Reproduction and puberty onset are regulated by the hypothalamic-pituitary-gonadal (HPG) axis, but despite much research, the mechanisms that can modulate the HPG axis, as well as disrupt the HPG axis, are not fully understood. To date, most research has focused primarily on the mechanisms within the hypothalamus that regulate the HPG axis, with little focus on how extra-hypothalamic brain regions may modulate reproduction. The amygdala is located in the medial temporal lobe and the medial nucleus of the amygdala (MeA), has numerous behavioral and physiological functions, including effects on puberty and reproductive physiology. However, the mechanisms by which the MeA modulates puberty onset and reproduction are completely unknown. The neuropeptide kisspeptin regulates reproduction by activating GnRH neurons. Kisspeptin neurons are detected in several discrete brain areas, primarily the hypothalamus and MeA, but the regulation and function of kisspeptin in the MeA is poorly understood. Thus, kisspeptin in the MeA may be one mechanism by which the amygdala modulates reproduction.
Aim 1 will examine the role of kisspeptin in the MeA?s modulation of reproduction by: 1) examining possible reproductive functions of MeA Kiss1 neurons in adulthood by selectively destroying or activating MeA Kiss1 neurons; 2) identify the molecular phenotype of MeA Kiss1 neurons to understand what other signaling factors, if any, are made in kisspeptin neurons, as well as identify receptors in MeA Kiss1 neurons that may give insight into how these neurons are regulated; 3) examine how the MeA region may be ?talking? to the HPG axis by determine if there are neural projections from the MeA to hypothalamic Kiss1 and GnRH neurons. Like kisspeptin, glutamate and GABA neurons are also highly expressed in the MeA and have been shown to regulate puberty, implicating glutamate and GABA as additional mechanisms by which the MeA may modulate puberty.
Aim 2 focuses on the role of 1) GABA in the anterior MeA and 2) glutamate and kisspeptin in the posterior MeA, in regulating puberty onset. It is also currently unknown whether the MeA modulates adult reproduction and puberty onset in males as it does in females, and this proposal will examine both males and females to identify any sex differences, especially since puberty onset is sexually dimorphic (females earlier than males). In summary, this proposal seeks to identify the molecular mechanism(s) and specific cell types involved in the MeA?s modulation of reproductive endocrinology. This work may provide important novel information relevant to treatments in infertility, anovulation, idiopathic hypogonadotropic hypogonadism, and amenorrhea, as well as understanding reproductive physiology in disorders associated with aberrant amygdala function, such as autism and schizophrenia. The MeA is also known to modulate numerous emotions and physiological states and therefore, this project may provide new insight regarding how social information modulates reproductive physiology.

Public Health Relevance

The medial nucleus of the amygdala (MeA), a brain region located in the medial temporal lobe, is implicated in modulating adult reproduction and puberty, but the mechanisms in the MeA influences the reproductive axis are completely unknown. This proposal will examine if MeA kisspeptin, glutamate, and GABA, all of which have been shown to influence reproduction and/or puberty, are potential mechanisms by which the MeA modulates adult reproduction and puberty in both females and males. This work may provide important novel information relevant to treatments of infertility, anovulation, amenorrhea, and idiopathic hypogonadotropic hypogonadism, in addition to offering new insight into reproductive functions of kisspeptin neurons and the interplay between reproduction and behaviors mediated by the amygdala.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Career Transition Award (K99)
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National Institute of Child Health and Human Development Initial Review Group (CHHD)
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Ravindranath, Neelakanta
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University of California, San Diego
Obstetrics & Gynecology
Schools of Medicine
La Jolla
United States
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Stephens, Shannon B Z; Di Giorgio, Noelia P; Liaw, Reanna B et al. (2018) Estradiol-Dependent and -Independent Stimulation of Kiss1 Expression in the Amygdala, BNST, and Lateral Septum of Mice. Endocrinology 159:3389-3402