Cellular Information Processing in the Hippocampus

海马体的细胞信息处理

基本信息

批准号：
8729516
负责人：
DANIEL JOHNSTON
金额：
$ 33.46万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8729516
关键词：
Accounting Animal Model Animals Anxiety Behavior Brain Cells Chronic Clinical Comorbidity Coupled Data Dendrites Dimensions Disease Disease model Dorsal Electrophysiology (science)Epilepsy Gated Ion Channel Goals Heterogeneity Hippocampus (Brain)Immunohistochemistry Injection of therapeutic agent Ion Channel Kainic Acid Learning Length Link Literature Location Major Depressive Disorder Measures Membrane Potentials Memory Mental Depression Mental disorders Methods Modeling Mood Disorders Neurons Physiology Play Prevalence Property Publishing Radial Rattus Regulation Reporting Resistance Role Seizures Slice Stress Structure Synapses Synaptic plasticity System Temporal Lobe Epilepsy Testing Western Blotting Work depressive symptoms hippocampal pyramidal neuron in vivo information processing inward rectifier potassium channel nervous system disorder neurobiological mechanism neuronal cell body neuronal excitability patch clamp public health relevance research study tissue fixing voltage

项目摘要

DESCRIPTION (provided by applicant): There is compelling evidence for the involvement of the mammalian hippocampus in learning and memory as well as certain neurological and psychiatric disorders. Our long-term objective is to understand how single pyramidal neurons integrate input from the tens of thousands of synapses impinging on their dendrites and thereby participate in normal and abnormal functioning of the hippocampus. In previous work we discovered the dendritic expression of a number of voltage-gated ion channels (e.g., Na+, Ca2+, and K+) and demonstrated how these channels regulate both synaptic integration and the induction and expression of synaptic plasticity. We also found that several of these dendritic channels, including h channels, undergo activity-dependent plasticity, called Intrinsic Plasticity, which regulates the excitability of neurons. In animal models for temporal lobe epilepsy (TLE), we found a significant reduction in dendritic K+ and h channels, and recently we showed that a knockdown of the HCN1 subunit for h channels in dorsal hippocampus produces anti-depression and anti-anxiety like behaviors in rats. From the clinical literature there appears to be a strong co-morbidity for depression and anxiety in epilepsy. The findings that a loss of h channels occurs in TLE and a knockdown of h channels produces anti-depressive behaviors, however, appear to be contradictory with this clinical literature. Our preliminary data suggest that this apparent contradiction may be due to a different involvement of the dorsal and ventral hippocampus in these disease models. We propose here to determine 1) the electrophysiological properties of single pyramidal neurons along the entire dorsal-ventral axis of the hippocampus, 2) whether h channels and inward rectifier K+ channels are differentially expressed in these regions, and 3) whether these channels are altered in a region-specific manner in animal models for temporal lobe epilepsy and depression. The experiments will utilize hippocampal brain slices from rats, somatic and dendritic patch-clamp electrophysiology, and immunohistochemistry and western blotting.

描述（由申请人提供）：有令人信服的证据表明哺乳动物海马体参与学习和记忆以及某些神经和精神疾病。我们的长期目标是了解单个锥体神经元如何整合来自冲击其树突的数万个突触的输入，从而参与海马体的正常和异常功能。在之前的工作中，我们发现了许多电压门控离子通道（例如Na+、Ca2+和K+）的树突表达，并证明了这些通道如何调节突触整合以及突触可塑性的诱导和表达。我们还发现，其中一些树突通道（包括 h 通道）具有依赖于活动的可塑性，称为固有可塑性，它调节神经元的兴奋性。在颞叶癫痫 (TLE) 动物模型中，我们发现树突 K+ 和 h 通道显着减少，最近我们发现背侧海马 h 通道的 HCN1 亚基敲低可产生抗抑郁和抗焦虑样行为在老鼠身上。从临床文献来看，癫痫患者的抑郁和焦虑似乎有很强的共病性。然而，关于 TLE 中 h 通道缺失以及 h 通道敲除产生抗抑郁行为的发现似乎与该临床文献相矛盾。我们的初步数据表明，这种明显的矛盾可能是由于这些疾病模型中背侧和腹侧海马的不同参与所致。我们在此建议确定 1) 沿海马整个背腹轴的单个锥体神经元的电生理特性，2) h 通道和内向整流 K+ 通道在这些区域是否有差异表达，以及 3) 这些通道是否被改变在颞叶癫痫和抑郁症动物模型中以特定区域的方式进行研究。实验将利用大鼠海马脑切片、体细胞和树突膜片钳电生理学、免疫组织化学和蛋白质印迹法。