Sex differences in the dynamic epigenetic regulation of learning and memory.

学习和记忆的动态表观遗传调控的性别差异。

• 批准号: RGPIN-2018-04638
• 负责人: Perreault, Melissa
• 金额: $ 2.11万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761160
• 关键词: Sex; differences; dynamic; epigenetic; regulation

Males and females are physiologically different, and often exhibit distinct behavioural responses to environmental stimuli. Yet, there is a significant lack of knowledge regarding how the sexes differ in the biological mechanisms that regulate behaviour, a deficit that can likely be attributed to the large focus on male responses in preclinical research. As a result, innate sex differences in gene regulation, cell signaling, and brain systems communication mechanisms that underlie behavior have been poorly characterized. Thus, the long-term objective of this research program is to evaluate sex differences in the dynamic neurobiological changes, from the gene up to the system, that regulate behaviour. Animal behavior serves as a bridge between the molecular and physiological aspects of biology with the environment, and plays a critical role in biological adaptations. It is known that while salient stimuli can result in long-term stable biological changes, they can also induce dynamic changes of shorter duration, both processes of which play pivotal roles in behavioural variation. A key principle that has recently emerged from behavioural neuroscience research is that is that dynamic changes in the epigenetic regulation of gene expression in response to environmental stimuli play a critical role in the manifestation of specific behaviours, such as learning and memory. There is an almost complete lack of knowledge, however, regarding sex differences in the epigenetic regulation of learning and memory processes. Therefore, aligning with the overall objective of the research program, in this proposal we will evaluate sex differences in the dynamic epigenetic changes that occur at the gene for brain derived neurotrophic factor (bdnf), a protein widely shown to positively contribute to learning and memory. Sex differences in temporal changes in histone acetylation will first be evaluated at various bdnf gene protomers in specific sub-regions of the prefrontal cortex and hippocampus during spatial and reversal learning. Next, we will evaluate the transient changes in bdnf mRNA expression in these brain sub-regions during learning, and assess DNA methylation patterns at specific bdnf promoters and associated exons. Finally, as neuronal communication within, and between, the prefrontal cortex and hippocampus are critical to learning and memory processes, we will evaluate how altering histone acetylation and DNA methylation in these regions impacts on neuronal oscillatory activity during learning in male and female rats. The findings from this research will not only improve our knowledge of the fundamental differences between the male and female brain, but will also provide an additional level of understanding on how learning and memory may be differentially regulated in the two sexes.

男性和女性在生理上是不同的，并且通常对环境刺激表现出不同的行为反应。然而，人们对两性在调节行为的生物机制方面的差异知之甚少，这一缺陷可能是由于临床前研究过于关注男性的反应。因此，先天性别差异的基因调控，细胞信号，和大脑系统的通信机制，行为的基础已经很差的特点。因此，这项研究计划的长期目标是评估从基因到系统的动态神经生物学变化中的性别差异，这些变化调节行为。 动物行为是生物学的分子和生理方面与环境之间的桥梁，在生物适应中起着关键作用。众所周知，虽然显著刺激可以导致长期稳定的生物学变化，但它们也可以引起持续时间较短的动态变化，这两个过程在行为变化中起着关键作用。最近从行为神经科学研究中出现的一个关键原则是，对环境刺激作出反应的基因表达的表观遗传调节的动态变化在特定行为的表现中发挥关键作用，例如学习和记忆。然而，关于学习和记忆过程的表观遗传调节中的性别差异，几乎完全缺乏知识。因此，与研究计划的总体目标相一致，在本提案中，我们将评估发生在脑源性神经营养因子（bdnf）基因上的动态表观遗传变化的性别差异，bdnf是一种被广泛证明对学习和记忆有积极贡献的蛋白质。在空间和反向学习过程中，组蛋白乙酰化的时间变化的性别差异将首先在前额皮质和海马特定亚区的不同bdnf基因原体中进行评估。接下来，我们将评估学习过程中这些脑亚区bdnf mRNA表达的瞬时变化，并评估特定bdnf启动子和相关外显子的DNA甲基化模式。最后，由于前额叶皮层和海马内和之间的神经元通信对学习和记忆过程至关重要，我们将评估这些区域中组蛋白乙酰化和DNA甲基化的改变如何影响雄性和雌性大鼠学习过程中的神经元振荡活动。这项研究的发现不仅将提高我们对男性和女性大脑之间根本差异的认识，而且还将提供对两性学习和记忆如何差异调节的额外理解。