Mechanisms of Entorhinal Cortex Function

描述（由申请人提供）：这一竞争性的继续申请侧重于增加我们对内鼻腔皮层中主动维持空间和非空间信息以及情景记忆编码的细胞机制的理解。这包括分析内嗅神经元网格细胞放电特性的细胞机制，以及分析持续放电活动的细胞机制，这些活动可能涉及工作记忆和感觉输入的连续维度的表征。这项工作将增强我们对记忆相关神经系统疾病的理解，如阿尔茨海默病，这与内嗅皮层的广泛病理有关，以及对精神分裂症、焦虑症和抑郁症等精神疾病的记忆成分的理解。Aim #1的研究将使用电流钳和电压钳技术来分析沿内嗅皮层背腹轴的阈下振荡频率的差异，该数据建立在初步数据中，并被接受发表在《科学》杂志上。这些实验验证了计算模型的预测，该模型显示，在清醒、行为正常的大鼠的记录中，时间频率的差异如何成为沿内嗅皮层背腹轴网格细胞单元反应空间周期性差异的基础。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，并确定代谢型谷氨酸受体在这一诱导过程中的作用，如初步数据部分所示的初步实验所示。Aim #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，测试持续尖峰的细胞机制在维持神经元群中的神经尖峰活动序列中的作用。综上所述，这些研究将有助于理解内嗅皮层在表现环境刺激以主动维持和编码为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.