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

经验依赖性大脑可塑性的关键时期：从早期发育到老年

• 批准号: RGPIN-2019-05628
• 负责人: Metz, Gerlinde
• 金额: $ 5.68万
• 依托单位: University of Lethbridge
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=738411
• 关键词: Critical; Periods; Experience; dependent; Brain

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.

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因经历而改变的能力。早期大脑发育的关键时期是大脑特别适应新体验的时期。关键时期的早期生活压力（ELS）被认为是决定大脑发育和持久影响的最有效因素。我在nserc资助下的研究表明，ELS“编程”了大脑在一生甚至几代人之间的可塑性和行为。我发展了应激脆弱性理论，该理论指出，关键时期的压力决定了大脑的可塑性和一生中的行为，并根据年龄、性别、遗传和表观遗传因素决定了后代的行为，从而决定了个体的应激脆弱性和恢复能力。我的跨学科和转化研究项目将使用先进的高分辨率技术来识别大脑可塑性和行为基础研究中应激反应的活动依赖生理、代谢、遗传和表观遗传调节因子。总体目标是确定从早期发育到老年和跨代的大脑可塑性的经验依赖决定因素。我们将研究实验模型中的三个具体假设。假设1：压力易感性改变了大脑发育的关键时期。我们将研究ELS如何改变大脑发育、神经连通性和行为结果的机制。假设2：内在因素导致压力易感性的个体差异。我们将研究年龄、性别和潜在可遗传的表观遗传标记等内在因素在多大程度上决定了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决定的。我们将研究ELS如何在后代中不同地影响神经可塑性和行为特征。意义：本文提出的神经可塑性研究的多学科研究方法将显著促进对经验依赖的脑发育和脑衰老调节的神经生物学机制的认识。由于经验依赖的大脑可塑性反映在多层次的生物特征中，这项工作将为分子神经可塑性调节因子提供新的见解。我的长期愿景是了解跨代表观遗传如何塑造神经和行为可塑性。这项研究将产生新的生物标志物组学技术，这将对当前和未来的技术趋势产生影响。