The role of neuroepigenetics in bidirectional behavioral states

摘要 在过去的十年中，表观遗传机制调节基因的作用日益明显。 表达在脑功能和功能障碍中起着重要作用。神经表观遗传学研究进展 发育过程，如DNA甲基化和组蛋白乙酰化，会导致智力低下和 认知障碍。最近，神经表观遗传过程也与成人的行为有关， 比如上瘾和记忆力。这就开启了这样一种可能性，即这些机制或许能够控制 行为状态的建立和维持。然而，潜在的机制是通过 哪些神经表观遗传过程可以调节回路兴奋性的变化来确定行为状态 保持神秘感。此外，由于哺乳动物大脑的复杂性和异质性，我们有 不知道环境和行为之间整合的遗传位点，以及 在特定的回路中控制它们的神经通路。这是解锁的主要障碍。 大脑和环境之间的接口及其在人类健康和疾病中的作用。在这里，我们提出一种 这个问题的三管齐下的解决方案：大脑显示保守的神经化学和 神经表观遗传机制，但与神经元和同质电路相比少了几个数量级 对于哺乳动物的大脑，受环境(饥饿和饱腹感)调节的行为，以及 实验上可控的环境(禁食与再喂养；正常饮食与高糖饮食)。 守恒回路的兴奋性和可塑性的变化决定了输出的进食状态，如饥饿 和饱腹感。这些变化发生缓慢，持续数小时，取决于生理状态，并且 双向的。因此，它们可以在神经表观遗传学上编码，以改变重要关键基因的表达 来调节电路的兴奋性。此外，由于大量的代谢中间体起到了 辅因子为染色质修饰酶，生理性变化的代谢物和营养物质可直接 改变基因表达。我的实验室开创了技术先河，并建立了独特的合作关系，以 阐述神经表观遗传过程在调节特定回路活动中的功能作用 在进食状态的背景下。我们建议绘制环境输入如何作用于染色质和基因 表达，以指导神经元兴奋性的变化，这是输出摄食行为的基础。首先，我们将 确定特定的染色质通路，它们在一个独特的回路中起作用，这对切换行为状态很重要 苍蝇在饥饿和饱足之间徘徊。然后我们将绘制整合的功能性遗传基因座图 通过检测这些通路在染色质上的占有率来检测生理状态和输出行为状态 以及它们对行为和神经活动的影响。然后我们将剖析环境投入的变化 (禁食时的能量匮乏，再喂食时的能量可获得性，以及高糖饮食中的能量过剩) 通过改变这些途径的活性及其整合的遗传位点来影响基因表达。对这件事 最后，我们将与分析化学家合作，开发新的方法来测量 血液、大脑和特定回路，并与计算生物学家一起利用机器学习分析 整合新陈代谢和基因表达数据集以确定作用于界面的分子途径 在输入和效应器机制之间，以调节输出行为状态。因为内分泌和 饥饿和饱腹感背后的生理变化是进化保守的，我们的方法将 提供环境如何在功能上决定双向触发器行为的模型 通过神经表观遗传机制。更广泛地说，这些研究将揭示表观遗传学 机制可以充当“行为状态”(正常和异常)的守门人，以提供 环境“条件反射”效应的分子和生理机制(从营养到 产妇护理)对神经可塑性的影响。

Abstract In the last decade it has become increasingly apparent that epigenetic mechanisms regulating gene expression play an important role in brain function and dysfunction. Disruption in neuroepigenetic developmental processes such as DNA methylation and histone acetylation result in mental retardation and cognitive impairments. More recently, neuroepigenetic processes have also been implicated in adult behaviors, such as addiction and memory. This opens the possibility that these mechanisms may be able to control the establishment and maintenance of behavioral states. However, the underlying mechanisms through which neuroepigenetic processes can mediate changes in circuit excitability to determine behavioral states remain mysterious. Moreover, because of the complexity and heterogeneity of the mammalian brain, we have no knowledge about the genetic loci of integration between the environment and behavior, and the identity of the neural pathways that control them in specific circuits. This presents a major roadblock towards unlocking the interface between brain and environment and their role in human health and disease. Here we propose a three-prong solution to this problem by using: a brain that shows conserved neurochemistry and neuroepigenetic mechanisms, but with orders of magnitude fewer neurons and homogenous circuits compared to mammalian brains, behaviors that are regulated by the environment (hunger and satiety), and an environment that is experimentally controllable (fasting vs. re-feeding; normal diet vs. high sugar diet). Changes in the excitability and plasticity of conserved circuits determine outputs feeding states like hunger and satiety. These changes occur slow, are persistent over hours, depend on the physiological state and are bidirectional. Thus, they could be encoded neuroepigenetically to alter the expression of key genes important to modulate circuit excitability. Furthermore, because a large number of metabolism intermediates functions as cofactors for chromatin modifying enzymes, physiological changes in metabolites and nutrients can directly alter gene expression. My lab has pioneered techniques and established unique collaborations to address the functional role of neuroepigenetic processes in regulating the activity of specific circuits in the context of feeding states. We propose to map how environmental inputs act on chromatin and gene expression to direct the changes in neuronal excitability that underlie output feeding behaviors. First, we will identify the specific chromatin pathways that act in a unique circuit important to switch the behavioral state of the fly between hungry and sated. We will then map the functional genetic loci of integration between physiological state and output behavioral states by examining the occupancy of these pathways on chromatin and their effect on behavior and neural activity. We will then dissect how changes in environmental input (energy scarcity in fasting, energy availability in re-feeding, and energy surplus in a high sugar diet) directly affect gene expression by altering the activity of these pathways and their genetic loci of integration. To this end, we will work with analytical chemists to develop new methods to measure changes in metabolites in the blood, brain and specific circuits and with computational biologists to harness machine learning analysis to integrate metabolism and gene expression datasets to identify the molecular pathways that act at the interface between input and effector mechanisms to regulate output behavioral states. Because the endocrine and physiological changes that underlie hunger and satiety are evolutionary conserved, our approach will provide a model of how the environment can functionally determine bidirectional, flip-flop behavioral states through neuroepigenetic mechanisms. More broadly, these studies will uncover how epigenetic mechanisms may function as gatekeepers of “behavioral states” (normal and abnormal), to provide the molecular and physiological mechanisms underlying the “conditioning” effect of environments (from nutrients to maternal care) on neural plasticity.