Impact of extrahippocampal excitatory inputs on hippocampal CA1 neuron activation

描述（由申请人提供）：所有哺乳动物的长期陈述性记忆都是在大脑中一个叫做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做到这一点，这些信息编码了有关生物体环境及其内部状态的高度处理的复杂信息。海马体处理的最后阶段之一是一个叫做CA1的输出结构。CA1本身对记忆进行短暂编码，然后传递到大脑的其他部分，在那里记忆被长期存储。CA1接收来自大脑中编码不同类型信息的两个区域的大量输入。其中的内侧内嗅皮层负责对生物体的环境信息进行编码。另一个区域，丘脑的团聚核，传递来自内侧前额皮质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。核团聚会影响记忆的形成，而记忆的形成更多的是情感内容。随后，团聚核输入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团结核对海马CA1编码的影响不同，但这两种输入都投射到CA1的同一区域，并在CA1中产生相似的群体反应。然而，海马体CA1中由这两种输入参与的确切神经元和网络仍然知之甚少。本研究旨在鉴定海马CA1神经元由内嗅皮层和丘脑重聚核激活。为此，我们将在投射到海马CA1的内侧内嗅皮层或重组核的神经元中选择性地表达chief - tdtomato光遗传兴奋蛋白。这将允许我们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荧光标记的CA1神经元不同亚型的影响。这将使我们能够确定海马CA1中的哪些神经元被两种不同的输入激活最多，以及海马CA1的主要锥体细胞的结果可能是什么。从这些研究中获得的数据对于理解这些输入如何影响海马CA1中涉及记忆形成的细胞和网络过程至关重要。此外，对核团聚的研究可能有助于在细胞和网络水平上理解病理记忆是如何在一些精神疾病中形成的。0925-0001/0002 （Rev. 08/12）页延续格式页

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