Defining the metabolic principles of neuronal network oscillations

PROJECT SUMMARY Nutrition and fasting have long been known to have major effects on the brain. Previous work linking metabolic energy to brain function has focused on the neural control of feeding, while key mechanisms by which metabolic states control cognitive function remain unknown. Here we investigate how different metabolic pathways support the fast spiking of inhibitory interneurons, which in turn generate gamma oscillations (30-100 Hz) that are linked to cognitive domains such as memory formation, motor behavior, perception, and consciousness. The subset of fast-spiking inhibitory interneurons defined by expression of the calcium-binding protein Parvalbumin (PV) are necessary and sufficient to drive gamma oscillations. These fast-spiking PV interneurons have tremendous energy needs, supported by high metabolism and mitochondria function. While the extraordinary metabolic activity in PV neurons is well-characterized, the mechanisms regulating their activity and the consequences of activity regulation on brain oscillations and cognitive function are not established. We therefore propose to investigate the function of a vertebrate-specific candidate protein (distinctively expressed in these fast-spiking interneurons) involved in energy generation, and to identify new candidate proteins by a genetically targeted mitochondrial proteome screen from PV neurons. The main goal of this screen is to identify proteins that sustain the high energy generation rate as well as proteins that can tune down PV interneuron metabolic activity. Manipulations of these proteins will then be used to identify the consequences of regulating energy metabolism in PV interneurons on neuronal network oscillations, with the long-term goal to understand how metabolic homeostasis and dysregulation in neurons alters brain function in healthy individuals as well as those with brain disorders such as Alzheimer's disease. Our studies are poised to reveal fundamental insights into the mechanisms that orchestrate energy sources for network oscillations and that link metabolism to higher order cognitive functions. These insights will form the basis for a broader understanding of the link between nutrition, brain function and mental health by determining the consequences of dysfunction of the molecular machinery for energy production in interneurons on brain oscillations that are critical for cognitive function.