of the subject and the strong social respect for reproductive autonomy. Health communication ethics highlights these issues such as the use of persuasive tactics, the risk of stigmatization, and undue attribution of responsibility. If designed effectively with these challenges in mind, health communication campaigns for infertility prevention have the potential to adequately inform the public, thus fostering reproductive autonomy and health, without causing iatrogenic damage. The ‘ethics of empowerment’, with its requirements for assigning only prospective individual responsibility, providing concrete resources and involving communities in social change, helps in identifying the needs for policy solutions that address the social context in order to enhance reproductive health and reproductive autonomy.

OBJETIVO: Identificar o perfil da clientela atendida na Unidade de Cuidados Intensivos Neonatal Externa (UCINE); observar possíveis diferenças entre recém-nascidos e família de mães adolescentes e de mães adultas, e verificar a participação das famílias nos programas de humanização da unidade. MÉTODO: Estudo de coorte transversal prospectivo de 284 recém-nascidos (RN) e seus familiares admitidos na Unidade de Cuidados Intensivos Neonatal do Instituto da Criança de maio de 2005 a dezembro de 2006. Os dados foram coletados com as mães seguindo o conteúdo do formulário construído especificamente para este estudo, que incluía informações socioeconômicas e demográ-ficas, história antenatal, tipo de parto, dados relacionados ao recém-nascido como idade gestacional e cronológica, pesos de nascimento e de admissão, tipo de aleitamento à internação e na alta, doenças que geraram a internação, número de altas, óbitos e transferências, trata-mentos utilizados e participação da família durante a internação. RESULTADOS: Evidenciou-se em relação às condições sociodemográ-ficas que a maioria dos 284 pacientes (66,2%) procedia da cidade de São Paulo, principalmente da Zona Oeste, ou dos municípios. O pré-natal foi realizado por 96,1% das mães, e 59% dos RN nasceram de parto cesa-riano, com peso entre 600 e 4780g, idade gestacional mediana de 37,6 semanas, e na maioria adequados para a idade gestacional (77,5%). A mediana da idade à internação foi de 7 dias de vida, associada princi-palmente a causas infecciosas (32,0%) e respiratórias (25,0%), sendo o peso nesta ocasião de 600 a 5810g. A taxa de mães adolescentes ( 19 anos de idade) foi de 21,0%, e neste grupo observou-se índices inferiores de escolaridade e de número de consultas de pré-natal e, maior inci-dência de prematuridade (47,5%). As mães adultas apresentaram maior número de intercorrências durante a gestação e maior incidência de parto cesariano (63,6%). Em relação às características dos RN, não houve diferenças estatísticas entre mães adolescentes e adultas, entre-tanto observou-se a necessidade de internação mais precoce dos RN de mães adolescentes na unidade, e pesos menores à admissão. A sobre-vida foi de 91,2% e, a evolução dos RN não foi influenciada pela idade materna, quando questionada a participação das famílias nos programas de humanização da unidade, observou-se participação ativa dos fami-liares de ambas as faixas etárias nos cuidados ao RN e aumento da porcentagem de RN em aleitamento na alta (69,3%) comparada à admissão (51,7%). CONCLUSÕES: O perfil da clientela mostra que o atendimento é na sua maior parte regionalizado, e constituído por pacientes com doenças complexas que necessitam de atendimento em Unidade de Cuidados Intensivos Neonatal de nível terciário. As mães adolescentes apresentaram intercorrências durante a gestação como hipertensão arterial e diabetes mellitus que, além da idade, predispõem ao nascimento de recém-nascidos prematuros. A participação das famílias nos cuidados aos seus filhos demonstrou-se relevante, no entanto são necessárias medidas que aumentem a adesão e integração dos familiares nos programas de humanização / OBJECTIVES: Identify the profile of the patients assisted in the Neonatal Intensive Care Unit (NICU); observe the possible differences between the newborns from families of adult mothers and families of teenage mothers, and also verify the participation of the families in the unit humanization programs. METHOD: Prospective transversal cohort of 284 newborns (NB) and their family members, who were admitted in the Neonatal Intensive Care Unit of the Instituto da Criança, between