Neuromodulation and Cortical Memory Function

 描述（由申请人提供）：该资助申请是一项竞争性的更新，重点关注内侧内嗅皮层神经元空间编码产生中反弹尖峰的作用，以及内侧隔调节空间编码的调节输入的作用。本研究结合了全细胞贴片记录的内嗅神经元的内在特性的反弹尖峰和创新的操纵内侧隔输入的作用的计算建模，以测试如何调制反弹尖峰影响单位记录数据。具体目标1：这项资助将测试一个模型，其中星状细胞之间的反馈抑制调节反弹尖峰产生网格细胞的空间放电模式。将在全细胞膜片钳记录中测试该模型所需的反弹尖峰特性，该记录分析了对具有和不具有正弦基线振荡的超极化电流脉冲的响应。在该模型中，发射场之间的过渡速度取决于运行速度调制的反馈抑制的大小。通过测试不同幅度的超极化脉冲（代表抑制性输入）后的反弹尖峰的时间过程来分析这种机制。该模型还显示了不同的固有共振特性的神经元之间的发射场的不同的过渡。我们将分析h电流产生的具有不同固有共振特性的神经元如何改变其反弹尖峰的速度。细胞内记录的数据将提供一个重要的测试的调节尖峰活动依赖于细胞特性。具体目标#2：反弹扣球的网络模型也产生预测的网络动态影响模式的单位记录数据。来自格兰特上一个周期的细胞数据显示，胆碱能激活毒蕈碱受体降低了h电流的幅度，从而降低了共振频率并减缓了反弹尖峰。来自清醒的行为大鼠的内侧内嗅皮层的单元记录将测试模型对胆碱能调节作用的预测，所述胆碱能调节作用对具有锁相至内侧内嗅皮层中的局部θ节律的峰或谷的神经元的相对放电特性。实验还将测试模型关于增加或减少胆碱能紧张（由DREADDs调节）对网格细胞放电场之间的大小和间距的影响的预测。此外，场电位记录将测试胆碱能调制的光遗传学操作对在theta rhyhm振荡的不同阶段观察到的伽马频率振荡的影响。了解内嗅皮层的电路动力学将提供重要的理解与神经和精神疾病相关的记忆缺陷。内嗅皮层在包括抑郁症和精神分裂症在内的疾病中表现出体积减小。内嗅皮层也显示出阿尔茨海默病中神经元缠结病理的最早迹象和最高最终密度。了解内嗅皮层的细胞和电路动力学将有助于了解其对这些疾病的脆弱性。

 DESCRIPTION (provided by applicant): This grant application is a competing renewal focused on the role of rebound spiking in the generation of spatial coding of neurons in the medial entorhinal cortex, and on the role of modulatory input from the medial septum in regulating spatial coding. This research combines whole cell patch recording of the intrinsic properties of entorhinal neurons with computational modeling of the role of rebound spiking and innovative manipulations of medial septal input to test how modulation of rebound spiking influences unit recording data. Specific Aim #1: This grant will test a model in which rebound spiking regulated by feedback inhibition between stellate cells generates the spatial firing patterns of grid cells. The rebound spiking properties necessary for this model will be tested in whole cell patch clamp recordings that analyze the response to hyperpolarizing current pulses with and without a sinusoidal baseline oscillation. In the model, the speed of transition between firing fields depends upon running speed modulating the magnitude of feedback inhibition. This mechanism will be analyzed by testing the time course of rebound spiking after different magnitudes of hyperpolarizing pulses representing inhibitory input. The model also shows different transitions between firing fields for neurons with different intrinsic resonance properties. We will analyze how neurons with different intrinsic resonance properties generated by h current change their speed of rebound spiking. The intracellular recording data will provide an important test of the regulation of spiking activity dependent upon the cellular properties. Specific Aim #2: The network model of rebound spiking also generates predictions about the network dynamics influencing the pattern of unit recording data. Cellular data from the previous cycle of the grant showed that cholinergic activation of muscarinic receptors reduces the magnitude of h current, which reduces resonance frequency and slows rebound spiking. Unit recordings from medial entorhinal cortex of awake, behaving rats will test the predictions of the model for cholinergic modulatory effects on the relative firing properties of neurons with phase locking to the peak or the trough of the local theta rhythm in medial entorhinal cortex. Experiments will also test predictions of the model about the effects of increased or decreased cholinergic tone (regulated by DREADDs) on the size and spacing between grid cell firing fields. In addition, field potential recordings will test the effects of optogenetic manipulations of cholinergic modulation on the gamma frequency oscillations observed at different phases of theta rhyhm oscillations. Understanding the circuit dynamics of the entorhinal cortex will provide important understanding of the memory deficits associated with both neurological and psychiatric disorders. The entorhinal cortex shows volume reduction in disorders including depression and schizophrenia. The entorhinal cortex also shows the earliest signs and highest final density of neurofibrillary tangle pathology in Alzheimer's disease. Understanding the cellular and circuit dynamics of entorhinal cortex will assist in understanding its vulnerability to these disorders.