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AgRP neurons control structure and function of the medial prefrontal cortex

Abstract

Hypothalamic agouti-related peptide and neuropeptide Y-expressing (AgRP) neurons have a critical role in both feeding and non-feeding behaviors of newborn, adolescent, and adult mice, suggesting their broad modulatory impact on brain functions. Here we show that constitutive impairment of AgRP neurons or their peripubertal chemogenetic inhibition resulted in both a numerical and functional reduction of neurons in the medial prefrontal cortex (mPFC) of mice. These changes were accompanied by alteration of oscillatory network activity in mPFC, impaired sensorimotor gating, and altered ambulatory behavior that could be reversed by the administration of clozapine, a non-selective dopamine receptor antagonist. The observed AgRP effects are transduced to mPFC in part via dopaminergic neurons in the ventral tegmental area and may also be conveyed by medial thalamic neurons. Our results unmasked a previously unsuspected role for hypothalamic AgRP neurons in control of neuronal pathways that regulate higher-order brain functions during development and in adulthood.

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Fig. 1: Changes in prefrontal cortical cells after AgRP neuronal inhibition.
Fig. 2: Alterations in dopaminergic signaling in the mPFC after AgRP cell inhibition.
Fig. 3: Network connectivity between AgRP cells and the PFC.

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Acknowledgements

The authors thank Klara Szigeti-Buck and Alex Ralevski for technical assistance with electron microscopy preparation and imaging, Tamás Herczeg for immunohistochemistry and confocal imaging, Luis Varela for assistance in mitochondria quantification, and Naaman Mehta for assistance with behavioral experiments. This work was supported by the Yale University Neurobiology of Cortical Systems Training Grant [5-T32NS007224-30] to MJW, NIH grants AG052005, AG067329, DK045735, DK126447, DA046160, AG051459, funding from the Kavli Institute for Neuroscience at Yale University, and the Klarman Family Foundation to TLH, the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund (FK124434 and K138836 to FM; KKP126998 to BR, PS, FM), by the Hungarian Brain Research Program (2017-1.2.1-NKP-2017-00002 to FM) by the New National Excellence Program of the Ministry for Innovation and Technology (ÚNKP-21-5—ÁTE to FM). FM is a János Bolyai Research Fellow.

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TLH conceptualized the study. BS, MJW, MSP, FM, and TLH designed the experiments. BS, MJW, MSP, MOD, MS, BR, AM, PS, ZWL, XBG, and MS performed experiments. BS, MJW, MSP, MS, and TLH designed the project and wrote the paper.

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Correspondence to Tamas L. Horvath.

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Stutz, B., Waterson, M.J., Šestan-Peša, M. et al. AgRP neurons control structure and function of the medial prefrontal cortex. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01691-8

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  • DOI: https://doi.org/10.1038/s41380-022-01691-8

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