DREADD-Induced Silencing of the Medial Olfactory Tubercle Disrupts the Preference of Female Mice for Opposite-Sex Chemosignals

Abstract

Attraction to opposite-sex pheromones during rodent courtship involves a pathway that includes inputs to the medial amygdala (Me) from the main and accessory olfactory bulbs, and projections from the Me to nuclei in the medial hypothalamus that control reproduction. However, the consideration of circuitry that attributes hedonic properties to opposite-sex odors has been lacking. The medial olfactory tubercle (mOT) has been implicated in the reinforcing effects of natural stimuli and drugs of abuse. We performed a tract-tracing study wherein estrous female mice that had received injections of the retrograde tracer, cholera toxin B, into the mOT were exposed to volatile odors from soiled bedding. Both the anterior Me and ventral tegmental area sent direct projections to the mOT, of which a significant subset was selectively activated (expressed Fos protein) by testes-intact male (but not female) volatile odors from soiled bedding. Next, the inhibitory DREADD (designer receptors exclusively activated by designer drugs) receptor hM4Di was bilaterally expressed in the mOT of female mice. Urinary preferences were then assessed after intraperitoneal injection of either saline or clozapine-N-oxide (CNO), which binds to the hM4Di receptor to hyperpolarize infected neurons. After receiving CNO, estrous females lost their preference for male over female urinary odors, whereas the ability to discriminate these odors remained intact. Male odor preference returned after vehicle treatment in counterbalanced tests. There were no deficits in locomotor activity or preference for food odors when subject mice received CNO injections prior to testing. The mOT appears to be a critical segment in the pheromone–reward pathway of female mice.

DREADD‐induced silencing of the medial amygdala reduces the preference for male pheromones and the expression of lordosis in estrous female mice

“…Previous studies also reported that the preference to investigate urinary volatiles of male vs. estrous females was not reduced in female mice after surgical removal of the VNO (Keller et al ., ; Martel & Baum, ). The results of these latter studies along with those of the current experiment also contrast with our previous report (DiBenedictis et al ., ) that DREADD‐induced silencing of the mOT blocked the preference of estrous females to seek out both volatile and non‐volatile urinary chemosignals from testes‐intact males vs. estrous females. Presumably, volatile male pheromonal signals processed via the MOS lost their incentive value after silencing of the mOT.…”

Social Isolation During Postweaning Development Causes Hypoactivity of Neurons in the Medial Nucleus of the Male Rat Amygdala

“…In particular, inputs from the basolateral amygdala, including the lateral nucleus, guide behaviors in response to conditioned social cues (Martinez et al, 2011;Takahashi et al, 2013), and inputs from olfactory regions guide social behaviors in response to pheromones and other odor cues (Kang et al, 2009;Samuelsen and Meredith, 2009a;DiBenedictis et al, 2015). Diminished responses to these inputs is expected to lead to reduced production of social behaviors (DiBenedictis et al, 2015;Noack et al, 2015). However, the outcome of these impairments on MeApd and MeApv is different, with a general decrease of responsiveness in MeApv but a more specific deficit in MeApd at higher frequency inputs.…”

Sex differences in main olfactory system pathways involved in psychosexual function

“…49,58 In mice the PlCo responds to both attractive and aversive odors, 59 while ACo activation seems most selective for aversive odors. 49,58 In mice the PlCo responds to both attractive and aversive odors, 59 while ACo activation seems most selective for aversive odors.…”

“…It therefore seems that the involvement of the Me in olfactory-mediated sexually dimorphic behaviors will depend largely upon activation of the AOS, which complicates an assessment of MOS involvement in pheromone signaling. 58,[99][100][101] Lesions or chemogenetic inactivation of the Me disrupts innate preferences for these odors in both sexes. [93][94][95][96] Of course, the Me is heterogeneous, consisting of posterior and anterior, as well as dorsal and ventral subdivisions that differ both structurally and functionally.…”