Project Summary/Abstract
We propose to understand at cellular and circuit levels how Kiss1-expressing neurons in the anteroventral
periventricular hypothalamus (AVPV) regulate female mating behavior. The ventromedial hypothalamus
ventrolateralis (VMHvl) and AVPV have been shown to influence diverse female reproductive behaviors and
physiology. We recently showed that presynaptic termini of progesterone receptor (PR)-expressing neurons of
the VMHvl (Pvl) exhibit significant plasticity in the AVPV across the ovarian cycle. Optogenetic inhibition of this
projection of Pvl neurons to the AVPV essentially eliminates female sexual behavior. In preliminary studies, we
find that the subset of AVPV neurons expressing the neuropeptide Kisspeptin (Kiss1) are innervated by Pvl
neurons, and that Kiss1+ AVPV (Kavpv) neurons are important for regulating female sexual behavior in vivo.
Our proposed work is distinct from previous AVPV studies in that we will perform our unbiased circuit
mapping, imaging, and functional studies focusing exclusively on Kavpv neurons. The AVPV is heterogeneous
not only molecularly but also functionally, and brain-wide connections and behavioral contributions of distinct
AVPV neuronal subtypes remain poorly understood. Moreover, and in contrast to prior work in this region, our
studies will assess Kavpv neuronal connectivity and function across distinct phases of the female cycle, thereby
shedding new light into how physiologically distinct hormonal states influence Kavpv neurons and behavior. In
Aim 1, we will map the presynaptic inputs and postsynaptic projections of Kavpv neurons in an unbiased, brain-
wide manner and validate the synaptic connectivity across the estrus cycle using electrophysiology and in vivo
2-photon imaging. In Aim 2, we will determine the activity patterns of Kavpv neurons in female during sexual and
other social behaviors in freely moving animals. In Aim 3, we will test whether acute manipulation of Kavpv
neurons is essential for and, even when females are in a hormonal state that renders them unreceptive, sufficient
to induce female sexual behavior. The two PIs have complementary expertise for the proposed studies, and the
team is therefore well suited for this project. In summary, if successful our studies will uncover mechanisms
whereby an ovarian hormone sensitive hypothalamic circuit regulates female sexual and reproductive behaviors.
Health Relatedness: It is well known that ovarian sex hormones can influence behavioral, cognitive, and emotive
states in women. How these hormones regulate distinct behaviors and other states at the level of specific
neurons and synapses is poorly understood. In addition, translational research has identified diverse neuro-
psychiatric illnesses that are influenced by these hormones. Our basic research proposal, if successful, will
provide new insights into how ovarian hormone sensitive hypothalamic pathways regulate social interactions in
healthy animal models, and they have the potential to suggest new research avenues in translational work
focused on ovarian sex hormone influenced neural circuits in disease states.