The study of genetic and phenotypic individual differences that act as risk factors for neuropsychiatric disorders is providing insight into the underlying aetiology of such disorders. Our lab is particularly interested in those individual differences that underlie emotional dysregulation and changes in prefrontal activity, hallmark symptoms of many of these disorders. We use the common marmoset, a primate model with a well-developed prefrontal cortex that enables us to study the underlying molecular mechanisms alongside the neural circuitry involved in emotional regulation. We have identified genetic variation within the promoter region of the serotonin transporter gene (SLC6A4) that is associated with gene expression levels and anxious behavior. These genetic variants show a differential DNA-binding protein pattern and secondary structure stability, two putative mechanisms influencing gene expression. The PhD project will follow up these molecular studies by dissecting out the genetic effects on DNA-protein binding, secondary structure stability and putative epigenetic changes underlying the differential SLC6A4 gene expression. This part of the project will include molecular sub-cloning, expression analysis in tissue culture and pharmacological manipulations. In addition, we have revealed structural and neurochemical changes in emotional-processing brain areas associated with the SLC6A4 genetic variants and emotional behavior using neuroimaging. The PhD project would also determine whether these changes in the brain networks are necessary and sufficient to induce emotional dysregulation. This part of the project would set up and utilize designer receptors exclusively activated by designer drug (DREADD) technology for marmosets including stereotaxic viral brain infusion and histochemistry techniques.
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