May 2005 and December 2006. The data was collected from the mothers according to the contents of the form that was specifically designed for this study, which included demographic, social and economical information; the antenatal history; type of delivery; data related to the newborn such as gestation age and chronological age; birth and admission weight; type of feeding at the time of admission and at the time of discharge; the diseases that caused the admission; number of discharges, deaths and transfers; the treatments used; and the participation of the family during the stay in the NICU. RESULTS: We found that, as far as the social and demographical conditions are concerned, the majority of the 284 patients (66.2%) were from the city of São Paulo, mainly from its West Part, or from the cities belonging to the greater São Paulo area. The prenatal exam was carried out by 96.1% of the mothers, and 59% of the NB were delivered by cesarean sections, having a body weight varying from 600 to 4780 grams, average gestation age of 37.6 weeks, and the majority were physically adequate for their gestation age (77.5%). Their average age upon admission was of 7 days, being the causes for admission mainly associated with infectious (32%) and respiratory (25%) diseases, and their weight at the time varied from 600 to 5810 grams. The percentage of teenage mothers ( than 19 years old) was 21%, and in this particular group we found inferior schooling levels and inferior prenatal exam figures, and also in this group we found a greater incidence of preterm births (47.5%). The adult mothers presented a greater number of complications during pregnancy and a greater number of surgically assisted deliveries (63.6%). As far as the NB\'s characteristics, there were no statistical differences between teenage and adult mothers, however we found an earlier admission age of the NB from teenage mothers in the Unit, and also less weight upon admission. The survival rate was 91.2% and the evolution of the NB was not influenced by maternal age. When we asked about the families\' participation in Unit humanization programs, we found an active participation of the families of either teenage or adult mothers in the care to the NB and an increase in the percentage of NB being breastfed at the moment of discharge (69.3%) compared to the moment of admission (51.7%). CONCLUSIONS: The profile of the patients show that the assistance is in most part regionalized, being constituted of patients with complex diseases that needed care in a Level III NICU. The teenage mothers presented complications during pregnancy such as high blood pressure and diabetes mellitus, which, along with their age, prearranged the preterm birth of newborns. The participation of the families in the care to their infants has shown to be relevant, however some measures are necessary in order to increase and improve the participation of the family members in the humanization programs

OBJETIVO: Identificar o perfil da clientela atendida na Unidade de Cuidados Intensivos Neonatal Externa (UCINE); observar possíveis diferenças entre recém-nascidos e família de mães adolescentes e de mães adultas, e verificar a participação das famílias nos programas de humanização da unidade. MÉTODO: Estudo de coorte transversal prospectivo de 284 recém-nascidos (RN) e seus familiares admitidos na Unidade de Cuidados Intensivos Neonatal do Instituto da Criança de maio de 2005 a dezembro de 2006. Os dados foram coletados com as mães seguindo o conteúdo do formulário construído especificamente para este estudo, que incluía informações socioeconômicas e demográ-ficas, história antenatal, tipo de parto, dados relacionados ao recém-nascido como idade gestacional e cronológica, pesos de nascimento e de admissão, tipo de aleitamento à internação e na alta, doenças que geraram a internação, número de altas, óbitos e transferências, trata-mentos utilizados e participação da família durante a internação. RESULTADOS: Evidenciou-se em relação às condições sociodemográ-ficas que a maioria dos 284 pacientes (66,2%) procedia da cidade de São Paulo, principalmente da Zona Oeste, ou dos municípios. O pré-natal foi realizado por 96,1% das mães, e 59% dos RN nasceram de parto cesa-riano, com peso entre 600 e 4780g, idade gestacional mediana de 37,6 semanas, e na maioria adequados para a idade gestacional (77,5%). A mediana da idade à internação foi de 7 dias de vida, associada