Estresse precoce e programação do comportamento alimentar, processos emocionais e cognitivos : uma perspectiva translacional

A exposição a adversidades no início da vida é associada a susceptibilidades para o desenvolvimento de doenças metabólicas e psiquiátricas. Entretanto, os mecanismos por trás dessa associação, bem como as características que tornam o indivíduo resiliente ou susceptível, precisam ser melhor investigados. Assim, o objetivo desta tese foi investigar os efeitos de interações genéticas e ambientais no desenvolvimento de alterações de comportamento alimentar, processos emocionais e cognitivos. Inicialmente, desenvolvemos um estudo em modelos animais e investigamos os efeitos de diferentes protocolos de estresse no início da vida na predisposição a comportamento tipo-ansioso, alterações de peso corporal e comportamento alimentar. Os resultados mostram que animais machos submetidos ao estresse de privação materna apresentam diminuição de peso corporal ao longo da vida e essa diminuição está associada à redução de consumo de ração padrão. Por outro lado, tanto a separação quanto privação maternal induz aumento de consumo de alimentos palatáveis e comportamento do tipo-ansioso na idade adulta. De forma interessante, esses resultados são sexo-específicos: em fêmeas não observamos alteração de ansiedade e resultados opostos foram vistos com relação ao consumo de alimentos palatáveis, sugerindo comportamento tipoanedônico no grupo submetido a privação maternal. Observamos também que o estresse precoce induziu alterações de conteúdo serotoninérgico na amígdala e no hipotálamo, em ambos os sexos, e redução da expressão de POMC no hipotálamo em machos. A partir desses resultados, levantamos a hipótese que os efeitos do estresse no início da vida no comportamento alimentar poderiam ser resultado da interação com redes de genes funcionais. Nessa perspectiva, com o objetivo de desenvolver uma pesquisa translacional focando em redes de genes regiões-específicas que poderiam ser afetadas pelo estresse no início da vida, desenvolvemos um estudo que analisou interações entre a exposição a adversidades no início da vida e genes relacionados ao receptor de leptina. Para tanto, realizamos um estudo em duas coortes longitudinais humanas e avaliamos a suscetibilidade ao desenvolvimento de padrões alimentares em crianças com histórico de adversidade no início da vida, considerando à expressão da rede de genes que se co-expressam com o receptor de leptina no córtex pré-frontal e no hipotálamo como possível modulador dessa associação. Os resultados desse trabalho demonstram que a interação entre adversidades no início da vida e a rede de genes que se co-expressa com o receptor de leptina no córtex pré-frontal influencia o comportamento alimentar de crianças. Esses resultados foram replicados em diferentes idades e em ambas as coortes analisadas. Por fim, considerando nossos achados em modelos animais com relação ao sistema serotoninérgico, continuamos nossos estudos em humanos e avaliamos como processos cognitivos, epigenéticos e a densidade de matéria cinzenta encefálica são modulados pela interação entre adversidades no início da vida e a rede de genes que se co-expressa com o transportador de serotonina na amígdala. Os resultados desse trabalho demonstram que a interação entre adversidades em períodos sensíveis de desenvolvimento e a rede de genes que se co-expressa com o transportador de serotonina na amígdala modula comportamentos relacionados à atenção e hiperatividade, bem como variações de metilação de DNA ao longo do genoma, e que SNPs dessa rede também são associados a variações de densidade de matéria cinzenta encefálica. Em conjunto, por meio de um estudo translacional nesta tese, identificamos um perfil genético e funcional associado à sinalização da leptina no córtex pré-frontal como um importante modulador dos efeitos de experiências adversas no comportamento alimentar. Por outro lado, evidências consistentes em nossos achados apontam que a funcionalidade da rede de genes co-expressos com o transportador de serotonina na amígdala é importante para resiliência ou risco aumentado de desenvolver psicopatologias ao longo da vida, interagindo com a presença de adversidades precoces.Early life adversities have been associated with the susceptibility to develop metabolic and psychiatric diseases later in life. However, the mechanisms behind this association need to be further investigated, as well as the individual characteristics that provide vulnerability or resilience. Therefore, the aim of this dissertation was to investigate the effects of interactions between genetic and environmental factors on eating behavior, and emotional and cognitive processes. For this, we first investigated the effects of different animal models of early life stress on anxiety-like behavior, body weight, and eating behavior. The results showed that maternal deprivation decreases body weight throughout life and this decrease is associated with a reduction in standard chow intake. On the other hand, both maternal separation and deprivation increased consumption of palatable foods and anxiety-like behavior in male animals. Interestingly, these results were sex-specific: in females, we did not observe changes in anxiety, and opposite results were seen regarding palatable foods intake, suggesting anhedonia-like behavior in the maternal deprivation group. We also observed that both early stress models induced alterations in the serotonergic content in the amygdala and hypothalamus, and reduced POMC expression in the hypothalamus of males. From these results, we hypothesized that early life stress effects on eating behavior could result from the interaction with functional gene networks. Therefore, we developed a translational study that analyzed interactions between exposure to adversity in early life and genes associated with the leptin receptor on eating behavior patterns and metabolic parameters in children from two prospective births cohorts. The results demonstrated that the interaction between adversity in early life and a gene network that co-expresses with the leptin receptor in the prefrontal cortex influences feeding behavior of children. These results were replicated at different ages and different cohorts. Finally, considering our findings in animal models regarding the serotonergic system, we continued our studies in humans and evaluated whether cognitive, epigenetic processes, and brain gray matter density are modulated by the interaction between adversities in early life and the gene network that is co-expressed with the serotonin transporter in the amygdala. The results of this study demonstrated that the interaction between adversities early in life and the gene network that co-expresses with the serotonin transporter in the amygdala modulates behaviors related to attention and hyperactivity, as well as variations in DNA methylations; and SNPs from this network are also associated with variations in brain gray matter density. In conclusion, here we identified a genetic and functional profile associated with leptin signaling in the prefrontal cortex as an important modulator of the effects of early life adversity on eating behavior. On the other hand, strong evidence from our findings indicates that the interaction between the amygdala serotonin transporter gene network and early life adversities modulated the resilience or increased risk of developing psychopathologies throughout life

