Neuromodulation and Cortical Memory Function

 描述(由申请人提供)：这项资助申请是一项竞争性的更新，重点关注反弹尖峰在内侧内嗅皮层神经元空间编码产生中的作用，以及内侧隔区的调制输入在调节空间编码中的作用。这项研究将内嗅神经元内在特性的全细胞斑片记录与反弹峰作用的计算模型和内侧隔区输入的创新操作相结合，以测试反弹峰电位的调制如何影响单位记录数据。具体目标#1：这项拨款将测试一个模型，在该模型中，由星状细胞之间的反馈抑制调节的反弹尖峰产生网格细胞的空间放电模式。这个模型所需的反弹尖峰特性将在全细胞膜片钳记录中进行测试，该记录分析了在正弦基线振荡和不存在正弦基线振荡的情况下对超极化电流脉冲的响应。在该模型中，射野之间的转换速度取决于运行速度调节反馈抑制的大小。这一机制将通过测试不同幅度的代表抑制性输入的超极化脉冲后的反弹尖峰的时间过程来分析。该模型还显示了具有不同固有共振特性的神经元在激发场之间的不同转换。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。细胞内的记录数据将为依赖于细胞特性的尖峰活动的调节提供重要的测试。具体目标#2：反弹尖峰的网络模型还产生关于影响单元记录数据模式的网络动态的预测。来自前一个授予周期的细胞数据显示，M受体的胆碱能激活降低了h电流的幅度，从而降低了共振频率并减缓了反弹尖峰。来自清醒行为大鼠内侧内嗅皮层的单位记录将检验胆碱能调制效应模型对内侧内嗅皮层局部theta节律的峰值或低谷相锁定的神经元的相对放电特性的预测。实验还将测试该模型的预测，即增加或减少胆碱能张力(由DREADDS调节)对网格细胞激发区域的大小和间距的影响。此外，场电位记录将测试胆碱能调制的光遗传操作对在theta韵律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有助于理解与神经和精神障碍相关的记忆缺陷。在抑郁症和精神分裂症等疾病中，内嗅皮层显示体积减少。内嗅皮层也显示出阿尔茨海默病中神经原纤维缠绕病理的最早迹象和最高的最终密度。了解内嗅皮层的细胞和电路动力学将有助于理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.