Long-Term Recordings of Arcuate Nucleus Kisspeptin Neurons Reveals Patterned Activity That Is Modulated By Gonadal Steroids in Male Mice
Presentation Number: SUN 478
Date of Presentation: April 2nd, 2017
Charlotte HMH Vanacker*1, Manuel Ricu Moya2 and Suzanne M Moenter1
1University of Michigan, Ann Arbor, MI, 2University of Michigan
Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway for central regulation of fertility via episodic GnRH release. This release is modulated by steroid feedback primarily via afferent neurons. The episodic nature of GnRH release suggests coordination among these cells but where this rhythm arises is unknown. Arcuate kisspeptin (KNDy) neurons are a potential site for both rhythm generation and steroid feedback integration; they are steroid-sensitive and synapse on GnRH neurons. KNDy neurons have been postulated to be extrinsic drivers of pulsatile GnRH secretion via release of kisspeptin, which increases GnRH neuron activity and release. The long-term spontaneous firing activity of KNDy neurons exhibits peaks and nadirs, with peak frequency increased in castrate vs intact male mice. Peak intervals in KNDy neurons were strikingly similar to those observed in GnRH neurons. In GnRH neurons, peak interval in castrate males was restored to intact levels by estradiol, but not dihydrotestosterone (DHT). In contrast in short-term studies of KNDy neuron response to the neuromodulators neurokinin B and dynorphin, also produced by these cells, both E and DHT produced negative feedback effects. Because E affected the long-term firing pattern of GnRH neurons, we hypothesized that in long-term recordings, E, but not DHT, would restore firing peak frequency of KNDy neurons to intact levels. Firing pattern of GFP-identified KNDy neurons in 400µm brain slices from intact males was compared to castrates treated with E or DHT implants. Spontaneous action potential firing activity of KNDy neurons was monitored for 1-3.5h with targeted extracellular recordings. Peaks and nadirs in firing rate were analyzed with the Cluster8 algorithm. Both E and DHT restored peak frequency to that of intact mice (intact 0.7±0.2 peaks/h, estradiol 0.5±0.2 peaks/h, n=10,DHT 0.7±0.2 peaks/h, n=8), and all were decreased compared to that reported for castrate mice (1.7±0.2 peaks/h, n=7). Contrary to our hypothesis, the present results suggest that agonists of either estrogen receptors or androgen receptors modify long-term firing pattern of KNDy neurons. The steroid regulation of long-term firing pattern and short-term response to neuromodulators is thus similar in KNDy neurons, but the ability of DHT to reduce firing peak frequency in KNDy neurons is markedly different from its effects on GnRH neurons, on which DHT had no effect. These observations are consistent with the postulates that changes in KNDy neuron activity drive changes in GnRH activity and that estradiol sensitivity of this episodic pattern may arise in KNDy neurons. The differential response to DHT of GnRH and KNDy neurons may imply that androgens increase activity of other afferents to counteract their suppression of KNDy neurons, thus resulting in no net change in GnRH firing peak frequency.
Nothing to Disclose: CHV, MR, SMM