This study aimed to improve our understanding of how the hypothalamus mediates the effects of prenatal and postnatal challenges on behavior and sensitivity to stimuli. A pig model of virally initiated maternal immune activation (MIA) was used to investigate potential interactions of the prenatal challenge both with sex and with postnatal nursing withdrawal. The hypothalami of 72 females and males were profiled for the effects of MIA and nursing withdrawal using RNA-sequencing. Significant differential expression (FDR-adjusted p value < 0.05) was detected in the profile of 222 genes. Genes involved in the Gene Ontology biological process of regulation of hormone levels tended to be over-expressed in individuals exposed to both challenges relative to individuals exposed to either one challenge, and most of these genes were over-expressed in MIA females relative to males across nursing levels. Differentially expressed genes included Fshb, Ttr, Agrp, Gata3, Foxa2, Tfap2b, Gh1, En2, Cga, Msx1, and Npy. The study also found that prenatal and postnatal challenges, as well as sex, impacted the regulation of neurotransmitter activity and immune effector processes in the hypothalamus. In particular, the olfactory transduction pathway genes were over-expressed in weaned MIA males, and several transcription factors were potentially found to target the differentially expressed genes. Overall, these results highlight how multiple environmental challenges can interact and affect the molecular mechanisms of the hypothalamus, including hormonal, immune response, and neurotransmitter processes.
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