Cognitive development and brain gray matter susceptibility to prenatal adversities : moderation by the prefrontal cortex brain-derived neurotrophic factor gene co-expression network

Background: Previous studies focused on the relationship between prenatal conditions and neurodevelopmental outcomes later in life, but few have explored the interplay between gene co-expression networks and prenatal adversity conditions on cognitive development trajectories and gray matter density. Methods: We analyzed the moderation effects of an expression polygenic score (ePRS) for the Brain-derived Neurotrophic Factor gene network (BDNF ePRS) on the association between prenatal adversity and child cognitive development. A score based on genes co-expressed with the prefrontal cortex (PFC) BDNF was created, using the effect size of the association between the individual single nucleotide polymorphisms (SNP) and the BDNF expression in the PFC. Cognitive development trajectories of 157 young children from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) cohort were assessed longitudinally in 4-time points (6, 12, 18, and 36 months) using the Bayley-II mental scales. Results: Linear mixed-effects modeling indicated that BDNF ePRS moderates the effects of prenatal adversity on cognitive growth. In children with high BDNF ePRS, higher prenatal adversity was associated with slower cognitive development in comparison with those exposed to lower prenatal adversity. Parallel-Independent Component Analysis (pICA) suggested that associations of expression-based SNPs and gray matter density significantly differed between low and high prenatal adversity groups. The brain IC included areas involved in visual association processes (Brodmann area 19 and 18), reallocation of attention, and integration of information across the supramodal cortex (Brodmann area 10). Conclusion: Cognitive development trajectories and brain gray matter seem to be influenced by the interplay of prenatal environmental conditions and the expression of an important BDNF gene network that guides the growth and plasticity of neurons and synapses

Leptin receptor co-expression gene network moderates the effect of early life adversity on eating behavior in children

