Prolactin-Releasing Peptide Contributes to Stress-Related Mood Disorders and Inhibits Sleep/Mood Regulatory Melanin-Concentrating Hormone Neurons in Rats

Abstract

Stress disorders impair sleep, quality of life, however, their pathomechanisms are unknown. Prolactin-releasing peptide (PrRP) is a stress mediator, therefore, we hypothesised 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 up-regulated by sleep deprivation, while down-regulated by REM sleep rebound. Both in learned helplessness paradigm and after peripheral inflammation, impaired coping with sustained stress was associated with (i) overactivation of PrRP cells, (ii) PrRP protein and receptor depletion in the DLH, and (iii) dysregulation of MCH expression. Exposure to stress in 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 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.

Causal Relationship Between Sleep Traits and Hypothalamic-Pituitary-Target Gland Axis Function: A Mendelian Randomization Study

“…Vas et al’s latest animal study found that PrRP plays a critical role in regulating sleep and affective states, and normal PrRP signaling appears to protect Wistar rat models from stress-induced damage. However, persistent sleep deprivation can lead to overactivation of PrRP cells and depletion of PrRP protein and receptors, 36 which is consistent with the findings of this study. Due to the anterior pituitary, PRL secretion is regulated by a variety of other modalities in addition to being stimulated by hypothalamic prolactin-releasing hormone.…”

Brain RFamide Neuropeptides in Stress-Related Psychopathologies

“…Tissue homogenates of the large brain regions all contained PrRPR mRNA, except for the midbrain [196]. Expression of PrRPR mRNA was detected in the dorsal hypothalamic area and LHA in postmortem human hypothalamic samples via RT-PCR [190].…”

“…PrRP fibers primarily target the HTH [181], which is probably also the case in humans [188] and suggests functions in homeostatic regulation. The most densely innervated areas are the PVN, the DMN, the perifornical area, and the LHA [130,177,189,190]. Several hypothalamic areas receive moderate PrRP innervation, such as the anteroventral periventricular area (AV3V), the magnocellular nuclei, and the PeN, including the ependymal layer.…”

“…High or moderate PrRPR expression has been detected in the BNST, HTH (preoptic nuclei, AV3V, DMN, PeN, PVN), AMY, LC, NTS, and AP (Figure 3). Several other brain areas, such as the perifornical area, the LHA, and the PBN show lower levels of PrRPR expression [19,179,190,194,195].…”

Of artificial intelligence, machine learning, and the human brain. Celebrating Miklos Palkovits' 90th birthday

“…Miklos' current research working with collaborators across the globe includes the characterization of the human brain (g)lymphatic system (Mezey and Palkovits, 2015;Mezey et al, 2021), identifying SARS-CoV-2 entry sites into the human brain (Vitale-Cross et al, 2022), identifying the role of neuropeptides and their signaling in neuropsychiatric disorders (Barde et al, 2016(Barde et al, , 2024Hökfelt et al, 2018;Zhong et al, 2022;Samardžija et al, 2023;Vas et al, 2023), and neurogenetics (Roy et al, 2017;Dóra et al, 2022;Hardwick et al, 2022).…”