Sexual differentiation and development of forebrain reproductive circuits

Males and females exhibit numerous anatomical and physiological differences in the brain that often underlie important sex differences in physiology or behavior, including aspects relating to reproduction. Neural sex differences are both region-specific and trait-specific and may consist of divergences in synapse morphology, neuron size and number, and specific gene expression levels. In most cases, sex differences are induced by the sex steroid hormonal milieu during early perinatal development. In rodents, the hypothalamic anteroventral periventricular nucleus (AVPV) is sexually differentiated as a result of postnatal sex steroids, and also specific neuronal populations in this nucleus are sexually dimorphic, with females possessing more kisspeptin, dopaminergic, and GABA/glutamate neurons than males. The ability of female rodents, but not males, to display an estrogen-induced luteinizing hormone (LH) surge is consistent with the higher levels of these neuropeptides in the AVPV of females. Of these AVPV populations, the recently identified kisspeptin system has been most strongly implicated as a crucial component of the sexually dimorphic LH surge mechanism, though GABA and glutamate have also received some attention. New findings have suggested that the sexual differentiation and development of kisspeptin neurons in the AVPV is mediated by developmental estradiol signaling. Although apoptosis is the most common process implicated in neuronal sexual differentiation, it is currently unknown how developmental estradiol acts to differentiate specific neuronal populations in the AVPV, such as kisspeptin or dopaminergic neurons.