Critical Periods of Experience-dependent Brain Plasticity: From Early Development to Old Age

大脑可塑性，或神经可塑性，指的是大脑在不断变化的环境中经历变化的能力。早期大脑发育的标志是大脑对新体验特别适应的关键时期。关键时期的早期生活压力(ELS)被认为是决定大脑发育的唯一最有力的因素，并产生持久的后果。我由NSERC资助的研究表明，ELS对大脑的可塑性能力和行为进行了编程，贯穿一生，甚至跨越几代人。我提出了压力脆弱性理论，指出关键时期的压力取决于年龄、性别、遗传和表观遗传因素，决定了大脑的可塑性和未来几代人的行为，以确定个人的应激脆弱性和韧性。*我的跨学科和翻译研究计划将使用先进的高分辨率技术，在大脑可塑性和行为的基础研究中识别依赖活动的应激反应的生理、代谢、遗传和表观遗传调节因素。首要目标是确定大脑可塑性从早期发育到老年和跨代的依赖于经验的决定因素。我们将在实验模型中研究三个具体的假设。*假设1：应激脆弱性改变大脑发育的关键时期。我们将研究ELS如何改变大脑发育、神经连接和行为结果的机制。*假设2：内在因素计划在应激脆弱性中的个体间差异。我们将考察内在因素，如年龄、性别和潜在的可遗传表观遗传标记，在多大程度上决定大脑可塑性和行为对ELS的反应。*假设3：应激脆弱性和大脑可塑性是由跨代遗传编程的。我们将研究ELS如何不同地影响下一代的神经可塑性和行为特征。*意义：这里提出的研究神经可塑性的多学科研究方法将显著促进对大脑发育和脑老化的经验依赖性调节的神经生物学机制的理解。由于经验依赖的大脑可塑性反映在多水平的生物学特征中，这项工作将为分子神经可塑性调节提供新的见解。我的长期愿景是了解跨代表观遗传如何塑造神经和行为的可塑性。这项研究将产生新的生物标记组学技术，这些技术将对当前和未来的技术趋势产生影响。

Brain plasticity, or neuroplasticity, refers to the brain's ability to change as a result of experience in a changing environment. Early brain development is marked by critical periods during which the brain is particularly adaptable to new experiences. Early life stress (ELS) during critical periods is considered the single most potent factor in determining brain development with lasting consequences. My NSERC-funded work has demonstrated that ELS “programs” the brain's plastic capacity and behaviour throughout life and even across generations. I developed the STRESS VULNERABILITY THEORY stating that stress during critical periods determines brain plasticity and behaviour across the lifespan and in subsequent generations depending on age, sex, genetic and epigenetic factors, to determine individual stress vulnerability and resilience.**** My INTERDISCIPLINARY and TRANSLATIONAL research program will use advanced, high-resolution technologies to identify activity-dependent physiological, metabolic, genetic and epigenetic regulators of stress response in fundamental studies of brain plasticity and behavior. The OVERARCHING GOAL is to identify experience-dependent determinants of brain plasticity from early development to old age and across generations. We will investigate three specific hypotheses in experimental models.**** HYPOTHESIS 1: Stress Vulnerability Shifts Critical Periods of Brain Development. We will examine mechanisms how ELS alters brain development, neural connectivity and behavioural outcome.**** HYPOTHESIS 2: Intrinsic Factors Program Inter-individual Variation in Stress Vulnerability. We will examine the degree to which intrinsic factors, such as such as age, sex, and potentially heritable epigenetic markers, determine the response to ELS in terms of brain plasticity and behaviour.**** HYPOTHESIS 3: Stress Vulnerability and Brain Plasticity are Programmed by Transgenerational Inheritance. We will examine how ELS differentially affects neuroplasticity and behavioural traits in subsequent generations.**** SIGNIFICANCE: The multidisciplinary research approach to the study of neuroplasticity proposed here will significantly advance the understanding of neurobiological mechanisms of experience-dependent regulation of brain development and brain aging. Because experience-dependent brain plasticity is reflected in multi-level biological signatures, this work will provide novel insights into molecular neuroplasticity regulators. My LONG-TERM VISION is to understand how transgenerational epigenetic inheritance shapes neural and behavioural plasticity. This research will generate new biomarker omics technologies that will have an impact on current and future technology trends.*********