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Stress integration by an ascending adrenergic-melanocortin circuit

Neuropsychopharmacology (2024)Cite this article

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Abstract

Stress is thought to be an important contributing factor for eating disorders; however, neural substrates underlying the complex relationship between stress and appetite are not fully understood. Using in vivo recordings from awake behaving mice, we show that various acute stressors activate catecholaminergic nucleus tractus solitarius (NTSTH) projections in the paraventricular hypothalamus (PVH). Remarkably, the resulting adrenergic tone inhibits MC4R-expressing neurons (PVHMC4R), which are known for their role in feeding suppression. We found that PVHMC4R silencing encodes negative valence in sated mice and is required for avoidance induced by visceral malaise. Collectively, these findings establish PVHMC4R neurons as an effector of stress-activated brainstem adrenergic input in addition to the well-established hypothalamic-pituitary-adrenal axis. Convergent modulation of stress and feeding by PVHMC4R neurons implicates NTSTH → PVHMC4R input in stress-associated appetite disorders.

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Fig. 1: Stress robustly activates NTSTH → PVH axons.
Fig. 2: Stress evokes noradrenergic release onto PVHMC4R neurons.
Fig. 3: PVHMC4R neurons are inhibited by stress.
Fig. 4: PVHMC4R silencing encodes negative valence.
Fig. 5: PVHMC4R inhibition is required for LiCl-induced avoidance.

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Acknowledgements

We thank Dr. Kamal Rahmouni and Dr. Deng-Fu Guo for providing Mc4r-cre x ai14 mice. We thank Dr. Huxing Cui and Dr. Uday Singh for providing Mc4r-cre mice.

Funding

This work is supported by NIH to D.A. R01DK126740 and NIH to C.L. F31HL168820.

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Authors and Affiliations

  1. Department of Neuroscience and Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA

    Connor Laule, Nilufer Sayar-Atasoy, Iltan Aklan, Hyojin Kim, Tayfun Ates, Debbie Davis & Deniz Atasoy

  2. Iowa Neuroscience Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA

    Deniz Atasoy

  3. Fraternal Order of Eagles Diabetes Research Center (FOEDRC), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA

    Deniz Atasoy

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Contributions

CL performed behavioral experiments; CL, NSA performed in vivo imaging experiments; CL, IA performed surgeries; CL performed electrophysiology experiments; CL, HK, TA performed post hoc analysis; NSA performed genotyping; DD managed mouse colony; DA, CL, NSA conceived experiments; DA, CL, NSA analyzed data; DA and CL wrote the manuscript.

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Correspondence to Deniz Atasoy.

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Laule, C., Sayar-Atasoy, N., Aklan, I. et al. Stress integration by an ascending adrenergic-melanocortin circuit. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01810-9

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