Genotype and sex effects on anxiety behavior and functional activation in corticolimbic circuits in serotonin transporter knockout mice (5-HTT KO)

In humans, the serotonin transporter linked polymorphic region (5-HTTLPR) results in altered transcriptional efficiency of the transporter gene, as well as uptake of serotonin (5-HT) by neurons. The low expressing 's' allele of this polymorphism has been linked to increased susceptibility to stress and altered connectivity of corticolimbic neural circuits, the disruption of which is widely invoked to explain emotional dysregulation in anxiety and mood disorders.;Serotonin transporter (5-HTT) knockout (KO) mice offer a promising model for psychiatric research as close parallels exist between the human polymorphism and the mouse model at the level of serotonergic profile, behavior, physiological function, and stress hormone response. Although much work has gone into characterizing 5-HTT KO mice, little work to date has examined functional activation patterns and connectivity of circuits involved in emotional regulation in these mice. The experiments outlined in this dissertation address this gap in knowledge by examining sex and genotypic differences in the underlying functional activation of corticolimbic circuits. The inclusion of females in this study provides important information about how sex differences in serotonergic function alter brain function. Functional connectivity analysis is also undertaken in a combined male/female groups to determine genotypic effects on a network level.;Overall, the experiments contained in this dissertation contribute novel information about the role of sex and 5-HTT genotype in anxiety like behavior and function of corticolimbic circuits. Specifically, this is the first study using whole brain functional perfusion mapping in the 5-HTT KO mouse model. Furthermore, these studies support sex differences in functional regulation of the prefrontal-amygdala network in a fear-conditioned paradigm. These studies establish the translational value of functional brain mapping endpoints and suggest greater specificity than the behavioral endpoints. Future studies could address the underlying molecular and structural changes accompanying functional changes seen in 5-HTT KO mice.