This project explores the connections between brain metabolism, anxiety and cognition in the elderly population. In the face of changing diets and a rapidly growing elderly population, there is exceptional need for better understanding of the mechanisms of brain metabolism and its effects on the brain. Although this project is designed to address a basic research question, the results have obvious implications for disorders of the brain due to altered metabolism. The work done in this project takes a unique approach to examine an understudied aspect of cognition, and has the potential to shift the focus of neuroscience research in a new direction. In addition, educational benefits include the participation of two undergraduate and two high school research interns through collaboration with a local high school and the HHMI sponsored Scholars Program through Lewis and Clark University. A high school student joins the laboratory from the Saturday Academy. A team of two HHMI sponsored undergraduates and two high school students work together on aspects of this project under the guidance of the PI during the summer. Community education on issues such as the role of cholesterol in brain function are fostered through the Healthy Aging Alliance, a program in which researchers join the public for presentations of their work and discussions on healthy aging. The PI also participates in Let's Get Healthy, an outreach program focused on encouraging healthy habits in middle and elementary school children in underserved communities. Research collaboration and outreach in undertreated areas of rural Oregon are promoted by the Central Oregon Research Coalition.
The scientific objective of this project is to investigate the interaction between apolipoprotein E (apoE) and the low-density lipoprotein receptor (LDLR) as a modulator of brain metabolism, anxiety and cognition. The PI hypothesizes that compared to apoE2 and apoE3, apoE4 acts as an "aging accelerator" via interaction with the LDLR, causing alterations in brain metabolism that lead to cognitive and behavioral changes. The PI-team tests this hypothesis by examining anxiety and cognitive function, as well as determining brain "metabolic profiles?", in mice that express human apoE isoforms and human LDLR. The intellectual merit of this project lies in its integrative systems biology approach: the aims merge detailed behavioral and cognitive analyses with unbiased metabolomic profiling. The plan is hypothesis driven, and is based on evidence from both the cardiovascular and neuroscience fields. The project is a creative combination of metabolomics and behavioral neuroscience, and employs a unique animal model to study a crucial proteinprotein interaction in the brain for the first time. The PI received graduate training at the University of North Carolina from two pioneers in the fields of lipoprotein biology and genetics. The Sponsoring Scientist has an established track record in neuroscience and specializes in complex behavioral analyses in animal models, in particular measurements of anxiety and learning and memory in mice. The Sponsor also has ample resources for the proposed project, including state of the art behavioral testing equipment, videotracking and data analysis software, solid grant support, and a productive collaboration with a specialist in metabolomic analyses.
