Genetic Dissection of Neurocircuits Controlling Energy Balance and Glucose Homeostasis

The neural circuits in the brain that regulate hunger and metabolism are unknown. In essence, we lack the “wiring diagram”. This is due to inherent complexity within the brain. Recent transformative advancements make it possible to now “solve” this complexity. With these tools, which are enabled by mice expressing cre in specific neurons (see figure), we are mapping connections between neurons and establishing the function of neurocircuits. Specifically, we utilize genetic engineering techniques in mice, in conjunction with electrophysiology, optogenetics, chemogenetics (i.e. DREADDs) and rabies mapping, to elucidate the underlying neurocircuits.  Cre-dependent AAV viral approaches are used to deliver the optogenetic, chemogenetic and monosynaptic rabies mapping tools to cre-expressing neurons. The goal of these studies is to link neurobiologic processes within defined sets of neurons with specific behaviors and physiologic responses. The ultimate goal is to mechanistically understand the “neurocircuit basis” for regulation of food intake, energy expenditure and glucose homeostasis. Given our expertise in gene knockout and transgenic technology, in conjunction with the BADERC Transgenic Core, we can efficiently and rapidly create numerous lines of genetically engineered mice, important examples being neuron-specific ires-Cre knockin mice, which enable cre-dependent AAV technology (as shown in the figure). This allows us to bring novel, powerful approaches to bear on the neural circuits underlying behavior and metabolism. Our combined use of mouse genetic engineering, brain slice electrophysiology, and whole animal physiology is ideally suited to studying these problems.


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