Cholinergic control of neural network function

描述（由申请人提供）：该项目的长期目标是更好地了解神经递质乙酰胆碱的释放如何影响大脑原型皮质区的功能，该皮质区与长期记忆的形成至关重要。更具体地说，我们感兴趣的是来自大脑中称为内侧隔/布罗卡斜角带（释放乙酰胆碱）的区域的输入如何影响大脑皮层区域（海马CA 1）的输出结构中的神经信息处理，这对长期记忆的形成至关重要。这些研究将对开发阿尔茨海默病和精神分裂症的治疗方法具有重要意义。投射到大脑皮层结构的胆碱能神经元的丧失是阿尔茨海默病的标志。此外，延长细胞外空间中乙酰胆碱存在的药物是用于缓解阿尔茨海默病患者症状的治疗方法之一。此外，神经元烟碱受体功能障碍与某些家族性精神分裂症相关。这个为期五年的项目的具体目标是了解乙酰胆碱释放如何影响抑制性中间神经元功能，并最终影响海马CA 1区的信息处理。为了做到这一点，我们将在胆碱能神经元中表达一种名为ChIEF的蛋白质，当暴露于蓝光时，它可以激发神经元及其过程。这将使我们能够在海马CA 1区完整的活体切片上引发乙酰胆碱的释放，只需在它们上面闪烁蓝光。然后，我们将研究如何通过激活烟碱和毒蕈碱受体的乙酰胆碱释放影响中间神经元的功能，并最终海马CA 1网络功能。我们将通过全细胞膜片钳方法记录海马CA 1区中间神经元和锥体神经元的电反应，并通过使用电压敏感染料成像记录整个网络的活动。这些研究的结果将对阿尔茨海默病和某些家族性精神分裂症的治疗产生重要影响。 公共卫生相关性：在大脑中释放一种称为乙酰胆碱的神经递质的神经元的丧失是阿尔茨海默病的标志。此外，结合乙酰胆碱的分子功能障碍与某些家族性精神分裂症有关。这些研究将调查乙酰胆碱如何影响大脑中参与长期记忆形成的区域，并将对阿尔茨海默病和某些家族性精神分裂症的治疗产生重要影响。

DESCRIPTION (provided by applicant): The long term goal of this project is to have a better understanding of precisely how the release of the neurotransmitter acetylcholine affects function in a prototypic cortical area of the brain crucially involved in the formation of long term memories. More specifically, we are interested in how the inputs from an area of the brain called the medial septum/diagonal band of Broca, (which releases acetylcholine), affects processing of neural information in an output structure of a cortical area of the brain, (hippocampal CA1), crucial to the formation of long term memories. These studies will have important implications for developing treatments for Alzheimer's disease and possibly schizophrenia. The loss of cholinergic neurons that project to cortical structures in the brain is a hallmark of Alzheimer's disease. Furthermore, drugs that prolong the presence of acetylcholine in the extracellular space are one of the treatments used to alleviate symptoms in Alzheimer's patients. Moreover, dysfunction of neuronal nicotinic receptors has been correlated to some familial forms of schizophrenia. The specific aims for this five year project are to understand how acetylcholine release affects inhibitory interneuron function and ultimately the processing of information in hippocampal CA1. To do this we will express a protein called ChIEF in cholinergic neurons that can excite neurons and its processes when exposed to blue light. This will allow us to elicit the release of acetylcholine in live intact slices of hippocampal CA1 by merely flashing blue light upon them. We will then examine how acetylcholine release through the activation of both nicotinic and muscarinic receptors affects interneuron function and ultimately hippocampal CA1 network function. We will do this by recording electrical responses in interneurons and pyramidal neurons of hippocampal CA1 via whole cell patch clamp methods, and by recording activity in the entire network by using voltage-sensitive dye imaging. The results from these studies will have important implications for the treatment of Alzheimer's disease and some familial forms of schizophrenia. PUBLIC HEALTH RELEVANCE: The loss of neurons that release a neurotransmitter called acetylcholine in the brain is a hallmark of Alzheimer's disease. Furthermore, dysfunction of molecules that bind acetylcholine have been correlated to some familial forms of schizophrenia. These studies will investigate how acetylcholine affects an area of the brain involved in the formation of long term memories and will have important implications for the treatment of Alzheimer's disease and some familial forms of schizophrenia.