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: 10428590
• 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/10428590
• 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; Hippocampus (Brain); Hobbies; Hypothalamic structure; Intake; Intervention; Leisure Activities; Lesion; Link; Medial; Mediating; Mental Depression; Mental Health; Metabolic; Modeling; Mood Disorders; Moods; Muscimol; Neurons; Outcome; Palate; Pathway interactions; Pattern; Pharmacology; 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; base; biological adaptation to stress; body-mind; brain reward regions; designer receptors exclusively activated by designer drugs; experience; health management; hypothalamic-pituitary-adrenal axis; improved; negative mood; neural circuit; obesogenic; perceived stress; pleasure; positive emotional state; preference; prevent; protective effect; public health priorities; recruit; relating to nervous system; resilience; response; reward circuitry; skills; social; stress management; 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.

项目概要 从事愉快的消遣活动（例如爱好、运动和其他休闲活动）可以改善情绪和 减少感知压力，表明这些活动是增强抗压能力的有效手段。 慢性压力往往是不可避免的，因此制定增强抗压能力的策略是一个明确的任务 优先预防或改善与压力相关的疾病，因为有益的行为可能会促进疾病的发生。 通过激活大脑愉悦和奖励电路来缓冲压力，我们开发并表征了 使用间歇性获得自然奖励、限制蔗糖摄入量（LSI）的大鼠压力缓冲模型。 减少慢性压力的不良行为影响（例如，社交能力和威胁评估减弱） 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 由无热量甜味剂和其他自然奖励行为（性活动）复制，但不是由 蔗糖灌胃，支持 LSI 的应激保护作用主要是由于其 我们的初步数据表明，LSI 通过改变自上而下的监管来发挥作用。 基底外侧杏仁核（BLA）由前边缘内侧前额皮质（PL mPFC）投射。 神经元可以根据其不同的传出投射部位分为多个子集，并且可以发挥作用 因此，LSI 可以减少压力诱导的神经激活 (cFos)。 在 BLA 中，对不同 BLA PN 人群的影响可能是其在压力恢复中的支持作用的基础。 根据这个想法，LSI 减少了腹侧海马 (vHPC) 中应激后 cFos 的表达，并增加了 终纹前背床核 (adBST) – 接收直接 BLA 输入的两个区域 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。 降低直接 BLA-vHPC 预测的活性，并增加直接 BLA-adBST 的活性 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弹性 连接 mPFC、BLA、vHPC 和 adBST 的神经回路 第一个目标测试 PL 自上而下的贡献。 BLA 的监管，而第二个目标测试特定 BLA 预测对 vHPC 的贡献和 adBST.化学遗传学（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（激活和抑制）对社交性的影响。 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。 重要的意义，表明存在用于压力缓冲的内源性神经回路，可以 通过参与自然奖励行为来加深对这些神经回路的理解。 可以利用机制来制定治疗策略，最大限度地减少慢性病的不利影响 压力对心理健康的影响，并可能指导优化缓解压力的替代干预措施。