Sex-dependent pathophysiology as predictors of comorbidity of major depressive disorder and cardiovascular disease.

There is a strong and growing literature showing that key aspects of brain development may be critical antecedents of adult physiology and behavior or may lead to physiological and psychiatric disorders in adulthood. Many are significantly influenced by sex-dependent factors. Neurons of the paraventricular nucleus (PVN) of the hypothalamus occupy a key position in regulating homeostatic, neuroendocrine, and behavioral functions. This brain area is a critical link for our understanding of the etiology of a number of disorders with components ranging from mood to feeding and energy balance and to autonomic nervous system regulation. Thus, based on common brain circuitry, the PVN may be a critical anatomical intersection for understanding comorbidities among depression, obesity, and cardiovascular risk. Historically, the majority of approaches to brain development examine neuronal, glial, and vascular factors independently, with notably less emphasis on vascular contributions. The realization that the PVN undergoes a unique vascular developmental process places added value on discerning the cellular and molecular mechanisms that drive its late-onset angiogenesis and further implications for neuronal differentiation and function. This has ramifications in humans for understanding chronic, and sometimes fatal, comorbidities that share sex-dependent biological bases in development through functional and anatomical intersections with the hypothalamus.