Hungarian Brain Research Program Grants(2017-1.2.1-NKP-2017-00002)
National Development Agency Grant(KTIA_NAP_13-1-2013-0001)
(KTIA_13_NAPA-II/14)
NKFIH(K 115422,)
(TKP2021-EGA-25)
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.
