Dopaminergic Regulation of KNDy Neurons: Implications for GnRH Pulses and PCOS

ABSTRACT KNDy neurons in the arcuate nucleus (ARC) control GnRH pulsatility through the interplay of neurokinin B (NKB) and dynorphin, creating kisspeptin pulses that directly stimulate GnRH neurons. Disruptions in this system can lead to various reproductive disorders, from hypothalamic amenorrhea to polycystic ovary syndrome (PCOS). Our recent work has shown that peripherally restricted kappa opioid receptor agonists (PRKAs) can activate dynorphin's receptor (KOR) in the mediobasal hypothalamus, decreasing LH release and restoring reproductive markers in a PCOS mouse model. Intriguingly, this effect persists even without KOR in Kiss1 neurons, suggesting an upstream target. We aim to identify and characterize the neuronal population that is peripherally accessible, responsive to dynorphin, and capable of modifying KNDy neuron activity. Tuberoinfundibular dopaminergic (TIDA) neurons emerge as prime candidates, exhibiting oscillatory patterns similar to KNDy neurons and correlating with prolactin and LH pulses. Moreover, our preliminary data has identified that KNDy neurons are uniquely enriched with dopamine receptor 2 (Drd2) in the ARC, and dopamine levels are reduced in PCOS models. Our overarching hypothesis posits that TIDA and KNDy neurons form a major oscillatory network controlling GnRH release, with decreased dopamine tone in PCOS leading to KNDy neuron hyperactivation, reversible by PRKAs. We will investigate this through three aims: 1) examining KNDy activity in normal and PCOS-like conditions and their PRKA response, 2) characterizing dopamine's role in KNDy neuron activity, and 3) elucidating TIDA neurons' role in KNDy neuron control under various conditions. This project promises to unveil novel mechanisms in reproductive neuroendocrinology and may lead to innovative PCOS treatments.