The overarching goal of this proposal is to understand the functional role of the glycolytic end-product lactate in the nervous system. Astrocytes, the most abundant CNS cell-type, are the most significant producers of lactate in the CNS. A leading hypothesis on metabolite fluxes in the CNS postulates that astrocytes transfer the lactate they produce to neurons for use as fuel, but this hypothesis remains controversial. Importantly, variations in CNS lactate levels are associated with a number of pathological states and fatal diseases. However, the exact role of astrocyte-produced lactate in the CNS remains unclear, severely limiting our interpretation of these observations and our basic understanding of brain energy metabolism regulation in health and disease. Here, we hypothesize that astrocytic lactate production supports diverse CNS functions and is required for maintaining viability and normal function of both astrocytes and neurons. To study this, we propose three complimentary aims, making use of human and rodent in vitro neuron and astrocyte systems as well as a novel mouse model for in vivo studies.
In Aim 1 we will measure the effect of inhibiting lactate production on astrocytic viability, metabolism, and function in vitro.
In Aim 2 we will measure the effect of silencing astrocytic lactate production on neuronal viability and metabolism in vitro.
In Aim 3 we will measure the effect of ablating astrocytic lactate production on motor, cognitive, and sensory functions in vivo. We propose several novel approaches to studying this question: direct measurements of astrocyte-neuron lactate transfer through stable- isotope labeling techniques in compartmentalized cell-cultures, combining metabolic and metabolomic measurements with longitudinal cell-specific function and viability studies, and the use of a novel mouse model which targets lactate manipulations specifically to astrocytes. We hypothesize that astrocytic lactate production is required for maintaining viability and normal function of both astrocytes and neurons in diverse CNS functions. This application seeks a comprehensive fellowship training plan which incorporates training in new techniques within the lab, technical training at cutting-edge extramural workshops, intellectual development through attending and presenting at multiple seminar series, ethical training through formal coursework, and career development training through scientific seminars and workshops focused on pathways to independence. The proposed project is an entirely new project devised by the applicant which compliments the sponsor?s extensive research program, such designed to foster independence while being supported by the sponsor?s extensive expertise in areas related to the project. The research environment at Weill Cornell Medical College is consistently ranked among the top in the country and provides all the necessary facilities, resources, and career development support required for the success of this proposal.
Energy homeostasis in the nervous system is a complex process which requires coordination of different metabolic functions across multiple cell-types. Astrocytes and neurons within the brain and spinal cord are tightly integrated and cooperate to sense energy demand and regulate energy supply to meet the high resting energy requirements of the nervous system and to support neurotransmission. In this proposal we aim to answer critical questions regarding the role of lactate transfer between astrocytes and neurons in nervous system energetics.
