Activity of KNDy Neurons and the Melanocortin System During Pubertal Development in Female Sheep

The increase in luteinizing hormone (LH) that elicits puberty in many species results from a decrease in sensitivity to estradiol (E2) negative feedback. The neural mechanisms underlying this change are unknown, but do not occur at the gonadotropin-releasing hormone (GnRH) neurons as they lack estrogen receptor-alpha (ERα). A potentially important area is the arcuate nucleus of the hypothalamus (ARC), where neurons coexpressing kisspeptin, neurokinin B (NKB), and dynorphin (KNDy neurons) reside. KNDy neurons express ERα and while our previous work indicated that KNDy cells were critical for puberty, immunopositive cell numbers went unchanged during development, raising the likelihood of additional neuronal inputs. Herein, we used ovariectomized ewes implanted with E2 at prepubertal, peripubertal, or postpubertal ages to examine whether activation of KNDy neurons changed in association with increased LH secretion. Further, a potential role for the melanocortin system (proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons) was assessed. Activation of KNDy neurons increased with increased LH secretion. POMC cell numbers were unchanged, but activation of POMC cells and number of POMC-positive contacts onto KNDy neurons increased with age. In contrast, AgRP cell numbers and activity decreased. In addition, the percentage of POMC and AgRP neurons expressing Erα did not change. Thus, puberty-related increases in LH secretion are associated with activation of KNDy neurons and POMC neurons, but reduced activation and decreased numbers of AgRP neurons. To this point, no predictable changes in ERα expression within KNDy, POMC, or AgRP cell populations have been noted.