Individuals with autism spectrum disorders (ASDs) are impaired in cognitive processes and emotional regulation, and exhibit stereotyped behaviours. Dopamine (DA) modulates executive functions, learning, memory, emotional processing and social cognition; all of which are impaired in individuals with ASDs. Because DA modulates a number of processes that are impaired in individuals with ASDs, genes in the dopaminergic pathway are good candidates for genes influencing autistic behaviours. As our previous findings suggested a role for a dopamine-related gene in families with only affected males, this thesis describes a comprehensive study of five genes affecting DA synthesis, levels and function in mothers and affected males with ASDs in an initial TEST cohort of 112 male-only affected sib-pair families as well as a replication study in three additional male-only family cohorts. I genotyped three to five polymorphisms in the TH, SLC6A3, DRD1, DRD2 and PPP1R1B genes and performed population-based single marker case-control comparisons, family-based association tests, quantitative transmission disequilibrium tests as well as haplotype-based analyses and tests for gene-gene interactions. I found evidence for association of the DRD1 (P=0.0027-0.040), DRD2 (P=0.0002-0.007) and PPP1R1B (P=0.00042-0.001) genes with autism in affected males from the TEST cohort. Evidence for DA-related gene interactions were found between polymorphisms in DRD1, DRD2 and PPP1R1B (P=0.0094-0.012) in affected males relative to a comparison group. Furthermore, I found that polymorphisms in the TH and DRD1 genes were associated with the risk for mothers having sons with ASD in the TEST families (P=0.007-0.025) and putative risk alleles in DRD1 and DRD2 were preferentially transmitted from mothers (P=0.016) and fathers (P=0.023) respectively, to affected children. All findings remained significant following corrections for multiple testing. The TEST cohort findings were not replicated in other family cohorts. However, an examination of dysmorphology data for the different family sets revealed phenotypic differences and thus, genetic differences are to be expected. In summary, I found evidence for a contribution of DA-related genes in a specific family cohort with ASDs. Additional functional and phenotypic studies will enable a better understanding of the contributions and implications of these findings to our understanding of autism. / Thesis (Ph.D, Physiology) -- Queen's University, 2009-03-18 13:58:12.223

Thesis advisor: Michael Numan / This paper will review research from our laboratory dealing with the neural basis of maternal behavior in rats. Specifically, my work investigates hypothalamic interaction with the mesolimbic dopamine system and the regulation of maternal responsiveness. Recent evidence has shown that increased dopamine activity in the nucleus accumbens, a major terminus of the mesolimbic dopamine pathway, results in a facilitation of maternal behavior in female rats who have been partially primed by hormones. However, the way in which dopamine and hormones act on these neural circuits is unclear. We hypothesize that one of these hormones, estradiol, acts on the MPOA and mesolimbic dopamine system through similar intracellular mechanisms as dopamine. My research goals are twofold: (1) to discern which G-protein coupled pathway dopamine utilizes to act in the nucleus accumbens and (2) to investigate whether estradiol is having rapid effects at the cell membrane and whether these effects are mediated by G-protein coupled receptors. / Thesis (BA) — Boston College, 2008. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Psychology. / Discipline: College Honors Program.

Melanocortins (MCs) play an important role in feeding, metabolism, and energy expenditure. While melanocortin receptor (MCR) mRNA has been found in the mesolimbic dopamine (DA) pathway, the ability of melanocortins to regulate feeding and other behaviors through actions on the mesolimbic DA system have not been examined. Short-hairpin RNAs (shRNAs) were created targeting MC3R and MC4R and were tested via in vitro studies for their ability to knockdown their target receptor. A total of three shRNAs were created targeting each receptor, and each shRNA caused successful knockdown. These shRNAs are tools that can be used for future in vivo studies to examine the various behavioral effects of melanocortins on the mesolimbic DA pathway.