Estrogen-regulated peptidergic input to gonadotropin-releasing hormone neurons from the lateral septal kisspeptin network

Abstract

While hypothalamic kisspeptin (KP) neurons play well-established roles in the estrogen-dependent regulation of reproduction, little is known about extrahypothalamic KP-producing (KPLS) neurons of the lateral septum. Our studies on Kiss1-Cre/ZsGreen transgenic mice revealed that KP expression in the LS is linked to puberty and estrogen receptor signaling and neurons reach higher numbers in females. Viral tracing uncovered that KPLS axons abundantly innervate gonadotropin-releasing hormone neurons, the hypothalamic supramammillary nucleus and various limbic structures. RNA-Seq analysis of laser-microdissected KPLS neurons revealed a unique transcriptome profile containing markers of GABAergic and peptidergic (Penk, Cartpt, Vgf) cotransmission and 571 estrogen-dependent transcripts. Immunohistochemical evidence for homologous neurons in the post mortem human brain indicate that the KPLS neurons may contribute to evolutionarily conserved regulatory mechanisms. The KPLS system now emerges as a novel player in the estrogen-dependent control of gonadotropin-releasing hormone neurons and currently unknown hypothalamic and limbic functions requiring clarification.