Embryonic birthdate of hypothalamic leptin-activated neurons in mice.

The hypothalamus plays a critical role in the regulation of energy balance. Neuroanatomical and mouse genetic data have defined a core circuitry in the hypothalamus that mediates many of the effects of leptin on feeding and energy balance regulation. The present study used 5-bromo-2'-deoxyuridine (a marker of dividing cells) and a neuronal marker to systematically examine neurogenesis in the mouse embryonic hypothalamus, particularly the birth of neurons that relay leptin signaling. The vast majority of neurons in hypothalamic nuclei known to control energy balance is generated between embryonic days (E) 12 and E16, with a sharp peak of neurogenesis occurring on E12. Neurons in the dorsomedial and paraventricular nuclei and the lateral hypothalamic area are born between E12 and E14. The arcuate and ventromedial nuclei exhibit a relatively longer neurogenic period. Many neurons in these nuclei are born on E12, but some neurons are generated as late as E16. We also examined the birth of leptin-activated cells by coupling the 5-bromo-2'-deoxyuridine staining with cFos immunohistochemistry. Remarkably, the majority of leptin-activated cells in the adult hypothalamus were also born during a discrete developmental window on E12. These results provide new insight into the development of hypothalamic neurons that control feeding and identify important developmental periods when alterations in the intrauterine environment may affect hypothalamic neurogenesis and produce long-term consequences on hypothalamic cell numbers.