CHEMOGENETIC & OPTOGENETIC METHODS FOR STUDYING THE ROLE OF THE NUCLEUS SOLITARY TRACT IN SATIATION
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Increased meal size on a western diet is a major contributor to development and maintenance of obesity. This also leads to decreased sensitivity to the satiating effects of the western diet. Excitation of cells during consumption of a meal in the caudal two-thirds of the nucleus solitary tract (cNTS) in the brainstem are thought to produce satiation and inhibit feeding. Currently, it is unknown how excitation of these cells inhibits feeding. A major obstacle has been the inability to selectively manipulate these cells without affecting intermixed cells that mediate other autonomic functions. We propose a novel approach using inducible, activity-dependent chemogenetics or optogenetics to test whether artificial excitation of cells in the caudal two-thirds of the nucleus solitary tract (cNTS) activated during satiation can reduce food intake and could contribute to preventing or reversing obesity in humans.
We tested four different mouse models with potential for answering this question: double transgenic mice with cFos-tTA & Tet-O-hM3Dq genes, a single transgenic cFos-tTA mouse with a virally delivered hM3Dq gene injected into the cNTS, a double transgenic mice with the TRAP2- tdTomato genes and double transgenic mice with c-Fos-tTA and ChEF genes. Evidence suggested that clozapine-N-oxide might activate satiation-related cells in the absence of the hM3Dq receptor and this should be taken into consideration for future experiments. All four models had promising aspects for studying feeding as well as serious limitations. These limitations will need to be considered when deciding to use any of these models to study any feeding behaviors, especially satiation.