Mechanisms of Entorhinal Cortex Function

描述(由申请人提供)：这项竞争性的延续申请侧重于增加我们对内嗅觉皮质细胞机制的理解，以主动维持空间和非空间信息以及编码情景记忆。这包括分析内嗅神经元格细胞放电特性的潜在细胞机制，以及可能涉及工作记忆和表达感觉输入的连续维度的持续放电活动的细胞机制分析。这项工作将增进我们对阿尔茨海默病等记忆相关神经疾病的理解，以及对精神障碍包括精神分裂症、焦虑障碍和抑郁的记忆成分的理解。阿尔茨海默病与内嗅皮层的广泛病理有关。AIM#1的研究将使用电流钳和电压钳技术，根据初步数据显示并接受发表在《科学》杂志上的数据，分析沿内嗅皮层背腹轴的亚阈值振荡频率的差异。这些实验测试了来自计算模型的预测，这些预测表明，在清醒的行为大鼠的记录中，时间频率的差异如何导致沿内嗅皮层背腹轴的网格单元反应的空间周期性的差异。Aim#2的研究将扩展先前关于内嗅皮层V、III和II层持续尖峰的单细胞机制的详细模型，开发通过突触刺激诱导这种持续尖峰的模型，并确定代谢性谷氨酸受体在这一诱导过程中的作用，如初步数据部分显示的初步实验所展示的那样。目标3的研究将集中在振荡和持续放电机制在维持神经活动序列中的作用，测试持续尖峰放电的细胞机制在维持一组神经元的神经尖峰活动序列中的作用。总之，这些研究将有助于理解内嗅皮层在代表环境刺激以进行主动维持和编码进入情景记忆中的动态作用。

DESCRIPTION (provided by applicant): This competing continuation application focuses on increasing our understanding of the cellular mechanisms in entorhinal cortex for active maintenance of spatial and non-spatial information and for encoding of episodic memory. This includes analysis of cellular mechanisms underlying the grid cell firing properties of entorhinal neurons, and analysis of the cellular mechanisms underlying persistent firing activity which could be involved in working memory and representation of continuous dimensions of sensory input. This work will enhance our understanding of memory-related neurological disorders such as Alzheimer's disease, which is associated with extensive pathology in entorhinal cortex, and understanding of memory components of mental disorders including schizophrenia, anxiety disorders and depression. Research in Aim #1 will use current clamp and voltage clamp techniques to analyze differences in frequency of subthreshold oscillations along the dorsal-ventral axis of entorhinal cortex building on data shown in PRELIMINARY DATA and accepted for publication in Science. These experiments test predictions from computational models showing how differences in temporal frequency could underlie differences in spatial periodicity of grid cell unit responses along the dorsal-ventral axis of the entorhinal cortex in recordings from awake, behaving rats. Research in Aim #2 will extend previous detailed models of single cell mechanisms for persistent spiking in layers V, III and II of entorhinal cortex, developing models for the induction of this persistent spiking with synaptic stimulation, and determining the role of metabotropic glutamate receptors in this induction process as demonstrated in preliminary experiments shown in the PRELIMINARY DATA section. Research in Aim #3 will focus on the role of oscillatory and persistent firing mechanisms in the maintenance of sequences of neural activity, testing the role of cellular mechanisms of persistent spiking in maintaining sequences of neural spiking activity across a population of neurons. Together these studies will assist in understanding the dynamic role of entorhinal cortex in representing environmental stimuli for active maintenance and encoding into episodic memory.