IDENTIFYING CELLULAR AND MOLECULAR SUBSTRATES OF TREATMENT-RESISTANT DEPRESSION.

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Modified Project Summary/Abstract My career goal is to lead a translational research team that uses cutting-edge neuroscience techniques to investigate conceptually novel leads into how mental illness develops and how it can be successfully treated. Specifically, I, and my future lab, will investigate how molecular signaling regulates dentate gyrus function to mediate stress resilience and antidepressant responses. My research strategy will integrate innovative molecular techniques and in vivo imaging in mice, with translational work in human brain samples to increase the clinical value of our findings. My primary expertise is in neuropsychopharmacology and my career development plan expands on these methods by providing essential new training in bioinformatics, in vivo brain imaging, and analysis of human postmortem brain tissue. My career goal is to integrate these techniques to generate unique insight into the exact neural circuits and neurobiological processes that lead to disease and that could be harnessed by novel treatments. My success as an independent researcher therefore depends on developing the skills that I propose to learn in this proposal. Research Project Identifying the neurobiological mechanisms that determine response and resistance to psychiatric treatment is of paramount importance for developing improved drugs and therapies. While substantial evidence from humans and rodent models has demonstrated a crucial role for the neurotransmitter, serotonin (5HT), in antidepressant action, it is unknown why some individuals respond to treatment with selective serotonin reuptake inhibitors (SSRIs) while others do not. This lack of knowledge limits the development of effective drugs that could specifically target neurobiological substrates that confer treatment response. Our work has revealed the serotonin 1A receptor (5HT1AR) in dentate gyrus granule neurons of the hippocampus as a crucial mediator for neuronal inhibition and behavioral responses to SSRIs. However, how 5HT1ARs regulate neuronal function to elicit an antidepressant response remains elusive. Leading on from these findings, we hypothesize that antidepressant responses are mediated by inhibition of dentate gyrus activity. To test this, we will first examine the complex molecular networks by which 5HT1AR signaling inhibits dentate gyrus activity in mice and in human postmortem brain tissue. Then, we will use chemogenetic techniques to counteract or stimulate neuronal inhibition in the dentate gyrus of transgenic mice that do or do not respond to antidepressants, respectively. Finally, we will use innovative in vivo microscopy to image neuronal activity in the dentate gyrus of freely behaving responders and non-responders during stress and anxiety-related tasks. This project will provide a comprehensive investigation into how we can develop advanced antidepressant treatments based on inhibition of dentate gyrus activity.