Impact of extrahippocampal excitatory inputs on hippocampal CA1 neuron activation

描述(申请人提供)：所有哺乳动物的长期陈述性记忆都是在大脑的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实现这一点，这些区域编码了关于有机体环境及其内部状态的经过高度处理的复杂信息。海马体处理的最后阶段之一是名为CA1的输出结构。CA1本身对记忆进行瞬时编码，然后将其传递到大脑的其他部分，在那里记忆会存储更长时间。CA1接受来自大脑两个区域的大量输入，这两个区域编码不同类型的信息。其中之一，内侧内嗅皮层，编码关于有机体环境的信息。另一个区域是丘脑的联合核，负责传递来自内侧前额叶皮质的有关执行功能和情绪的信息。因为这两种结构承载着不同类型的信息，它们影响着海马体中不同类型记忆的形成。内侧内嗅觉皮质影响海马区空间记忆的形成。核团会影响记忆的形成，而记忆的内容更多的是情绪化。随后，核团传入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团核对海马CA1编码有不同的影响，但两种输入都投射到CA1的同一区域，并在CA1产生相似的群体反应。然而，这两种输入参与的海马CA1区准确的神经元和网络仍然知之甚少。这一建议试图确定由丘脑内侧内嗅觉皮质和核团激活的海马CA1区神经元。为了做到这一点，我们将选择性地在投射到海马CA1的内侧内嗅皮层或核的神经元中表达光发生兴奋蛋白oChIEF-tdTomato。这将允许我们用光刺激选择性地刺激这些输入，并测量它们对转基因小鼠不同亚型荧光标记的CA1神经元的影响。这将使我们能够确定两种不同的输入对海马CA1区哪些神经元最活跃，以及对海马CA1区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将是理解这些输入如何影响参与海马CA1记忆形成的细胞和网络过程的关键。此外，对核团的研究可能有助于在细胞和网络水平上理解某些精神障碍的病理性记忆是如何形成的。0925-0001/0002(08/12版)页面续格式页面

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