Spexin-expressing neurons in the magnocellular nuclei of the human hypothalamus

Highlights

• SPX-expressing neurons are present in the human supraoptic and paraventricular nuclei.

• SPX immunoreactivity is slightly higher in the supraoptic than in the paraventricular nucleus.

• The highest density of SPX-positive neurons is observed in the posterior part of supraoptic nucleus.

Abstract

Neuropeptides are involved in numerous brain activities being responsible for a wide spectrum of higher mental functions. The purpose of this concise, structural and qualitative investigation was to map the possible immunoreactivity of the novel neuropeptide spexin (SPX) within the human magnocellular hypothalamus. SPX is a newly identified peptide, a natural ligand for the galanin receptors (GALR) 2/3, with no molecular structure similarities to currently known regulatory factors. SPX seems to have multiple physiological functions, with an involvement in reproduction and food-intake regulation recently revealed in animal studies. For the first time we describe SPX expressing neurons in the supraoptic (SON) and paraventricular (PVN) nuclei of the human hypothalamus using immunohistochemical and fluorescent methods, key regions involved in the mechanisms of osmotic homeostasis, energy expenditure, consummatory behaviour, reproductive processes, social recognition and stress responses. The vast majority of neurons located in both examined neurosecretory nuclei show abundant SPX expression and this may indirectly implicate a potential contribution of SPX signalling to the hypothalamic physiology in the human brain.

Introduction

The hypothalamus is a unique brain structure that plays a fundamental role in the origin and integration of central autonomous functions. This includes precise regulation of food intake, osmotic homeostasis, circadian rhythm, reproductive processes, thermoregulation, cardiovascular physiology and even aspects of affective activities. The potential role of hypothalamic related pathways in the origin of several neuropsychiatric dysfunctions is also widely postulated.

Spexin (SPX) is a newly discovered multifunctional neuropeptide acting at both central and peripheral levels. SPX was identified in 2007 by Mirabeau and colleagues (2007) as a transcript of the Ch12orf39 gene. In the rat brain, SPX-expressing neurons have been detected with the highest expression being in the hypothalamic magnocellular nuclei (Porzionato et al., 2010). The chemical structure of SPX is distinctly conserved among species, the rat molecule differs from the human form by only one C-terminal amino acid (Porzionato et al., 2010). SPX is an alternative endogenous ligand for the GALR2/3 receptors, with even higher affinity toward GALR3 than galanin itself (Kim et al. 2014). SPX has recently been linked to multiple physiological functions such as reproduction, food-intake regulation (Ma et al., 2018, Wong et al. 2013), cardiovascular/renal function and nociception (Toll et al., 2012; Porzionato et al., 2012). Due to potent anorexigenic properties of SPX, it has been suggested that a potential excess in hypothalamic SPX signalling may be involved in the pathogenesis of anorexia nervosa (Pałasz et al., 2018). A recent study therefore suggests a possible application of SPX for obesity therapy (Walewski et al., 2014). Supporting this, glucose-triggered insulin secretion may increase SPX gene expression in the goldfish brain (Ma et al. 2017). A role of SPX as a potential biomarker of glucose metabolism in humans has been also suggested (Hodges et al., 2018). Despite the accumulating animal studies on SPX biology, its distribution and physiology are so far lacking within the human brain. To date, there is no information available about spexin chemoarchitecture in the human hypothalamus. In the present study we aim to provide a structural investigation of the human hypothalamus to reveal the first outline for the neurochemical map of SPX expression within the neurosecretory magnocellular nuclei, allowing a potential deeper mechanistic understanding of SPX biology to aid future therapeutic study.