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A hippocampus to prefrontal cortex neural pathway inhibits food motivation through glucagon-like peptide-1 signaling

Abstract

The hippocampus and the medial prefrontal cortex (mPFC) are traditionally associated with regulating memory and executive function, respectively. The contribution of these brain regions to food intake control, however, is poorly understood. The present study identifies a novel neural pathway through which monosynaptic glutamatergic ventral hippocampal field CA1 (vCA1) to mPFC connectivity inhibits food-motivated behaviors through vCA1 glucagon-like peptide-1 receptor (GLP-1R). Results demonstrate that vCA1-targeted RNA interference-mediated GLP-1R knockdown increases motivated operant responding for palatable food. Chemogenetic disconnection of monosynaptic glutamatergic vCA1 to mPFC projections using designer receptors exclusively activated by designer drugs (DREADDs)-mediated synaptic silencing ablates the food intake and body weight reduction following vCA1 GLP-1R activation. Neuropharmacological experiments further reveal that vCA1 GLP-1R activation reduces food intake and inhibits impulsive operant responding for palatable food via downstream communication to mPFC NMDA receptors. Overall these findings identify a novel neural pathway regulating higher-order cognitive aspects of feeding behavior.

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Acknowledgments

We thank the following individuals for notable contributions to this work: Dr Alan G. Watts, Dr Larry W. Swanson, Brian Zingg, Sandhya Prathap, Emily Nakamoto, Lilly Taing, Hrant Gevorgian, Joanna Liang, Ryan Usui, Mehul Trivedi, Agustina Kim, Allison Apfel, Kaitlin Sontag, Anish Reddy, and Natalie Demirjian. This study was supported by the National Institute of Health grants: DK104897 (SEK), DK096139 (MRH), DK107333 (TMH) and pilot grant funding from the USC Diabetes and Obesity Research Institute (SEK). We report no biomedical financial interests or potential conflicts of interest.

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Hsu, T.M., Noble, E.E., Liu, C.M. et al. A hippocampus to prefrontal cortex neural pathway inhibits food motivation through glucagon-like peptide-1 signaling. Mol Psychiatry 23, 1555–1565 (2018). https://doi.org/10.1038/mp.2017.91

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