Impact of extrahippocampal excitatory inputs on hippocampal CA1 neuron activation

描述（由申请人提供）：所有哺乳动物物种的长期陈述性记忆都是在大脑中称为海马体的区域形成的。海马体通过整合来自大脑其他区域的信息来实现这一点，这些信息编码了关于有机体环境及其内部状态的高度加工的复杂信息。海马体中处理的最后阶段之一是称为CA 1的输出结构。CA 1本身对记忆进行短暂编码，然后将其传递到大脑的其他部分，在那里记忆被长期存储。CA 1从大脑的两个区域接收大量输入，这两个区域编码不同类型的信息。其中之一，内侧内嗅皮层，编码有关生物体环境的信息。另一个区域是丘脑的联合核，负责传递来自内侧前额叶皮层的有关执行功能和情绪的信息。由于这两种结构携带不同类型的信息，它们会影响海马体中不同类型记忆的形成。内侧内嗅皮层影响海马空间记忆的形成。核团的重聚影响着记忆的形成，而记忆的形成更多的是情感内容。随后，神经核的功能障碍可能导致与焦虑症和创伤后应激障碍相关的病理性记忆形成。尽管内侧内嗅皮层和核reuniens对海马CA 1编码的不同影响，这两个输入项目的CA 1的同一区域，并产生类似的群体反应在CA 1。然而，这两种输入参与海马CA 1区的精确神经元和网络仍然知之甚少。本研究旨在确定由内侧内嗅皮层和丘脑的核团激活的海马CA 1区神经元。为此，我们将选择性地在投射到海马CA 1的内侧内嗅皮层或核团聚体的神经元中表达光遗传学兴奋性蛋白oChIEF-tdTomato。这将使我们能够用光刺激选择性地激发这些输入，并测量它们对转基因小鼠中不同亚型的荧光标记CA 1神经元的影响。这将使我们能够识别海马CA 1区的哪些神经元最受两种不同输入的激活，以及海马CA 1区的主要锥体细胞可能产生的结果。从这些研究中获得的数据将是必不可少的了解这些输入如何影响海马CA 1区记忆形成所涉及的细胞和网络过程。此外，对重聚核的研究可能有助于在细胞和网络水平上了解病理记忆如何在一些精神疾病中形成。0925-0001/0002（2012年8月修订版）续页格式页

DESCRIPTION (provided by applicant): Long-term declarative memories in all mammalian species are formed in an area of the brain called the hippocampus. The hippocampus does this by integrating information from other regions of the brain that encode highly processed complex information about an organism's environment and its internal state. One of the final stages of processing in the hippocampus is an output structure called CA1. CA1 itself encodes memories transiently that are then relayed to other parts of the brain where memories are stored longer term. CA1 receives a large amount of input from two regions of the brain that encode different types of information. One of these, the medial entorhinal cortex, encodes information about an organism's environment. The other region, the nucleus reuniens of the thalamus, relays information from the medial prefrontal cortex concerning executive function and emotion. Because these two structures carry different types of information, they influence the formation of different types of memory in the hippocampus. The medial entorhinal cortex affects the formation of spatial memory in the hippocampus. The nucleus reuniens influences memory formation that has more of an emotional content. Subsequently, dysfunction of the nucleus reuniens input may result in pathological memory formation associated with anxiety disorders and post-traumatic stress disorders. Despite the different effects that the medial entorhinal cortex and nucleus reuniens have on hippocampal CA1 encoding, both inputs project to the same region of CA1 and produce similar population responses in CA1. However, the precise neurons and networks in hippocampal CA1 engaged by these two inputs remain poorly understood. This proposal seeks identify the hippocampal CA1 neurons activated by the medial entorhinal cortex and nucleus reuniens of the thalamus. To do this we will selectively express the optogenetic excitatory protein oChIEF-tdTomato in neurons of the medial entorhinal cortex or nucleus reuniens that project to hippocampal CA1. This will permit us to excite these inputs selectively with light stimulation and measure their impact in different subtypes of fluorescently labeled CA1 neurons in genetically-modified mice. This will allow us to identify which neurons in hippocampal CA1 are most activated by the two different inputs and what the outcome may be on the principal pyramidal cells of hippocampal CA1. The data obtained from these studies will be essential for understanding how these inputs influence the cellular and network processes involved in memory formation in hippocampal CA1. Furthermore, studies of the nucleus reuniens may help provide some insight for understanding at the cellular and network level how pathological memories may be formed in some psychiatric disorders. 0925-0001/0002 (Rev. 08/12) Page Continuation Format Page