princi-palmente a causas infecciosas (32,0%) e respiratórias (25,0%), sendo o peso nesta ocasião de 600 a 5810g. A taxa de mães adolescentes ( 19 anos de idade) foi de 21,0%, e neste grupo observou-se índices inferiores de escolaridade e de número de consultas de pré-natal e, maior inci-dência de prematuridade (47,5%). As mães adultas apresentaram maior número de intercorrências durante a gestação e maior incidência de parto cesariano (63,6%). Em relação às características dos RN, não houve diferenças estatísticas entre mães adolescentes e adultas, entre-tanto observou-se a necessidade de internação mais precoce dos RN de mães adolescentes na unidade, e pesos menores à admissão. A sobre-vida foi de 91,2% e, a evolução dos RN não foi influenciada pela idade materna, quando questionada a participação das famílias nos programas de humanização da unidade, observou-se participação ativa dos fami-liares de ambas as faixas etárias nos cuidados ao RN e aumento da porcentagem de RN em aleitamento na alta (69,3%) comparada à admissão (51,7%). CONCLUSÕES: O perfil da clientela mostra que o atendimento é na sua maior parte regionalizado, e constituído por pacientes com doenças complexas que necessitam de atendimento em Unidade de Cuidados Intensivos Neonatal de nível terciário. As mães adolescentes apresentaram intercorrências durante a gestação como hipertensão arterial e diabetes mellitus que, além da idade, predispõem ao nascimento de recém-nascidos prematuros. A participação das famílias nos cuidados aos seus filhos demonstrou-se relevante, no entanto são necessárias medidas que aumentem a adesão e integração dos familiares nos programas de humanização / OBJECTIVES: Identify the profile of the patients assisted in the Neonatal Intensive Care Unit (NICU); observe the possible differences between the newborns from families of adult mothers and families of teenage mothers, and also verify the participation of the families in the unit humanization programs. METHOD: Prospective transversal cohort of 284 newborns (NB) and their family members, who were admitted in the Neonatal Intensive Care Unit of the Instituto da Criança, between May 2005 and December 2006. The data was collected from the mothers according to the contents of the form that was specifically designed for this study, which included demographic, social and economical information; the antenatal history; type of delivery; data related to the newborn such as gestation age and chronological age; birth and admission weight; type of feeding at the time of admission and at the time of discharge; the diseases that caused the admission; number of discharges, deaths and transfers; the treatments used; and the participation of the family during the stay in the NICU. RESULTS: We found that, as far as the social and demographical conditions are concerned, the majority of the 284 patients (66.2%) were from the city of São Paulo, mainly from its West Part, or from the cities belonging to the greater São Paulo area. The prenatal exam was carried out by 96.1% of the mothers, and 59% of the NB were delivered by cesarean sections, having a body weight varying from 600 to 4780 grams, average gestation age of 37.6 weeks, and the majority were physically adequate for their gestation age (77.5%). Their average age upon admission was of 7 days, being the causes for admission mainly associated with infectious (32%) and respiratory (25%) diseases, and their weight at the time varied from 600 to 5810 grams. The percentage of teenage mothers ( than 19 years old) was 21%, and in this particular group we found inferior schooling levels and inferior prenatal exam figures, and also in this group we found a greater incidence of preterm births (47.5%). The adult mothers presented a greater number of complications during pregnancy and a greater number of surgically assisted deliveries (63.6%). As far as the NB\'s characteristics, there were no statistical differences between teenage and adult mothers, however we found an earlier admission age of the NB from teenage mothers in the Unit, and also less weight upon admission. The survival rate was 91.2% and the evolution of the NB was not influenced by maternal age. When we asked about the families\' participation in Unit humanization programs, we found an active participation of the families of either teenage or adult mothers in the care to the NB and an increase in the percentage of NB being breastfed at