Abstract
Anorexia nervosa (AN) is a debilitating and deadly disease characterized by low body mass index due to diminished food intake, and oftentimes concurrent hyperactivity. A high percentage of AN behavioral and metabolic phenotypes can be replicated in rodents given access to a voluntary running wheel and subject to food restriction, termed activity-based anorexia (ABA). Despite the well-documented bodyweight loss observed in AN human patients and ABA rodents, much less is understood regarding the neurobiological underpinnings of these maladaptive behaviors. Hunger-promoting hypothalamic agouti-related peptide (AgRP) neurons have been well characterized in their ability to regulate appetite, yet much less is known regarding their activity and function in the mediation of food intake during ABA. Here, feeding microstructure analysis revealed ABA mice decreased food intake due to increased interpellet interval retrieval and diminished meal number. Longitudinal activity recordings of AgRP neurons in ABA animals exhibited a maladaptive inhibitory response to food, independent of basal activity changes. We then demonstrated that ABA development or progression can be mitigated by chemogenetic AgRP activation through the reprioritization of food intake (increased meal number) over hyperactivity, but only during periods of food availability. These results elucidate a potential neural target for the amelioration of behavioral maladaptations present in AN patients.
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Acknowledgements
We would like to thank Dr. Alexxai Kravitz for the development of and extensive help with FED3 devices. We thank Dr. Bryan Roth for the CNO used in chemogenetic experiments. We also thank N. Martin and B. Gloss of the NIEHS Viral Vector Core for producing the AAVs used in chemogenetic experiments. We thank all members of Dr. Krashes’ lab for technical support and guidance during this project. This research was supported by the Intramural Research Program of the National Institutes of Health, the National Institutes of Diabetes and Digestive and Kidney Diseases (DK075088 to M.J.K. and DK075087-06 to M.J.K.) and the Nancy Nossal Fellowship (NIH-NIDDK; to A.K.S.-H.).
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A.S.-H. and M.J.K. designed experiments. A.S.-H. and S.C.D. performed initial experiments in WT mice. A.S.-H., S.C.D., A.M.S., A.S. constructed FED3 devices used throughout experiments. A.S.-H., L.E.M. performed chemogenetic and photometry experiments. A.S.-H., E.O.K. performed behavioral experiments used in conjunction with ex vivo electrophysiology experiments. C.L. performed ex vivo electrophysiology experiments. A.S.-H., C.L. performed surgery for photometry experiments. A.K.S. performed analysis on all experiments. A.S.-H. and M.J.K. wrote the manuscript with input from S.C.D. and C.L.
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Sutton Hickey, A.K., Duane, S.C., Mickelsen, L.E. et al. AgRP neurons coordinate the mitigation of activity-based anorexia. Mol Psychiatry 28, 1622–1635 (2023). https://doi.org/10.1038/s41380-022-01932-w
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DOI: https://doi.org/10.1038/s41380-022-01932-w