Tuberal hypothalamic neurons secreting the satiety molecule Nesfatin-1 are critically involved in paradoxical (REM) sleep homeostasis.

Sonia Jego,Masatomo Mori,Romain Goutagny,Patrice Fort,Leslie Renouard,Denise Salvert,Pierre-Hervé Luppi,Denis Burdakov

doi:10.1371/journal.pone.0052525

Sonia Jego, Masatomo Mori + Show 6 more

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https://doi.org/10.1371/journal.pone.0052525

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Abstract

The recently discovered Nesfatin-1 plays a role in appetite regulation as a satiety factor through hypothalamic leptin-independent mechanisms. Nesfatin-1 is co-expressed with Melanin-Concentrating Hormone (MCH) in neurons from the tuberal hypothalamic area (THA) which are recruited during sleep states, especially paradoxical sleep (PS). To help decipher the contribution of this contingent of THA neurons to sleep regulatory mechanisms, we thus investigated in rats whether the co-factor Nesfatin-1 is also endowed with sleep-modulating properties. Here, we found that the disruption of the brain Nesfatin-1 signaling achieved by icv administration of Nesfatin-1 antiserum or antisense against the nucleobindin2 (NUCB2) prohormone suppressed PS with little, if any alteration of slow wave sleep (SWS). Further, the infusion of Nesfatin-1 antiserum after a selective PS deprivation, designed for elevating PS needs, severely prevented the ensuing expected PS recovery. Strengthening these pharmacological data, we finally demonstrated by using c-Fos as an index of neuronal activation that the recruitment of Nesfatin-1-immunoreactive neurons within THA is positively correlated to PS but not to SWS amounts experienced by rats prior to sacrifice. In conclusion, this work supports a functional contribution of the Nesfatin-1 signaling, operated by THA neurons, to PS regulatory mechanisms. We propose that these neurons, likely releasing MCH as a synergistic factor, constitute an appropriate lever by which the hypothalamus may integrate endogenous signals to adapt the ultradian rhythm and maintenance of PS in a manner dictated by homeostatic needs. This could be done through the inhibition of downstream targets comprised primarily of the local hypothalamic wake-active orexin- and histamine-containing neurons.

Highlights

It is accepted that the brainstem is sufficient for the generation of paradoxical (REM) sleep (PS)
To further investigate the PS-enhancing potency of Nesfatin-1, we assessed how sleep was affected by the acute blocking of endogenous signaling through the infusion of a specific antiserum [18]
By combining pharmacology and functional neuronanatomy, we demonstrated that endogenous Nesfatin-1 signaling is involved in PS regulation, a role owed to Nesfatin-1 secreting neurons restricted to the tuberal hypothalamus (THA)

Summary

Introduction

It is accepted that the brainstem is sufficient for the generation of paradoxical (REM) sleep (PS). During waking and slow wave sleep (SWS), they are tonically inhibited by GABAergic inputs from the ventrolateral part of the periaqueductal gray and adjacent deep mesencephalic reticular nucleus. This inhibition must be removed to allow the SLD activation required for PS induction [2,3,4,5,6,7]. Electrophysiological recordings coupled with juxtacellular labeling confirmed that MCHsecreting neurons fire selectively during PS [10] This observation, strengthened by the fact that intracerebroventricular (icv) administration of MCH enhances SWS and PS, points to a role of MCH signaling in sleep [9,11,12]

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