Polycystic ovary syndrome (PCOS) is a leading cause of female infertility worldwide. The syndrome is diagnosed
by ovarian symptoms, including cystic ovaries, disrupted or absent menstrual cycles and hyperandrogenism.
However, changes in the brain play a significant role in the development of PCOS. Under normal conditions,
neurons in the hypothalamus release gonadotropin-releasing hormone (GnRH) in a pulsatile manner to elicit the
secretion of luteinizing hormone (LH) from the pituitary gland. LH pulses act at the ovary to control
folliculogenesis and steroid hormone release. Ovarian steroid hormones, in turn, act back in the brain through
an afferent network to suppress GnRH secretion in a homeostatic negative feedback loop. In women with PCOS,
the ability of steroid hormones to suppress the frequency of pulsatile GnRH/LH secretion is impaired, leading to
ovarian dysfunction. The neuronal population with a diminished response to steroid hormone feedback is
currently unknown. However, cells that express Kisspeptin, Neurokinin B, and Dynorphin peptides, termed KNDy
cells, are a promising candidate as they are hypothesized to play a role in steroid hormone feedback and
demonstrate synchronized episodes of activity that generate GnRH/LH pulses. Our recent research using a
mouse model of PCOS induced using prenatal androgen (PNA) exposure demonstrated that KNDy cells have
lower expression of receptors required for steroid hormone feedback and a significant reduction in synaptic
innervation by GABAergic afferent networks. Based on these findings, we hypothesize that increased GnRH/LH
pulse frequency in PCOS is mediated by changes in the regulation of KNDy cells by steroid hormones and
afferent networks. To investigate this, our first aim will use in vivo calcium imaging, which permits the visualization
of individual cell activity within a population of neurons in freely behaving mice, to define if increased LH pulse
frequency in PNA mice is associated with an impaired ability of estradiol and progesterone to suppress KNDy
cell activity. Our second aim will identify the origin of reduced GABAergic afferent input to KNDy cells using
retrograde monosynaptic rabies-mediated tract tracing. We will then define how a loss in GABAergic afferent
input functionally impacts KNDy cell activity by combining in vivo calcium imaging of KNDy cells in fertile mice
whilst optogenetically manipulating the activity of apposing GABAergic axon terminals. Finally, we will use
chronic chemogenetic inhibition of KNDy cells to determine if exogenously regulating KNDy cell-mediated
GnRH/LH pulse generation is sufficient to override neuroendocrine dysfunction in PNA mice and restore
reproductive capacity. Together, this research will greatly improve our understanding of how GnRH pulse
generation is regulated, both in individuals who are healthy and in those who develop PCOS. As there are
ongoing clinical studies aiming to reduce synchronized KNDy cell activity in PCOS patients, such as through the
use of pharmaceutical antagonists against the neurokinin B receptor, this research may offer valuable information
to guide the development of treatments targeting central dysfunction in the syndrome.
