Significance of the orexinergic system in modulating stress-related responses in an animal model of post-traumatic stress disorder

Shlomi Cohen,Hagit Cohen,Joseph Zohar,Ella Vainer,Michael A. Matar,Zeev Kaplan

doi:10.1038/s41398-020-0698-9

Shlomi Cohen, Hagit Cohen + Show 4 more

Open Access

https://doi.org/10.1038/s41398-020-0698-9

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Abstract

Converging evidence indicates that orexins (ORXs), the regulatory neuropeptides, are implicated in anxiety- and depression-related behaviors via the modulation of neuroendocrine, serotonergic, and noradrenergic systems. This study evaluated the role of the orexinergic system in stress-associated physiological responses in a controlled prospective animal model. The pattern and time course of activation of hypothalamic ORX neurons in response to predator-scent stress (PSS) were examined using c-Fos as a marker for neuronal activity. The relationship between the behavioral response pattern 7 days post-exposure and expressions of ORXs was evaluated. We also investigated the effects of intracerebroventricular microinfusion of ORX-A or almorexant (ORX-A/B receptor antagonist) on behavioral responses 7 days following PSS exposure. Hypothalamic levels of ORX-A, neuropeptide Y (NPY), and brain-derived neurotrophic factor (BDNF) were assessed. Compared with rats whose behaviors were extremely disrupted (post-traumatic stress disorder [PTSD]-phenotype), those whose behaviors were minimally selectively disrupted displayed significantly upregulated ORX-A and ORX-B levels in the hypothalamic nuclei. Intracerebroventricular microinfusion of ORX-A before PSS reduced the prevalence of the PTSD phenotype compared with that of artificial cerebrospinal fluid or almorexant, and rats treated with almorexant displayed a higher prevalence of the PTSD phenotype than did untreated rats. Activated ORX neurons led to upregulated expressions of BDNF and NPY, which might provide an additional regulatory mechanism for the modulation of adaptive stress responses. The study indicates that the activated ORX system might promote adaptive responses to PSS probably via stimulation of BDNF and NPY secretion, and early intervention with ORX-A reduces the prevalence of the PTSD phenotype and increases the prevalence of adaptive phenotypes. The findings provide some insights into the mechanisms underlying the involvement of the ORX system in stress-related disorders.

Highlights

Orexins (ORXs; called hypocretins), which are neuropeptides derived from the prepro-orexin precursor by post-translational proteolytic cleavage, are exclusively localized in the lateral and posterior hypothalamic nuclei[1,2]
An increased number of c-Fos-positive nuclei was observed in the paraventricular nucleus (PVN) and lateral hypothalamus (LH) in rats exposed to predator-scent stress (PSS) (Fig. 1)
Greater activation of orexin neurons in the hypothalamic nuclei was correlated with minimal response phenotypes (MBR) and lesser activation of orexin neurons in the hypothalamic nuclei was correlated with post-traumatic stress disorder (PTSD) phenotype (EBR). (3) The blockade of the ORX receptor exacerbated the behavioral effects of PSS, indicating a protective role of the endogenous ORXergic system

Summary

Introduction

Orexins (ORXs; called hypocretins), which are neuropeptides derived from the prepro-orexin precursor by post-translational proteolytic cleavage, are exclusively localized in the lateral and posterior hypothalamic nuclei[1,2]. ORX1R has a tenfold greater affinity for ORX-A than for ORX-B, whereas ORX2R has nearly equal affinity for both neuropeptides[2]. ORX neurons receive functional inputs from multiple systems distributed in the cortex, limbic system, and subcortical areas (including the hypothalamus and thalamus) and ascending projections from the brain stem cholinergic nuclei, reticular formation, midbrain raphe nuclei, and periaqueductal gray[1]. These ORX neurons project throughout the central nervous system[3,4,5,6,7].

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