Bradford B. Lowell, M.D., Ph.D.

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.

References.

1. Kong D*, Vong L*, Parton LE*, Ye C, Tong Q, Hu X, Choi B, Brüning JC, Lowell BB. Glucose stimulation of hypothalamic MCH neurons involves KATP channels, is modulated by UCP2, and regulates peripheral glucose homeostasis. Cell Metabolism 12: 545-52, 2010. *joint first authors. (PMC2998191).

2. Krashes MJ*, Koda S*, Ye CP, Rogan SC, Adams AC, Cusher DS, Maratos-Flier E, Roth BL, Lowell BB. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest 121: 1424-8, 2011. *joint first authors. (PMC3069789).

3. Vong L*, Ye C*, Yang Z, Choi B, Chua Jr SC, Lowell BB. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71: 142-54, 2011. *joint first authors. (PMC3134797).

4. Cohen JY, Haesler S, Vong L, Lowell BB, Uchida N. Dopaminergic and GABAergic neurons in the ventral tegmental area convey distinct signals for reward and punishment. Nature 482: 85-8, 2012. (PMC3271183).

5. Liu T*, Kong K*, Shah BP*, Ye C*, Koda S, Saunders A, Ding JB, Yang Z, Sabatini BL and Lowell BB. Fasting Activation of AgRP Neurons Requires NMDA Receptors and Involves Spinogenesis and Increased Excitatory Tone. Neuron 73: 511-22, 2012. *joint first authors. (PMC3278709).

6. Kozorovitskiy Y, Saunders A, Johnson CA, Lowell BB, Sabatini BL. Recurrent network activity drives striatal synaptogenesis. Nature 485: 646-50, 2012. (PMC3367801).

7. Kong D*, Tong Q*, Ye C, Koda S, Fuller PM, Krashes MJ, Vong L, Ray RS, Olson DP, Lowell BB. GABAergic RIP-Cre neurons in the arcuate nucleus selectively regulate energy expenditure. Cell 151: 645-57, 2012. *joint first authors. (PMC3500616).

8. Krashes MJ, Shah BP, Koda S, Lowell BB. Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators, GABA, NPY and AgRP. Cell Metab 18: 588-95, 2013. (PMC3822903)

9. Krashes MJ*, Shah BP*, Madara JC, Olson DP, Strochlic DE, Garfield AS, Vong L, Pei H, Watabe-Uchida M, Uchida N, Liberles SD, Lowell BB. An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507: 238-42, 2014. PMCID: PMC3822903 [Available on 2014/10/1]

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