Dynamics of neural ensembles in emotional stress

描述（由申请人提供）：情绪压力影响着数百万人，是美国一项主要的健康相关支出。尽管我们对所涉及的分子、细胞和遗传因素的了解有了很大的进步，但我们对情绪应激对神经元回路和神经元群的影响知之甚少，而神经回路和神经元群是细胞病理和功能失调行为之间的介质。最近的进展使我们第一次能够同时记录一个（或几个）大脑区域的许多神经元，并对这些数据应用新的分析方法。这些进步现在已经准备好对网络的动态行为产生新的见解。我们建议同时记录哺乳动物大脑中与情绪压力和药物成瘾有关的部分的许多神经元，包括腹侧被盖区（VTA）、前额叶皮层（PFC）和伏隔核（NAc）。这些记录将在遭受社会失败行为协议（SD）的老鼠身上进行，SD被用作情绪压力的动物模型，它会导致两种不同的行为表型，称为弹性和易感。我们将比较SD对这两种行为表型的神经群体之间的动态行为和相互作用的影响，以验证SD诱导（或至少与之相关）中脑边缘系统动态网络特性变化的假设。本研究与以往在这一领域的大多数工作不同，它结合了三个关键特征：1)它不是关注单个神经元，而是关注相关大脑网络内的动态行为和相互作用；2)与动物的行为状态有关，3)它将在体内进行，而不是在体外进行。因此，它将提供新的信息，目前还没有，关于神经元集合占据一个关键的中间脑水平，单个神经元和整个动物行为。因此，它将揭示与情绪压力有关的大脑机制，并将提供评估药物有效性的新方法。

DESCRIPTION (provided by applicant): Emotional stress affects millions of people, and is a major health-related expense in the US. Despite great advances in our knowledge of the molecular, cellular and genetic factors that are involved, precious little is known about the effects of emotional stress on the neuronal circuits and ensembles that are the mediators between the cellular pathologies and the dysfunctional behavior. Recent advances have made it possible, for the first time, to record simultaneously from many neurons in one (or several) brain areas, and to apply new analysis methods to such data. These advances are now poised to produce new insights into the network's dynamical behavior. We propose to record simultaneously from many neurons in those parts of the mammalian brain that have been shown to be involved in emotional stress and drug addiction, which include the Ventral Tegmental Area (VTA), Prefrontal Cortex (PFC) and Nucleus Accumbens (NAc). The recordings will be carried out in mice that have been subjected to the behavioral protocol of social defeat (SD), which is used as an animal model for emotional stress, and which results in two distinct behavioral phenotypes, called resilient and susceptible. We shall compare the effect of SD on the dynamical behavior and interactions among the neural populations in these two behavioral phenotypes, to test the hypothesis that SD induces (or is at least correlated with) changes in the dynamical network properties of the mesolimbic system. This research differs from most of the previous work in this area in combining 3 crucial features: 1) It focuses not on individual neurons, but on the dynamical behavior and interactions within the relevant brain networks; 2) It is related to the behavioral state of the animal, and 3) It will be carried out in vivo, rather than in vitro. It will therefore provide new information, not currently available, about the neuronal ensembles that occupy a critical intermediate brain level, between single neurons and whole animal behavior. It will thus shed new light on the brain mechanisms that are involved in emotional stress, and will provide new ways to assess the effectiveness of drugs. PUBLIC HEALTH RELEVANCE: We plan to use modern methods of network analysis to investigate the hypothesis that emotional stress is caused by changes in the dynamical behavior of neuronal groups in specific parts of the brain. After being exposed to aggressive behavior from other mice, some mice show signs of emotional stress, while others remain resilient. We shall compare the network properties of the stressed and resilient mice to discover how the emotional stress changes the group behavior of their neuronal ensembles.