RESUMO
Neurodevelopmental disorders, such as ASD and ADHD, affect males about three to four times more often than females. 16p11.2 hemideletion is a copy number variation that is highly associated with neurodevelopmental disorders. Previous work from our lab has shown that a mouse model of 16p11.2 hemideletion (del/+) exhibits male-specific behavioral phenotypes. We, therefore, aimed to investigate with magnetic resonance imaging (MRI), whether del/+ animals also exhibited a sex-specific neuroanatomical endophenotype. Using the Allen Mouse Brain Atlas, we analyzed the expression patterns of the 27 genes within the 16p11.2 region to identify which gene expression patterns spatially overlapped with brain structural changes. MRI was performed ex vivo and the resulting images were analyzed using Voxel-based morphometry for T1-weighted sequences and tract-based spatial statistics for diffusion-weighted images. In a subsequent step, all available in situ hybridization (ISH) maps of the genes involved in the 16p11.2 hemideletion were aligned to Waxholm space and clusters obtained by sex-specific group comparisons were analyzed to determine which gene(s) showed the highest expression in these regions. We found pronounced sex-specific changes in male animals with increased fractional anisotropy in medial fiber tracts, especially in those proximate to the striatum. Moreover, we were able to identify gene expression patterns spatially overlapping with male-specific structural changes that were associated with neurite outgrowth and the MAPK pathway. Of note, previous molecular studies have found convergent changes that point to a sex-specific dysregulation of MAPK signaling. This convergent evidence supports the idea that ISH maps can be used to meaningfully analyze imaging data sets.
Assuntos
Deleção Cromossômica , Variações do Número de Cópias de DNA , Expressão Gênica , Substância Cinzenta/patologia , Animais , Transtorno Autístico/genética , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 16/genética , Imagem de Difusão por Ressonância Magnética , Modelos Animais de Doenças , Feminino , Humanos , Hibridização In Situ , Deficiência Intelectual/genética , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transtornos do Neurodesenvolvimento/genéticaRESUMO
Early life development, through gestation and lactation, represents a timeframe of extreme vulnerability for the developing fetus in general, and for the central nervous system in particular. An adverse perinatal environment can have a lasting negative impact on brain development, increasing the risk for developmental disorders and broader psychopathologies. A major determinant of the fetal developmental environment is maternal diet. The present review summarizes the current literature regarding the effect of poor maternal perinatal nutrition on offspring brain development, with an emphasis on reward-related neural systems and behaviors. Epigenetic mechanisms represent a likely link between maternal diet and persistent changes in offspring brain development, and these mechanisms are presented and discussed within the context of perinatal maternal nutrition.
