Sex Steroid Hormone Receptor Content of Medial Preoptic Efferents to the Ventral Tegmental Area Is Sexually Dimorphic: Implications for Sex Differences in Mesolimbic Reward Processing

Introduction: The medial preoptic area (mPOA) is an important regulator of natural and drug-induced reward. However, despite the mPOA being implicated in sexually dimorphic reward responses, sex differences in medial preoptic efferents to the ventral tegmental area (VTA) have not been fully investigated.

Methods: Two cohorts of male and female rats received unilateral injections of the tract-tracer Fluoro-Gold (FLG) into the VTA. Immunohistochemical staining was used to quantify co-labeled FLG-positive neurons with γ-aminobutyric acid (GABA), estrogen receptor α (ERα), and androgen receptors (AR).

Results: Results revealed a pattern of VTA innervation that was comparable between males and females; more efferents emerged from the rostrocentral portions of the mPOA than caudal portions. Results also indicated that males and females had the same percentage of GABAergic mPOA-VTA projections. Differences emerged when investigating the hormone receptor profile of projections to the VTA, where females had a greater percentage of efferents expressing ERα and males had a greater percentage of efferents expressing AR, in the central portion of the mPOA. Lastly, FLG-positive cells were colocalized with GABA and ERα in cohort 1 and GABA and AR in cohort 2. The majority of AR-expressing cells colocalized with GABAergic efferents to the VTA, but only a portion of ERα-expressing cells colocalized with GABAergic efferents to the VTA.

Conclusion: Results indicate that sex differences are present in the sex-steroid hormone receptor content of mPOA-VTA projections, particularly among efferents arising from the central region of the mPOA. These sexually dimorphic connections may influence a wide range of sex differences in reward responses.