Prolactin-Releasing Peptide Contributes to Stress-Related Mood Disorders and Inhibits Sleep/Mood Regulatory Melanin-Concentrating Hormone Neurons in Rats
- Szilvia Vas1,2,
- Rege S. Papp3,
- Katalin Könczöl4,
- Emese Bogáthy1,
- Noémi Papp1,
- Csaba Ádori5,
- Máté Durst4,
- Klaudia Sípos4,
- Klementina Ocskay4,
- Imre Farkas6,7,
- Flóra Bálint7,
- Szilamér Ferenci8,
- Bibiána Török9,10,
- Anita Kovács10,
- Evelin Szabó10,
- Dóra Zelena9,10,
- Krisztina J. Kovács8,
- Anna Földes11,
- Erzsébet Kató12,
- László Köles11,12,
- György Bagdy1,2,13,
- Miklós Palkovits3,4, and
- Zsuzsanna E. Tóth4
- 1Department of Pharmacodynamics, Semmelweis University, Budapest, 1089, Hungary
- 2MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Semmelweis University, Budapest, 1089, Hungary
- 3Human Brain Tissue Bank and Laboratory, Semmelweis University, Budapest, 1094, Hungary
- 4Laboratory of Neuroendocrinology and In Situ Hybridization, Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, 1094, Hungary
- 5Department of Neuroscience, Karolinska Institutet, Stockholm, 17177, Sweden
- 6Laboratory of Reproductive Neurobiology, Institute of Experimental Medicine, Eötvös Loránd Research Network, Budapest, 1083, Hungary
- 7Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Eötvös Loránd Research Network, Budapest, 1083, Hungary
- 8Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Eötvös Loránd Research Network, Budapest, 1083, Hungary
- 9Laboratory of Behavioral and Stress Studies, Institute of Experimental Medicine, Eötvös Loránd Research Network, Budapest, 1083, Hungary
- 10Institute of Physiology, Medical School, University of Pécs, Centre for Neuroscience, Szentágothai Research Center, Pécs, 7624, Hungary
- 11Department of Oral Biology, Semmelweis University, Budapest, 1089, Hungary
- 12Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, 1089, Hungary
- 13NAP2-SE New Antidepressant Target Research Group, Budapest, 1085, Hungary
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Author contributions: S.V., R.S.P., K.K., E.B., N.P., C.A., M.D., K.S., K.O., I.F., F.B., S.F., B.T., A.K., E.S., D.Z., A.F., E.K., L.K., and M.P. performed research; S.V., R.S.P., K.S., I.F., A.K., E.S., K.J.K., and Z.E.T. analyzed data; S.V., C.A., and Z.E.T. wrote the first draft of the paper; S.V. and Z.E.T. edited the paper; S.V. and Z.E.T. wrote the paper; G.B. and Z.E.T. designed research.
Abstract
Stress disorders impair sleep and quality of life; however, their pathomechanisms are unknown. Prolactin-releasing peptide (PrRP) is a stress mediator; we therefore hypothesized that PrRP may be involved in the development of stress disorders. PrRP is produced by the medullary A1/A2 noradrenaline (NA) cells, which transmit stress signals to forebrain centers, and by non-NA cells in the hypothalamic dorsomedial nucleus. We found in male rats that both PrRP and PrRP-NA cells innervate melanin-concentrating hormone (MCH) producing neurons in the dorsolateral hypothalamus (DLH). These cells serve as a key hub for regulating sleep and affective states. Ex vivo, PrRP hyperpolarized MCH neurons and further increased the hyperpolarization caused by NA. Following sleep deprivation, intracerebroventricular PrRP injection reduced the number of REM sleep-active MCH cells. PrRP expression in the dorsomedial nucleus was upregulated by sleep deprivation, while downregulated by REM sleep rebound. Both in learned helplessness paradigm and after peripheral inflammation, impaired coping with sustained stress was associated with (1) overactivation of PrRP cells, (2) PrRP protein and receptor depletion in the DLH, and (3) dysregulation of MCH expression. Exposure to stress in the PrRP-insensitive period led to increased passive coping with stress. Normal PrRP signaling, therefore, seems to protect animals against stress-related disorders. PrRP signaling in the DLH is an important component of the PrRP's action, which may be mediated by MCH neurons. Moreover, PrRP receptors were downregulated in the DLH of human suicidal victims. As stress-related mental disorders are the leading cause of suicide, our findings may have particular translational relevance.
SIGNIFICANCE STATEMENT Treatment resistance to monoaminergic antidepressants is a major problem. Neuropeptides that modulate the central monoaminergic signaling are promising targets for developing alternative therapeutic strategies. We found that stress-responsive prolactin-releasing peptide (PrRP) cells innervated melanin-concentrating hormone (MCH) neurons that are crucial in the regulation of sleep and mood. PrRP inhibited MCH cell activity and enhanced the inhibitory effect evoked by noradrenaline, a classic monoamine, on MCH neurons. We observed that impaired PrRP signaling led to failure in coping with chronic/repeated stress and was associated with altered MCH expression. We found alterations of the PrRP system also in suicidal human subjects. PrRP dysfunction may underlie stress disorders, and fine-tuning MCH activity by PrRP may be an important part of the mechanism.
- Received November 15, 2021.
- Revision received August 31, 2022.
- Accepted September 30, 2022.
- Copyright © 2023 Vas et al.
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