Stress resilience by natural rewards: neurocircuit mechanisms

项目摘要 参与愉快的消遣（例如，爱好，运动和其他休闲活动）可以改善情绪， 减少感知压力，这表明这些活动是一种有效的手段，赋予压力弹性。 慢性压力往往是不可避免的，这使得发展战略，以提高压力的弹性， 优先预防或改善与压力有关的疾病。由于有益的行为可能会促进 通过激活大脑愉悦和奖励回路来缓冲压力，我们已经开发并表征了一种 大鼠模型的压力缓冲使用间歇性访问的自然奖励，有限的蔗糖摄入量（LSI）。LSI 减少慢性压力的不利行为影响（例如，社交能力和威胁评估降低）， 降低下丘脑-垂体-肾上腺皮质轴反应性。LSI提供的压力缓冲是 通过无热量的甜味剂和其他自然奖励行为（性活动）复制，但不是通过 蔗糖灌胃，支持LSI的应激保护作用主要是由于其 奖励财产。我们的初步数据表明，LSI通过改变自上而下的调节， 基底外侧杏仁核（BLA）通过前边缘内侧前额叶皮层（PL mPFC）。此外，BLA投影 神经元可以根据其不同的传出投射部位分为多个子集， 在BLA相关行为中的不同角色。因此，虽然LSI减少了总应力诱导的神经元激活（cFos）， 在BLA中，对不同BLA PN群体的影响可能是其在压力恢复中的作用的基础。支持 根据这一观点，LSI减少了腹侧海马（vHPC）中应激后cFos的表达，并增加了海马中应激后cFos的表达。 终纹前背床核（adBST）-两个接受直接BLA输入的区域 并对压力相关行为产生相反的影响。这表明LSI可以通过以下方式提供压力恢复能力： 降低直接BLA-vHPC投射的活性，并增加直接BLA-adBST的活性 预测。因此，本提案使用LSI模型来检验长期参与的假设， 自然奖励的经历通过改变压力-奖励来促进对慢性压力的行为恢复力 连接mPFC、BLA、vHPC和adBST的神经回路。第一个目标是测试PL自上而下的贡献 第二个目标测试特定BLA预测对vHPC的贡献， adBST。化学发生（DREADD）技术与逆行病毒方法相结合，以获得电路- 神经活动的特定调节。回路操作（激活和抑制）对社交能力的影响 和威胁评估行为的背景下评估慢性压力和/或奖励（LSI）。这项工作 重要的影响，这表明存在内源性神经回路的压力缓冲，可以 通过参与自然奖励行为来招募。更好地理解这些神经回路 可以利用这些机制来开发治疗策略，以最大限度地减少慢性炎症的不良反应。 这可能会对优化缓解压力的替代干预措施起到指导作用。

Project Summary Engaging in pleasurable pastimes (e.g., hobbies, sports, and other leisure activities) can improve mood and reduce perceived stress, suggesting that these activities are an effective means to confer stress resilience. Chronic stress is often unavoidable, making the development of strategies to enhance stress resilience a clear priority for the prevention or amelioration of stress-related diseases. Since beneficial behaviors likely promote stress buffering via activation of brain pleasure and reward circuitry, we have developed and characterized a rat model of stress buffering using intermittent access to a natural reward, limited sucrose intake (LSI). LSI reduces the adverse behavioral effects of chronic stress (e.g., diminished sociability and threat appraisal) and decreases hypothalamic-pituitary-adrenocortical axis reactivity. The stress-buffering provided by LSI is reproduced by a noncaloric sweetener and other naturally rewarding behaviors (sexual activity), but not by intragastric gavage of sucrose, supporting that the stress-protective effects of LSI are primarily due to its rewarding properties. Our preliminary data suggest that LSI acts by altering top-down regulation of the basolateral amygdala (BLA) by the prelimbic medial prefrontal cortex (PL mPFC). In addition, BLA projection neurons can be divided into multiple subsets based on their distinct efferent projection sites, and can play distinct roles in BLA-related behaviors. Thus, while LSI reduces total stress-induced neuronal activation (cFos) in the BLA, the impact on distinct BLA PN populations will likely underlie its role in stress resilience. In support of this idea, LSI reduces post-stress cFos expression in the ventral hippocampus (vHPC) and increases it in the anterodorsal bed nucleus of the stria terminalis (adBST) – two regions that have receive direct BLA input and exert opposing effects on stress-related behaviors. This suggests that LSI may provide stress resilience by reducing the activity of direct BLA-vHPC projections, and increasing the activity of direct BLA-adBST projections. This proposal therefore uses the LSI model to test the hypothesis that chronic engagement in naturally rewarding experiences promotes behavioral resilience to chronic stress by altering a stress-reward neurocircuitry linking the mPFC, BLA, vHPC and adBST. The first aim tests the contribution of PL top-down regulation of the BLA, while the second aim tests the contribution of specific BLA projections to the vHPC and adBST. Chemogenetic (DREADD) technology is combined with a retrograde viral approach to obtain circuit- specific modulation of neural activity. The effects of circuit manipulation (activation and inhibition) on sociability and threat appraisal behaviors is assessed in the context of chronic stress and/or reward (LSI). This work has important implications, suggesting the presence of endogenous neurocircuits for stress buffering that can be recruited by engaging in naturally-rewarding behaviors. An improved understanding of these neurocircuit mechanisms may be leveraged to develop therapeutic strategies that minimize the adverse effects of chronic stress on mental health, and may guide the optimization of alternative interventions for stress relief.