Stress resilience by natural rewards: neurocircuit mechanisms

通过自然奖励增强压力恢复能力：神经回路机制

• 批准号: 10669656
• 负责人: James P Herman
• 金额: $ 57.71万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-11 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669656
• 关键词: Acute; Address; Adverse effects; Affect; Amygdaloid structure; Anatomy; Anxiety; Axon; Bayesian Modeling; Behavior; Behavioral; Brain; Buffers; Cheese; Chronic; Chronic stress; Consumption; Data; Depressed mood; Development; Disease; Down-Regulation; Eating; Emotions; Event; Exploratory Behavior; Feeling; Food; Generations; Genetic; Hippocampus; Hobbies; Hypothalamic structure; Intake; Intervention; Leisure Activities; Lesion; Link; Medial; Mediating; Mental Depression; Mental Health; Metabolic; Modeling; Mood Disorders; Moods; Muscimol; Neurons; Outcome; Pathway interactions; Pattern; Pituitary Gland; Play; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Prevention; Property; Rattus; Reproducibility; Rewards; Risk; Risk Factors; Role; Saccharin; Schedule; Sex Behavior; Site; Social Interaction; Sports; Stress; Structure of terminal stria nuclei of preoptic region; Sucrose; Sweetening Agents; Technology; Testing; Therapeutic; Viral; Withdrawal; Work; acute stress; biological adaptation to stress; brain reward regions; designer receptors exclusively activated by designer drugs; experience; health management; hypothalamic-pituitary-adrenal axis; improved; mind/body; negative mood; neural; neural circuit; obesogenic; perceived stress; pharmacologic; pleasure; positive emotional state; preference; prevent; promote resilience; protective effect; public health priorities; recruit; resilience; response; reward circuitry; skills; social; stress management; stress reduction; stress resilience

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.

项目摘要 从事愉快的过去时间（例如，爱好，运动和其他休闲活动）可以改善情绪和 减少感知的压力，表明这些活动是赋予压力弹性的有效手段。 慢性压力通常是不可避免的，这使得增强压力弹性的策略变得清晰 预防或改善应激相关疾病的优先级。由于有益的行为可能会促进 通过激活大脑愉悦和奖励电路的压力缓冲，我们已经开发并表征了 使用自然奖励，有限的蔗糖摄入量（LSI）的大鼠压力缓冲模型。 减少了慢性压力的不利行为影响（例如，社交性和威胁评估降低）和 下丘脑 - 垂体 - 肾上腺皮质轴反应性的降低。 LSI提供的压力缓冲是 由非钙化甜味剂和其他自然奖励行为（性活动）重现，但不是 蔗糖的胃内膨胀性，支持LSI的压力保护作用主要是由于其 奖励特性。我们的初步数据表明，LSI通过改变自上而下的调节来起作用 基底外侧杏仁核（BLA）由前培养基前额叶皮层（PL MPFC）。此外，BLA投影 神经元可以根据其独特的有效投影位点分为多个子集，并且可以发挥作用 与BLA相关的行为中的独特作用。尽管LSI减少了总应激诱导的神经元激活（CFO） 在BLA中，对不同BLA PN种群的影响可能是其在压力弹性中的作用。支持 在这个想法中，LSI减少了腹侧海马（VHPC）中的压力后CFOS表达，并将其增加 Stria末端（ADBST）的前侧床核 - 两个接收直接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可以通过 减少直接BLA-VHPC项目的活动，并增加直接BLA-ADBST的活动 项目。因此，该提案使用LSI模型来检验以下假设。 自然奖励的经历通过改变压力回报来促进对慢性压力的行为韧性 将MPFC，BLA，VHPC和ADBST连接的神经记录。第一个目标测试PL自上而下的贡献 BLA的调节，而第二个目标测试了特定BLA项目对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。电路操纵（激活和抑制）对社交性的影响 在慢性压力和/或奖励（LSI）的背景下，评估了威胁评估行为。这项工作有 重要的含义，表明存在内源性神经环节应力缓冲可能是 通过从事自然奖励行为来招募。对这些神经电路的改进理解 可以利用机制来制定理论策略，以最大程度地减少慢性的不利影响 对心理健康的压力，并可能指导优化减轻压力的替代干预措施。