The Human Stress Response: Interaction of Life Stress History and Genetic Variation on Behavior, Brain Function, and the (Epi-)Genome

压力是一个广泛存在的社会问题，对一些脆弱的个体来说，它可能会带来巨大的健康成本，其中可能包括对大脑的损害和许多身心健康问题。然而，由于个体差异，很难预测谁更容易受到压力的不利影响。这些个体差异一定是由与压力相关的行为和反应有关的大脑回路产生的，这些行为和反应可能受到基因、个体生活经历以及基因和环境之间相互作用的共同变异的影响。这些相互作用是如何在人脑中发生的，目前尚不清楚。因此，该领域迫切需要一种综合的方法来研究基因与环境相互作用对人类行为、其介导的脑回路及其潜在的分子遗传机制。在美国国家科学基金会（National Science Foundation）的支持下，石溪大学（Stony Brook University）的图尔汉·坎利（Turhan Canli）博士及其同事将研究基因、生活压力和压力反应之间的相互作用。该项目包括对受试者进行分子基因分型，重点关注三种基因，这些基因被认为对应激反应中涉及的神经递质和激素级联反应很重要。遗传信息将与社会压力任务的行为反应相关联。遗传信息还将与大脑成像相关联，这将使研究人员能够看到特定大脑区域反应的个体差异如何受到遗传变异的影响。由于预期基因与环境的相互作用，生活史也将成为分析的一部分。最后，由于压力对大脑影响的主要理论预测了特定大脑区域的损伤，因此该研究还将涉及对死后人类大脑的分析，这些大脑来自已知生活史和基因图谱的个体。这个项目的意义在于，它将揭示影响健康、正常个体的脆弱性和复原力的遗传和环境因素。此外，本研究的预期结果将对创伤后应激障碍或抑郁症等情绪障碍具有重要意义。该项目在几个方面符合美国国家科学基金会的教育任务：该研究通过包括女性和/或少数民族学生来扩大代表性不足群体的参与。此外，该项目为遗传学和神经科学的交叉训练提供了独特的机会。

Stress is a widespread societal problem that can have dramatic health costs for some vulnerable individuals, which may include damage to the brain and numerous physical and mental health problems. Yet, individual differences make it difficult to predict who is vulnerable to the adverse effects of stress. These individual differences must be generated by brain circuits involved in stress-related behaviors and responses, which can be affected by common variations within genes, individuals' life experiences, and the interaction between gene and environment. How these interactions take place in the human brain is currently unknown. Thus, the field is in critical need of an integrated approach to the study of gene x environment interactions on human behavior, its mediating brain circuits, and its underlying molecular-genetic mechanisms. With support from the National Science Foundation, Dr. Turhan Canli and colleagues at Stony Brook University will examine the interaction between genes, life stress, and stress reactivity. The project involves molecular genotyping of subjects, with focus on three genes thought to be important for neurotransmitter and hormonal cascades involved in stress reactivity. Genetic information will be correlated with behavioral response on a well-characterized social stress task. The genetic information will also be correlated with brain imaging, which will allow the researchers to see how individual differences in the response of specific brain regions are influenced by genetic variation. Because gene x environment interactions are expected, life history will also be a part of the analysis. Lastly, because leading theories of the effects of stress on the brain predict damage in particular brain regions, the research will also involve an analysis of postmortem human brains, from individuals with known life histories and genetic profiles.This project's significance is that it will reveal much about the genetic and environmental factors that affect vulnerability and resilience in healthy, normal individuals. Furthermore, the anticipated findings from this research will have important implications for mood disorders such as post-traumatic stress disorder or depression. This project meets the educational mandate of NSF in several ways: The research broadens participation by underrepresented groups by including students who are female and/or minorities. Moreover, the project presents a unique opportunity for cross-training in genetics and neuroscience.