the moment of discharge (69.3%) compared to the moment of admission (51.7%). CONCLUSIONS: The profile of the patients show that the assistance is in most part regionalized, being constituted of patients with complex diseases that needed care in a Level III NICU. The teenage mothers presented complications during pregnancy such as high blood pressure and diabetes mellitus, which, along with their age, prearranged the preterm birth of newborns. The participation of the families in the care to their infants has shown to be relevant, however some measures are necessary in order to increase and improve the participation of the family members in the humanization programs

Advanced maternal age has been shown to influence follicular and luteal dynamics in bovine ovary resulting in reduced fertility. The overall objective of the four studies presented in this thesis is to identify the maternal age-associated transcriptional changes in granulosa cells of the dominant follicles during follicle development. In the first study, mRNA expression levels of housekeeping genes were measured by real–time quantitative PCR (RT-qPCR) in granulosa cells of dominant follicles and FSH-stimulated follicles to select and validate suitable reference genes for relative gene expression analyses during maternal and follicular aging. Stability of six reference genes (GAPDH, ACTB, EIF2B2, UBE2D2, SF3A1 and RNF20) was analyzed using GeNorm, DeltaCT and NormFinder programs and comprehensive ranking order was determined based on these programs. Geometric mean of multiple genes (UBE2D2, EIF2B2, GAPDH and SF3A1) was more appropriate reference control than individual genes for the comparison of relative gene expression among dominant and FSH-stimulated follicles during maternal and/or follicular aging studies. In the second study, maternal age-associated changes in the transcriptome of granulosa cells recovered at the time of selection of the dominant follicle from aged (n=3) and young cows (n=3) were determined by EmbryoGENE bovine oligo-microarrays (EMBV3, Agilent Technology). The mRNA expression of five transcripts (CYP19A1, PCNA, GJA1, TPM2, and VNN1) was confirmed in a different set of granulosa cell samples by RT-qPCR to validate microarray data. A total of 169 genes/isoforms were differentially expressed (≥ 2-fold-change; P ≤ 0.05) in aged cows vs. young cows. These transcripts revealed inefficient 1) control of gonadotropins, and gonadotropin-induced changes in the cytoskeleton and extracellular matrix, 2) lipid metabolism and steroidogenesis 3) cell proliferation, cell cycle control and intercellular communication, and 4) higher oxidative stress responses in aged cows vs. young cows. In the third study, changes in the transcriptome of granulosa cells of the preovulatory follicle 24 h after LH treatment from aged (n= 3) and young (n=3) were determined. A total of 1340 genes were expressed differentially (≥ 2-fold change; P ≤ 0.05) in aged cows vs. young cows. The mRNA expression of five transcripts (RGS2, PTGS2, TNFAIP6, VNN1, NR5A2 and GADD45B) was confirmed in a different set of granulosa cell samples to validate microarray data. These transcripts were related to delayed 1) response to LH treatment 2) cellular differentiation and luteinization and 3) progesterone synthesis. Intra-follicle levels of progesterone were lower (P < 0.05) in aged cows compared to young and mid-aged cows. The fourth study compared the aged-associated changes in the transcriptome of granulosa cells during follicle development from the time of dominant follicle selection to preovulatory stage (24 h after LH). In comparison to young cows, aged cows expressed fewer differentially expressed genes/isoforms (1206 vs. 2260, respectively) at ≥ 2-fold-change (P ≤ 0.05) in the granulosa cells of the preovulatory (24 h after LH treatment) vs. the dominant follicle at selection. These transcripts in aged cows were related to late and inefficient 1) organization of cytoskeleton and cytoplasm, 2) differentiation, 3) lipid and cholesterol metabolism, 4) proliferation and 5) higher response to oxidative stress and free radical scavenging in the preovulatory follicles vs. the dominant follicle at selection. In conclusion, maternal age-alters the gene expression of granulosa cells of the dominant follicles during follicle development and results in a compromised follicular environment.

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.