Odor hedonics: processing of male pheromones in the female mouse brain

Abstract

Female mice exhibit a hardwired preference to investigate pheromones released by male conspecifics. The neural pathways that convey pheromonal inputs to brain regions controlling motivated behaviors remain largely unknown. One brain region known to process pheromonal information conveyed via main- and accessory olfactory bulb inputs is the Medial Amygdala (Me), a limbic structure comprised of anterior (MeA) and posterior (MeP) subdivisions. Electrolytic lesions of the MeP blocked the normal preference of estrous female mice to investigate urinary odors emitted from breeding as opposed to castrated males whereas lesions of either the MeA or MeP significantly reduced females' display of the receptive lordosis posture in response to male mounts. Quantitative analysis of synaptic puncta in the efferent projection targets of these two amygdaloid subregions, visualized using fluorescent anterograde tract tracing techniques, revealed that the MeA and MeP differentially innervate several forebrain regions. The medial olfactory tubercle (mOT; a component of the ventral striatum) receives dense monosynaptic input from the MeA and responds selectively to breeding male (but not female) soiled bedding volatiles, indexed by augmented FOS expression. Using injections of the retrograde tracer, cholera toxin B (CTb), neurons were identified in the MeA and ventral tegmental area (VTA) that projected to the mOT in female mice and which also co-expressed FOS after exposure to breeding male, but not female, soiled bedding/urinary volatiles. This suggests that the MeA and VTA convey opposite-sex (male) pheromonal information to the mOT. Bilateral dopaminergic lesions of the anteromedial VS (a region which includes the mOT) eliminated females' preference for breeding male vs. female urinary pheromones, suggesting that dopaminergic modulation in the VS is necessary for the display of these behaviors. Lastly, bilateral silencing of mOT neuronal firing by the activation of the inhibitory DREADD receptor, hM4Di, induced by intraperitoneal injection of its ligand (CNO), also disrupted females' preference to investigate urinary odors from breeding males; this deficit was reversed when saline was administered instead of CNO. The Me, VTA, and mOT are essential segments of a neural reward circuit that motivates estrous female mice to seek out male pheromones, thereby facilitating mate recognition and reproductive success.