GHS-R1a Deficiency Alleviates Depression-Related Behaviors After Chronic Social Defeat Stress

Li Guo,Jie Yang,Yu Zhou,Zhishang Zhou,Shuhan Liu,Minglu Niu,Yuxiang Sun,Li Li

doi:10.3389/fnins.2019.00364

Abstract

Ghrelin is an important orexigenic hormone that regulates feeding, metabolism and glucose homeostasis in human and rodents. Ghrelin functions by binding to its receptor, the growth hormone secretagogue receptor 1a (GHS-R1a), which is widely expressed inside and outside of the brain. Recent studies suggested that acyl-ghrelin, the active form of ghrelin, is a persistent biomarker for chronic stress exposure. However, how ghrelin/GHS-R1a signaling contributes to stress responses and mood regulation remains uncertain. In this study, we applied the chronic social defeat stress (CSDS) paradigm to both GHS-R1a knock-out (Ghsr-/-) mice and littermate control (Ghsr+/+) mice, and then measured their depression- and anxiety-related behaviors. We found that Ghsr+/+ mice, but not Ghsr-/- mice, displayed apparent anxiety and depression after CSDS, while two groups mice showed identical behaviors at baseline, non-stress state. By screening the central and peripheral responses of Ghsr-/- mice and Ghsr+/+ mice to chronic stress, we found similar elevations of total ghrelin and adrenocorticotropic hormone (ACTH) in the serum of Ghsr-/- mice and Ghsr+/+ mice after CSDS, but decreased interleukin-6 (IL-6) in the serum of defeated Ghsr-/- mice compared to defeated Ghsr+/+ mice. We also found increased concentration of brain derived neurotropic factor (BDNF) in the hippocampus of Ghsr-/- mice compared to Ghsr+/+ mice after CSDS. The basal levels of ghrelin, ACTH, IL-6, and BDNF were not different between Ghsr-/- mice and Ghsr+/+ mice. Our findings thus suggested that the differential expressions of BDNF and IL-6 after CSDS may contribute to less anxiety and less despair observed in GHS-R1a-deficient mice than in WT control mice. Therefore, ghrelin/GHS-R1a signaling may play a pro-anxiety and pro-depression effect in response to chronic stress, while GHS-R1a deficiency may provide resistance to depressive symptoms of CSDS.

Highlights

Ghrelin is a 28-amino-acid peptide hormone which is principally synthesized in the stomach and normally associated with feeding behavior and energy homeostasis (Kojima et al, 1999)
The percentage of light box entries were similar as well between two groups of mice (Figure 1F; unpaired t-test, t = 0.4, P > 0.05). All these results indicated that Ghsr−/− mice had normal locomotor activity, same baseline anxiety as Ghsr+/+ mice
The Social interaction (SI) test indicated normal sociability of Ghsr−/− mice, as they exhibited same social interaction time as Ghsr+/+ mice (Figure 1I; unpaired t-test, t = 0.5, P > 0.05). All these findings demonstrated that growth hormone secretagogue receptor 1a (GHS-R1a) deficiency did not affect anxiety- and depression-like behaviors at baseline state without chronic stress exposure

Summary

Introduction

Ghrelin is a 28-amino-acid peptide hormone which is principally synthesized in the stomach and normally associated with feeding behavior and energy homeostasis (Kojima et al, 1999). Recent studies highlight that ghrelin and GHS-R1a play complex roles in the regulation of a diverse number of brain functions, including hunger and metabolism, learning and memory, reward and addiction, motivation, stress responses, anxiety, and depression (Muller et al, 2015; Spencer et al, 2015). Ghrelin was reported to both promote (Carlini et al, 2002, 2004; Hansson et al, 2011; Currie et al, 2012; Spencer et al, 2012; Meyer et al, 2014) and alleviate (Lutter et al, 2008; Spencer et al, 2012; Jensen et al, 2016; Huang et al, 2017) anxietyand depression-like behaviors, a dual but disparate effect which may depends on both contextual states (for example, non-stress vs stress, acute vs chronic stress, mild vs strong stress) and physiological states (for example, food availability) of the animal (Spencer et al, 2015)

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