A comprehensive analysis of sexual dimorphism in the midbrain dopamine system

Thesis (Ph.D.)--University of Washington, 2016-06

The dopamine system is widely thought to play a role in many crucial behaviors, including reward association, motivation, and addiction. Additionally, dopamine is also linked to multiple diseases, such as depression, post-traumatic stress disorder, schizophrenia, and autism. What is striking about these diseases is they present with sex differences in multiple aspects including susceptibility, progression, and response to treatment. However, we know very little about sex differences in the dopamine system, especially at a baseline state. In the current study, I provided a comprehensive analysis of the dopamine system in males and females, including circuitry, physiology, gene expression, and behavior. Employing retrograde viral tools, we characterized the inputs to the entire ventral tegmental area (VTA), to VTA dopamine neurons specifically, and compared the number of GABAergic, glutamatergic, and serotonergic inputs to the VTA; we also mapped VTA dopaminergic outputs through use of excitatory DREADDs. However, a comparison of the number of inputs in each brain area between males and females revealed no differences. An interesting discovery was the high amount of GABAergic inputs to the VTA, relative to glutamatergic and serotonergic. Further interrogation of this observation uncovered the presence of a strong inhibitory input onto VTA dopamine neurons, which was confirmed through slice electrophysiology and selective expression of neurotransmitter receptor mRNA transcripts. Isolation of ribosome-associated mRNA transcripts in dopamine neurons and subsequent microarray analysis yielded only two mRNAs with significant sex-dependent expression. Interestingly, these mRNAs encode for genes that are sex chromosome linked. Finally, a comparison of male and female mice in a serious of appetitive dopamine-dependent tasks revealed no consequential differences resulting from sex or hormone state. However, examination of locomotor response to cocaine sensitization indicated a strong effect of hormones in both males and females. Altogether, these data suggest that VTA dopamine circuitry, gene expression, and behavior are largely the same between male and female mice at a baseline state. This implies the need to look at upstream structures that may impart sex-specific qualities which may explain the sex differences we see in dopamine-related diseases.