Moore, Kelsey2024-01-052024-01-052019-01https://hdl.handle.net/11299/259776University of Minnesota Ph.D. dissertation. January 2019. Major: Neuroscience. Advisors: Robert Meisel, Paul Mermelstein. 1 computer file (PDF); ix, 159 pages.Sex behavior in female mammals is known to involve rewarding consequences that increase the motivation to copulate. I have utilized female hamsters as a model to examine the underlying circuitry and mechanisms of this natural reward. Despite a wealth of information detailing dopaminergic neurotransmission in this region during sexual behavior, the role of glutamate, although the major excitatory neurotransmitter in the brain, has been disproportionately understudied. The goal of this dissertation work was to help close this gap in knowledge to further develop an understanding of the complex underpinnings of female sexual reward and motivation. This understanding is vital in the effort towards evidence-based therapeutic targets in the treatment of disorders of sexual desire in women. In order to determine the role of glutamate in signaling the rewarding properties of sex, I utilized a multi-faceted approach. First, through establishing the use of enzymatic biosensing in the lab, I evaluated glutamate release patterning in key reward regions during sexual behavior in the female hamster. I discovered time-locked glutamate transients specifically in the core of the nucleus accumbens (NAc) in response to penile intromission from the male. Next, I sought to uncover the potential source of this glutamate innervation of the NAc. Immunohistochemical and retrograde tracing analyses determined the involvement of excitatory glutamatergic efferents from the medial prefrontal cortex (mPFC) to the NAc. Then, to determine if mPFC activity was driving the activation of the NAc during female sexual behavior, I employed designer receptors exclusively activated by designer drugs (DREADDs) to selectively inhibit these excitatory mPFC efferents. I demonstrated that this selective inhibition decreases sex-induced activation of the NAc, confirming the importance of the mPFC in driving increased glutamatergic activity in the NAc in response to sexual behavior in the female. The novel findings reported in this body of work demonstrate the involvement of glutamatergic neurotransmission in sexual reward through a prefrontal-accumbal circuit. These are not only exciting additions to the development of a comprehensive model of female sexual reward, but also provide potential targets for therapeutic intervention. Currently there are no effective treatment options for disorders of sexual desire in women and these results provide attractive avenues for pursuing target-specific and clinically-relevant therapies.enGlutamateMedial prefrontal cortexMotivated behaviorNucleus accumbensRewardSexual behaviorThesis or Dissertation