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

雄性和雌性在生理上是不同的，通常对环境刺激表现出不同的行为反应。然而，对于性别在调节行为的生物机制上有何不同，人们严重缺乏了解，这一缺陷很可能归因于临床前研究中对男性反应的大量关注。因此，作为行为基础的基因调控、细胞信号和大脑系统通讯机制的先天性别差异一直没有得到很好的描述。因此，这项研究计划的长期目标是评估从基因到调节行为的系统的动态神经生物学变化中的性别差异。*动物行为在生物学的分子和生理方面与环境之间起着桥梁作用，在生物适应中发挥着关键作用。众所周知，虽然显著刺激可以导致长期稳定的生物变化，但它们也可以诱导持续时间较短的动态变化，这两个过程在行为变化中都发挥着关键作用。最近从行为神经科学研究中出现的一个关键原理是，基因表达的表观遗传调控对环境刺激的动态变化在特定行为的表现中发挥着关键作用，如学习和记忆。然而，在学习和记忆过程的表观遗传调控中，几乎完全缺乏关于性别差异的知识。因此，为了与研究计划的总体目标保持一致，在这项提案中，我们将评估脑源性神经营养因子(BDNF)基因发生的表观遗传动态变化中的性别差异，BDNF是一种被广泛证明对学习和记忆有积极贡献的蛋白质。在空间和反转学习过程中，组蛋白乙酰化时间变化的性别差异将首先在前额叶皮质和海马区特定亚区的不同BDNF基因原型上进行评估。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，由于前额叶皮质和海马区内部和之间的神经元通讯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期间的神经元振荡活动。这项研究的发现不仅将提高我们对男性和女性大脑的根本差异的认识，还将提供更多层面的理解，即学习和记忆如何在两性中受到不同的调节。

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.