Role of caudate-putamen KISS1 neurons in minipuberty

The National Institute of Child Health and Human Development awarded Brigham & Women's Hospital Inc. $631,658 on June 5, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to investigate the role of caudate-putamen Kiss1 neurons in female minipuberty, reproductive maturation, and cognitive function.

The award funds research characterizing a sexually dimorphic population of Kiss1/GnRH co-expressing neurons in the caudate putamen that appear to drive luteinizing hormone pulses during female minipuberty in mice. The research comprises three specific aims: defining the temporal profile of Kiss1 and GnRH expression, mapping neuronal connectivity, and analyzing the transcriptome of these neurons; evaluating their role in puberty onset and fertility through genetic manipulation and chemogenetics during minipuberty; and investigating their impact on socio-sexual behavior and cognition in adulthood. The research employs genetic manipulation, chemogenetics, and behavioral testing to elucidate the developmental trajectory and functional significance of these neurons, with potential applications toward understanding reproductive disorders, sex differences in neurodevelopmental conditions, and long-term consequences of disrupted minipuberty.

Performance is located in Boston, Massachusetts. The period of performance runs from June 5, 2026, through February 28, 2031.

Abstract

Minipuberty, the transient activation of the hypothalamic-pituitary-gonadal axis shortly after birth, is a critical period in reproductive development. This proposal aims to investigate a novel population of KISS1 neurons in the caudate putamen (CPU) and their role in female mini-puberty, reproductive maturation, and cognitive function. Our preliminary data reveal a previously unknown, sexually dimorphic population of KISS1/gnrh CO-expressing neurons in the CPU that appear to drive LH pulses during female mini-puberty in mice. We propose to characterize these CPUKISS1 neurons through three specific aims. First, we will define the temporal profile of KISS1 and gnrh expression, map neuronal connectivity, and analyze the transcriptome of CPUKISS1 neurons. Next, we will evaluate the role of CPUKISS1 neurons in puberty onset and fertility by manipulating their function during mini- puberty. Finally, we will investigate the impact of CPUKISS1 neurons on socio-sexual behavior and cognition in adulthood. Using innovative approaches including genetic manipulation, chemogenetics, and behavioral testing, we will elucidate the developmental trajectory and functional significance of these neurons. This research has profound implications for women's health, potentially offering insights into the origins of reproductive disorders, SEX differences in neurodevelopmental conditions, and the long-term consequences of disrupted mini-puberty. Our findings could lead to novel therapeutic targets for reproductive and cognitive disorders, and contribute to improve women's healthcare.