Leptin influences eating behavior. Exposure to early adversity is associated with eating behaviour disorders and metabolic syndrome, but the role of the leptin receptor on this relationship is poorly explored. We investigated whether individual differences in brain region specific leptin receptor (LepR) gene networks could moderate the effects of early adversity on eating behavior and metabolism. We created an expression-based polygenic risk score (ePRS) reflecting variations in the function of LepR gene network in prefrontal cortex and hypothalamus to investigate the interactions between a cumulative index of postnatal adversity on eating behavior in two independent birth cohorts (MAVAN and GUSTO). To explore whether variations in the prefrontal cortex or hypothalamic genetic scores could be associated with metabolic measurements, we also assessed the relationship between LepR-ePRS and fasting blood glucose and leptin levels in a third independent cohort (ALSPAC). We identified significant interaction effects between postnatal adversity and prefrontal-based LepR-ePRS on the Child Eating Behavior Questionnaire scores. In MAVAN, we observed a significant interaction effect on food enjoyment at 48 months (β = 61.58, p = 0.015) and 72 months (β = 97.78, p = 0.001); food responsiveness at 48 months (β = 83.79, p = 0.009) satiety at 48 months (β = −43.63, p = 0.047). Similar results were observed in the GUSTO cohort, with a significant interaction effect on food enjoyment (β = 30.48, p = 0.006) food fussiness score (β = −24.07, p = 0.02) and satiety score at 60 months (β = −17.00, p = 0.037). No effects were found when focusing on the hypothalamus-based LepR-ePRS on eating behavior in MAVAN and GUSTO cohorts, and there was no effect of hypothalamus and prefrontal cortex based ePRSs on metabolic measures in ALSPAC. Our study indicated that exposure to postnatal adversity interacts with prefrontal cortex LepR-ePRS to moderate eating behavior, suggesting a neurobiological mechanism associated with the development of eating behavior problems in response to early adversity. The knowledge of these mechanisms may guide the understanding of eating patterns associated with risk for obesity in response to fluctuations in stress exposure early in life

Amygdala 5-HTT gene network moderates the effects of postnatal adversity on attention problems : anatomo-functional correlation and epigenetic changes

Variations in serotoninergic signaling have been related to behavioral outcomes. Alterations in the genome, such as DNA methylation and histone modifications, are affected by serotonin neurotransmission. The amygdala is an important brain region involved in emotional responses and impulsivity, which receives serotoninergic input. In addition, studies suggest that the serotonin transporter gene network may interact with the environment and influence the risk for psychiatric disorders. We propose to investigate whether/how interactions between the exposure to early life adversity and serotonin transporter gene network in the amygdala associate with behavioral disorders. We constructed a co-expression-based polygenic risk score (ePRS) reflecting variations in the function of the serotonin transporter gene network in the amygdala and investigated its interaction with postnatal adversity on attention problems in two independent cohorts from Canada and Singapore. We also described how interactions between ePRS-5-HTT and postnatal adversity exposure predict brain gray matter density and variation in DNA methylation across the genome. We observed that the expression-based polygenic risk score, reflecting the function of the amygdala 5-HTT gene network, interacts with postnatal adversity, to predict attention and hyperactivity problems across both cohorts. Also, both postnatal adversity score and amygdala ePRS-5-HTT score, as well as their interaction, were observed to be associated with variation in DNA methylation across the genome. Variations in gray matter density in brain regions linked to attentional processes were also correlated to our ePRS score. These results confirm that the amygdala 5-HTT gene network is strongly associated with ADHD-related behaviors, brain cortical density, and epigenetic changes in the context of adversity in young children

Amygdala 5-HTT gene network moderates the effects of postnatal adversity on attention problems : anatomo-functional correlation and epigenetic changes

Variations in serotoninergic signaling have been related to behavioral outcomes. Alterations in the genome, such as DNA methylation and histone modifications, are affected by serotonin neurotransmission. The amygdala is an important brain region involved in emotional responses and impulsivity, which receives serotoninergic input. In addition, studies suggest that the serotonin transporter gene network may interact with the environment and influence the risk for psychiatric disorders. We propose to investigate whether/how interactions between the exposure to early life adversity and serotonin transporter gene network in the amygdala associate with behavioral disorders. We constructed a co-expression-based polygenic risk score (ePRS) reflecting variations in the function of the serotonin transporter gene network in the amygdala and investigated its interaction with postnatal adversity on attention problems in two independent cohorts from Canada and Singapore. We also described how interactions between ePRS-5-HTT and postnatal adversity exposure predict brain gray matter density and variation in DNA methylation across the genome. We observed that the expression-based polygenic risk score, reflecting the function of the amygdala 5-HTT gene network, interacts with postnatal adversity, to predict attention and hyperactivity problems across both cohorts. Also, both postnatal adversity score and amygdala ePRS-5-HTT score, as well as their interaction, were observed to be associated with variation in DNA methylation across the genome. Variations in gray matter density in brain regions linked to attentional processes were also correlated to our ePRS score. These results confirm that the amygdala 5-HTT gene network is strongly associated with ADHD-related behaviors, brain cortical density, and epigenetic changes in the context of adversity in young children