Data_Sheet_6_Reward enhances resilience to chronic social defeat stress in mice: Neural ECs and mGluR5 mechanism via neuroprotection in VTA and DRN.ZIP

IntroductionStress often leads to emotional disorders such as depression. The reward might render this effect through the enhancement of stress resilience. However, the effect of reward on stress resilience under different intensities of stress needs more evidence, and its potential neural mechanism has been poorly revealed. It has been reported that the endogenous cannabinoid system (ECs) and downstream metabolic glutamate receptor 5 (mGluR5) are closely related to stress and reward, which might be the potential cerebral mechanism between reward and stress resilience, but there is a lack of direct evidence. This study aims to observe the effect of reward on stress resilience under different intensities of stress and further explore potential cerebral mechanisms underlying this effect.
MethodsUsing the chronic social defeat stress model, we applied reward (accompanied by a female mouse) under different intensities of stress in mice during the modeling process. The impact of reward on stress resilience and the potential cerebral mechanism were observed after modeling through behavioral tests and biomolecules.
ResultsThe results showed that stronger stress led to higher degrees of depression-like behavior. Reward reduced depression-like behavior and enhanced stress resilience (all p-value <0.05) (more social interaction in the social test, less immobility time in the forced swimming test, etc.), with a stronger effect under the large stress. Furthermore, the mRNA expression levels of CB1 and mGluR5, the protein expression level of mGluR5, and the expression level of 2-AG (2-arachidonoylglycerol) in both ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) were significantly upregulated by reward after modeling (all p-value <0.05). However, the protein expression of CB1 in VTA and DRN and the expression of AEA (anandamide) in VTA did not differ significantly between groups. Intraperitoneal injection of a CB1 agonist (URB-597) during social defeat stress significantly reduced depression-like behavior compared with a CB1 inhibitor (AM251) (all p-value <0.05). Interestingly, in DRN, the expression of AEA in the stress group was lower than that of the control group, with or without reward (all p-value <0.05).
DiscussionThese findings demonstrate that combined social and sexual reward has a positive effect on stress resilience during chronic social defeat stress, potentially by influencing the ECs and mGluR5 in VTA and DRN.

引言
应激常可引发抑郁等情感障碍。奖赏或可通过提升应激抵抗能力（stress resilience）来逆转这一效应。然而，不同应激强度下奖赏对机体应激抵抗能力的影响仍需更多证据支撑，其潜在的神经机制亦尚未得到充分阐明。已有研究表明，内源性大麻素系统（endogenous cannabinoid system, ECs）及其下游代谢型谷氨酸受体5（metabotropic glutamate receptor 5, mGluR5）与应激和奖赏过程密切相关，二者或为连接奖赏与应激抵抗能力的潜在脑内机制，但目前尚缺乏直接实验证据。本研究旨在观察不同应激强度下奖赏对机体应激抵抗能力的影响，并进一步探究该效应背后的潜在脑内机制。

方法
本研究采用慢性社交挫败应激模型，在小鼠造模过程中施加不同强度的应激，并同步给予奖赏（即伴随雌性小鼠接触）。造模结束后，通过行为学实验与生物分子检测，观察奖赏对应激抵抗能力的影响及其潜在脑内机制。

结果
结果显示，应激强度越高，小鼠的抑郁样行为程度越显著。奖赏可减轻小鼠的抑郁样行为并提升其应激抵抗能力（所有比较的P值均<0.05），具体表现为社交实验中社交互动时长增加、强迫游泳实验中不动时间缩短等，且在高强度应激下该改善效果更为显著。此外，造模后奖赏可显著上调腹侧被盖区（ventral tegmental area, VTA）与中缝背核（dorsal raphe nucleus, DRN）中CB1与mGluR5的mRNA表达水平、mGluR5的蛋白表达水平，以及2-AG（2-花生四烯酰甘油, 2-arachidonoylglycerol）的含量（所有比较的P值均<0.05）。但各组间VTA与DRN中CB1的蛋白表达水平，以及VTA中AEA（花生四烯酸乙醇胺, anandamide）的含量均无显著差异。与CB1抑制剂AM251相比，在社交挫败应激过程中腹腔注射CB1激动剂URB-597可显著减轻小鼠的抑郁样行为（所有比较的P值均<0.05）。值得注意的是，无论是否给予奖赏，应激组小鼠DRN中的AEA含量均低于对照组（所有比较的P值均<0.05）。

讨论
本研究结果表明，在慢性社交挫败应激过程中，社交与性奖赏的联合干预可对机体应激抵抗能力产生积极影响，其潜在机制可能与调控VTA与DRN中的内源性大麻素系统及mGluR5表达相关。