MON-056 - Neurons in the Brainstem That Express Neuropeptide Y Are Sufficient to Suppress Luteinizing Hormone Pulses in Mice in A Sex Steroid Dependent Manner.

Pulsatile secretion of gonadotropin-releasing hormone/luteinizing hormone (GnRH/LH) is critical for gonad function and stress suppresses GnRH/LH pulses. However, the precise mechanism for this inhibition of gonadotropin secretion is unknown. Neuropeptide Y (NPY) is expressed in several brain regions and is important for both hunger and stress circuits. In previous work, activation of norepinephrine neurons (NE) in the nucleus of the solitary tract (NTS-NE) was sufficient to suppress LH pulses and induced sickness-like behavior. Since NTS-NE neurons are heterogeneous and contribute to many physiological processes, we aimed to identify which subpopulation of NTS-NE cells are important for the suppression of LH secretion. Thus, we tested the hypothesis that chemogenetic activation of NTS-NPY neurons is sufficient to suppress LH secretion in mice and that the effect may be altered by gonadal steroids. To accomplish this, 12+ week old NPY-Cre transgenic male and female mice on a C57/BL6 background received AAV1-hSyn-DIO-hM3D(Gq) virus into the NTS; this virus contained the Cre recombinase-dependent stimulatory Designer Receptor Exclusively Activated by Designer Drugs (DREADD) receptor. Littermate Cre negative mice were used as controls for all groups (n = 6 - 10). Ten days after neurosurgery, mice were gonadectomized and received a SILASTIC implant containing either estradiol (females) or dihydrotestosterone (DHT; males) or empty/vehicle control implants (n = 6 - 10/group). Ten days after gonadectomy, frequent blood samples were collected before and after administration of a DREADD agonist (Clozapine N-oxide; CNO), and LH concentrations were determined with ELISA. Fixed neural tissue was collected following blood collection to assess transduction efficiency with combined immunohistochemistry and RNAscope (currently in progress). By Two-way ANOVA, mean LH concentrations were significantly reduced following CNO administration in Cre positive gonadectomized male and female mice without steroid replacement, but not in Cre negative mice. In contrast, DHT-replaced gonadectomized males had no change in LH secretion following CNO in Cre positive and Cre negative mice. Analysis of estradiol-replaced females and pulse frequency in all groups is ongoing. These data demonstrate that NTS-NPY neurons are sufficient to suppress LH secretion in gonadectomized animals, but DHT abrogates this effect, which is consistent with the notion that androgens reduce the sensitivity to stress.

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