Stress and aging: longitudinal evaluation of synaptic changes using in vivo SV2A PET

Yale University, New Haven CT

Investigators

Abstract

PROJECT SUMMARY This Mentored Research Scientist Career Development Award proposal will be conducted within the Department of Psychiatry at the Yale School of Medicine, world renown for its commitment to training and research. This proposal is designed to provide advanced training, expert mentoring, and hands-on research experience that will facilitate my successful transition to research independence. My primary career goal is to establish myself as a translational neuroscientist with specific expertise in the application of in vivo Positron Emission Tomography (PET) to animal models of stress and aging. To achieve this goal, I propose a comprehensive five-year plan designed to provide rigorous training in four key areas: 1) Basic training in the biology of stress and aging; 2) Practical training in molecular, behavioral, and synaptic assessments, including training in PET methodology; 3) Advanced biostatistical training; 4) Career development and mentorship to facilitate the transition to research independence. Integral to this training plan is completion of a novel research project which uses state-of-the-art in vivo PET imaging techniques that allow for the longitudinal evaluation of synapses in an animal model of chronic stress and aging. Using clinical neuroimaging in animal models provides an important translational bridge between basic science and the clinic, facilitating the dissemination of findings from bench-to-bedside. Typical aging is associated with widespread brain changes that can contribute to cognitive decline. Stress can similarly impact brain physiology, and it is hypothesized that these stress- and age-related brain alterations are driven in part by synaptic changes, including synaptic loss. Further, evidence suggests chronic stress may accelerate brain aging and contribute to premature cognitive decline. Previously, the hypothesis that stress accelerates synaptic aging could not be directly tested in vivo because no method existed for measuring synapses in the living human brain. However, this is no longer the case: with the recent development of radiotracers targeting synaptic vesicle protein 2A (SV2A), PET quantification of tracer binding provides a method for estimating synaptic density in vivo. Here, we propose using SV2A PET imaging in an animal model. Specifically, we aim to determine the effect of chronic stress on synaptic density using in vivo SV2A PET (Aim 1), investigate the impact of age on stress-induced synaptic changes (Aim 2), and explore relationships between stress- and age-related synaptic changes with cognitive function (Aim 3). Results of this study will provide potentially critical insight into synaptic mechanisms contributing to stress-accelerated brain aging and relationships with functional and cognitive decline. Completion of the proposed training and research plan will optimally prepare me for an independent career as a translational neuroscientist neuroimager, and ultimately establish a research program capable of improving our understanding of the biological underpinnings of stress- related neuropathology, aiding the development of novel treatments, and reducing stigma and suffering.