My career goal is to lead a translational research group that investigates the neurogenetic basis of both normal and pathological behavior. To acquire the specific training I will need to achieve this, I propose a project that examines the mechanisms underlying genetic and epigenetic sources of depression risk, as well as their potential interaction. Specifically, I, and my future lab, will investigate how common genetic and epigenetic variation in the serotonin 1a receptor gene (HTR1A) impacts HTR1A gene expression and contributes to both depression risk and anti-depressant drug responsiveness. To directly translate our findings, we will pursue complimentary techniques in post-mortem human tissue and a humanized HTR1A mouse model. My primary expertise is in mouse behavior, molecular cloning, and transgenic techniques;my career development plan expands on these methods, providing essential new training in epigenetic techniques, experimental use of post-mortem human tissue, and a deeper understanding of psychiatric disorders. Since it is my goal to lead a lab that studies the neurogenetics of behavior and how alterations in gene expression contribute to disease states, my success as an independent researcher depends on these skills. I also propose to further develop my training in translational neuroscience so that I may expand my clinical collaborations. Research Project Identifying the biological mechanisms underlying both heritable and non-heritable factors that impact depression risk and treatment response is of the utmost importance for designing better therapies and preventative interventions. While substantial evidence from both humans and rodent models has linked variation in serotonin 1a receptor (5-HT1A) levels with depression-related traits, the biological mechanisms underlying differences in receptor expression are not well understood. Preliminary evidence suggests that both rs6295, a common single nucleotide polymorphism (SNP) located upstream of the HTR1A gene, and methylation of the HTR1A promoter impact 5-HT1A levels. However, the direct contribution and potential interaction of these putative sources of variation in expression have not been demonstrated. Thus, we here propose to investigate the hypothesis that both epigenetic and genetic variation affect susceptibility to depression and resistance to antidepressants by modulating 5-HT1A levels. To test this, we will first examine the relationship between rs6295 and levels of HTR1A mRNA in post-mortem human brain tissue. Then we will use a humanized mouse model to determine the direct contribution of rs6295 to 5-HT1A levels, depression- related behavior, and antidepressant responsiveness. Using these mice, we will also examine the effects of stress exposure on HTR1A transcription, methylation of the human HTR1A promoter, and behavior. Finally, we will combine these lines of questioning to ask whether rs6295 interacts with stress exposure at a molecular (i.e., epigenetic) and/or behavioral level. !

Public Health Relevance

Depression is a disease with significant public health burden and economic costs that is influenced by both genetic and environmental factors. This proposal examines the molecular mechanisms underlying these factors by investigating how genetic and environmental variation influence the expression of a gene implicated in depression, the serotonin 1a receptor gene, in both mice and humans. This work will help refine treatments and preventative measures for mood disorders.!

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Career Transition Award (K99)
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Special Emphasis Panel (ZMH1)
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Chavez, Mark
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New York State Psychiatric Institute
New York
United States
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Gould, T D; Georgiou, P; Brenner, L A et al. (2017) Animal models to improve our understanding and treatment of suicidal behavior. Transl Psychiatry 7:e1092
Donaldson, Z R; le Francois, B; Santos, T L et al. (2016) The functional serotonin 1a receptor promoter polymorphism, rs6295, is associated with psychiatric illness and differences in transcription. Transl Psychiatry 6:e746
Donaldson, Zoe R; Hen, René (2015) From psychiatric disorders to animal models: a bidirectional and dimensional approach. Biol Psychiatry 77:15-21