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Major depressive disorder (MDD) is a debilitating illness that affects hundreds of millions globally, with substantial personal, medical, economic, and societal consequences. While depression occurs more commonly in females, the biology of the brain and sex underlying this skewed prevalence remains unclarified. This body of work explores two aspects of how biological sex may influence the brain at the level of gene expression: through intrinsic sex differences and through sex-mediated effects of depression risk genetics.The monoamine hypothesis of depression suggests that modulatory neurotransmitters including serotonin and norepinephrine constitute a key axis in development of MDD. Large-scale studies of MDD treatment response have found that women respond better to serotonergic agents, while males respond better to mixed serotonergic-noradrenergic agents, suggesting one or both of these cell types may play a role in sex-differentiated MDD risk biology. Using translating ribosome affinity purification (TRAP), gene expression in norepinephrine neurons of mouse locus coeruleus (LC) was profiled and compared across sexes, revealing over 100 genes with both sex-differential and LC-enriched expression. Three female-upregulated genes of interest emerged: SLC6A15 and LIN28B, implicated in MDD, and prostaglandin receptor PTGER3. Pharmacologic activation of PTGER3 had female-specific effects on LC electrophysiology and behavior, confirming that genetic sex differences in noradrenergic neurons have functional consequences on these neurons and behavior.The role of genetic variation in MDD has recently come to be appreciated as an underlying cause of MDD, though whether sex interacts with genetic risk factors remains unknown. The primary work in this thesis focused on over 1,000 noncoding, putatively transcription-regulating common variants from 31 MDD-associated genomic regions—including those near LIN28B and SLC6A15—using functional assays in mouse brain in vivo to examine sex-by-genotype interactions. This work identified extensive sex-by-allele effects in mature hippocampus and, using TRAP, its excitatory neurons in particular. Unbiased informatics approaches indicated a role for nuclear hormone receptors, further supported by comparative analysis of analogous experiments in neonates during the masculinizing testosterone surge and in older, hormonally quiescent juveniles. This study provides novel insights into MDD genetics as influenced by age, biological sex, and cell type, and provides a framework for in vivo parallel assays to functionally define interactions between disease-linked genetic variation and complex biological or environmental variables. |
