Stress resilience by natural rewards: neurocircuit mechanisms

项目摘要 参与愉快的消遣活动(例如，爱好、运动和其他休闲活动)可以改善情绪和 减少感知到的压力，这表明这些活动是增强压力韧性的有效手段。 慢性压力往往是不可避免的，这使得制定增强压力韧性的策略变得清晰起来 优先预防或改善与压力有关的疾病。因为有益行为可能会促进 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 采用间歇性获得自然奖赏、限制蔗糖摄入量(LSI)的方法建立压力缓冲大鼠模型。大规模集成电路 减少慢性压力的不良行为影响(例如，社交能力降低和威胁评估)和 降低下丘脑-垂体-肾上腺皮质轴的反应性。LSI提供的压力缓冲是 通过无热量甜味剂和其他自然奖励行为(性行为)繁殖，但不是通过 灌胃蔗糖，支持LSI的应激保护作用主要是由于其 物有所值。我们的初步数据表明，LSI通过改变自上而下的 杏仁基底外侧核(BLA)位于前内侧前额叶皮质(PL MPFC)。此外，BLA预测 神经元可以根据其不同的传出投射位置分为多个子集，并可以发挥作用 在血乳酸相关行为中扮演不同的角色。因此，虽然LSI减少了总的应激诱导的神经元激活(CFO) 在BLA中，对不同的BLA PN种群的影响可能是其在应激恢复中的作用。在支持中 根据这一想法，LSI减少了应激后海马腹侧(VHPC)中CFos的表达，并增加了 终纹背侧前床核(AdBST)--两个直接接受BLA输入的区域 并对与压力相关的行为产生相反的影响。这表明，LSI可能通过以下方式提供压力恢复能力 降低BLA-vHPC直接投射活性，增加直接BLA-adBST活性 投射。因此，该建议使用LSI模型来检验以下假设： 自然奖赏体验通过改变压力奖赏来提高对慢性压力的行为韧性 连接mPFC、BLA、vHPC和adBST的神经回路。第一个目标是检验物流自上而下的贡献 调节血乳酸，而第二个目的是测试特定血乳酸预测对vHPC的贡献，以及 AdBST。化学遗传学(DREADD)技术与逆转录病毒方法相结合，获得了电路- 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 威胁评估行为是在慢性压力和/或奖励(LSI)的背景下进行评估的。这项工作有 重要的暗示，表明内源性神经回路的存在可以缓冲压力 通过从事自然奖励行为而被招募的。对这些神经回路的更好的理解 可以利用这些机制来开发治疗策略，将慢性疾病的不良影响降至最低 压力对心理健康的影响，并可指导优化缓解压力的替代干预措施。

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.