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

大脑可塑性或神经可塑性是指大脑在不断变化的环境中因经验而变化的能力。大脑早期发育的特点是大脑特别适应新经验的关键时期。在关键时期的早期生活压力（ELS）被认为是决定大脑发育的最有效因素，具有持久的后果。我的NSERC资助的工作已经证明，ELS“程序”大脑的可塑性能力和行为在整个生命，甚至跨代。我开发了压力脆弱性理论，指出在关键时期的压力决定了整个生命周期和后代的大脑可塑性和行为，这取决于年龄，性别，遗传和表观遗传因素，以确定个人的压力脆弱性和弹性。 我的跨学科和翻译研究计划将使用先进的，高分辨率的技术，以确定活动依赖的生理，代谢，遗传和表观遗传调节压力反应在大脑可塑性和行为的基础研究。总体目标是确定从早期发育到老年以及跨代的大脑可塑性的经验依赖性决定因素。我们将研究实验模型中的三个具体假设。 假设1：压力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：内在因素程序在压力脆弱性个体间的变化。我们将研究内在因素，如年龄，性别和潜在的可遗传表观遗传标记，在大脑可塑性和行为方面决定对ELS的反应的程度。 假设3：压力脆弱性和大脑可塑性是由跨代遗传编程的。我们将研究ELS如何不同地影响后代的神经可塑性和行为特征。 重要性：本文提出的神经可塑性研究的多学科研究方法将大大推进对大脑发育和大脑衰老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层次的生物特征，这项工作将提供新的见解分子神经可塑性调节。我的长期愿景是了解跨代表观遗传如何塑造神经和行为可塑性。这项研究将产生新的生物标志物组学技术，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.*********