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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结