Embedding of Parental Experience within the Offspring Telencephalon

人生早期的不良经历可以极大地改变一个人日后健康问题的风险；然而，我们对这种关系究竟是如何形成的理解仍然很差。因此，这项拟议的研究计划旨在探索父母经历的压力如何影响大脑中那些已知对创造新记忆至关重要的区域的发育。我们已经表明，出生前的逆境(以母亲肥胖的形式)和童年时期的逆境(以社交隔离的形式)都能“深入”影响大脑发育，特别是在海马体(一个对记忆形成很重要的区域)。例如，我们发现肥胖母亲的后代在空间学习的某些行为指标上表现出与年龄和性别相关的显著障碍，而早期的社会隔离在不改变空间记忆的情况下影响某些可塑性相关蛋白质的表达。*研究目标*这项工作的长期目标将是继续建立一个研究计划，使用“细胞-行为”的观点来研究各种形式的早期生活经历如何影响大脑发育。*指导当前提议的短期目标是：*1)研究生命不同阶段的心理社会压力如何影响蛋白质、细胞过程、和与记忆形成相关的行为。*2)扩大我们的视野，考虑父亲的逆境可能对大脑发育产生的作用。*3)调查父母的逆境如何影响海马体和前额叶皮质(另一个重要的调节学习和记忆的区域)。*根据所述的目标，该提案将：*1)描述继发性创伤应激模型对成人大脑的影响。我们将检测可塑性相关蛋白的变化，可塑性的电生理测量，以及雄性和雌性大鼠的行为表型。*2)检测父母暴露在继发性创伤应激下对后代大脑的影响。雄性大鼠(在受孕前)和雌性大鼠(在怀孕的不同阶段)将经历压力，后代将在不同的年龄接受检查。*3)探索早期生活中的逆境是否提高了面对成年应激源的弹性。在怀孕期间，雌性大鼠将经历标准的住房条件，或暴露在继发性创伤应激中，它们的后代将继续经历类似的成年环境，或不匹配的成年环境。这项拟议的工作将扩大我们对早期逆境如何改变与记忆形成相关的大脑区域发育的理解。此外，解决复杂的翻译问题的机会，以及我们采用的“从细胞到行为”的方法，应该会提供一个独特的、有吸引力的学生培训环境。

GENERAL SUMMARY****Adverse experiences early in life can greatly alter a person's risk for health problems later in life; however, our understanding of exactly how this relationship takes shape remains poor. As a result, the proposed research programme aims to explore the way that stressors experienced by parents can affect the development of those areas of the brain known to be important for creating new memories.*******RECENT PROGRESS****We have shown that adversity both before birth (in the form of maternal obesity) and during childhood (in the form of social isolation) can “get under the skin” to affect brain development, particularly within the hippocampus (a region important to memory formation). For example, we discovered offspring of obese mothers show significant age and sex-related impairments in certain behavioural measures of spatial learning, and that early--life social isolation affects the expression of certain plasticity--related proteins without altering spatial memory.*******RESEARCH OBJECTIVES****The long-term objective of this work will be to continue building a research programme that uses a “cell to behaviour” perspective to examine how various forms of early-life experience affect brain development.****The short term objectives guiding the current proposal are to:****1) examine how psychosocial stress at different points in the lifespan affects proteins, cellular processes, and behaviours related to memory formation.****2) expand our view to consider the role that paternal adversity may have upon brain development.****3) investigate the way in which parental adversity affects both the hippocampus and the pre-frontal cortex (another area important for mediating learning and memory).*******SUMMARY OF PLANNED EXPERIMENTS****Following from the stated objectives, the proposal will:****1) Characterise the effect that a model of secondary traumatic stress can have upon the adult brain. We will examine changes in plasticity-related proteins, electrophysiological measures of plasticity, and the behavioural phenotype of male and female rats.****2) Examine the influence that parental exposure to secondary traumatic stress may have upon the offspring brain. Male rats (before conception) and female rats (at different stages of pregnancy) will experience stress, and offspring will be examined at different ages.****3) Explore whether early-life adversity enhances resiliency in the face of an adult stressor. During gestation, female rats will experience either standard housing conditions, or exposure to secondary traumatic stress and their offspring will go on to experience either a similar adult environment, or a mismatched one.*******EXPECTED SIGNIFICANCE****The proposed work will expand our understanding of how early-life adversity alters the development of brain regions related to memory formation. In addition, the opportunity to tackle complex, translational questions, and our adoption of a “cell to behaviour” approach, should provide a unique and engaging student training environment.*********