Dynamic Regulation of Feedforward Inhibition in the Visual Thalamus

描述(申请人提供)：丘脑在处理感官信息，将其传递到关键的皮质部位，以及调节觉醒和觉醒方面发挥着关键作用。丘脑外侧膝状核(LGN)是人们最感兴趣的区域，因为它是调节视觉信息流从视网膜到视觉皮质区域的主要脑区。LGN中的抑制性中间神经元具有解剖学特化，使它们能够从树突和轴突终末释放神经递质。这些细胞固有的电生理特性使它们能够利用这些特化来确定对丘脑皮质(TC)细胞的抑制的空间和时间特性，丘脑皮质(TC)细胞是LGN的主要输出细胞。目前，神经调节剂，特别是代谢性谷氨酸受体(MGluRs)如何与这些固有特性相互作用形成对TC细胞的抑制作用尚不清楚。该建议定义了一种确定mGluR介导的这种抑制的调节作用的行动方针。首先，将量化mGluR激活对TC细胞自发和诱发性抑制的影响。我们将探索由于单一输入、输入序列和生理上相关的输入模式而对这种抑制的调节。我们还将确定哪些其他有源电导对这种调制有贡献。接下来，我们将明确mGluR在LGN中间神经元中的激活作用，以及中间神经元输出状态与TC细胞抑制之间的关系。我们将探索导致这种变化的机制，其中最主要的是与这种神经调节系统相关的钙动力学属性的变化。最后，我们将把mGluR激活所引起的调节与另一神经调节系统--M胆碱能调节系统的作用联系起来。我们将定义这两种不同的神经调节剂如何协同工作来控制神经元间输出。 与公共健康相关：这项研究试图阐明丘脑外侧膝状核如何处理视觉信息，因为视觉信息从眼睛传递到更高脑区的解码位置。在这项研究的过程中，当我定义这个电路的参数时，我不仅将获得可能有助于阐明与视力缺陷相关的病理的信息，而且我还将加强我们对神经科学中基本过程的理解--因为在外侧膝状体中发现的电路特征也作为神经系统的模块重复。了解前馈抑制的神经调节机制、钙依赖的细胞内在生理调节和动态状态依赖性的输出不仅有助于我们理解视觉信息是如何在丘脑中处理的，而且也将有助于我们理解信息是如何在整个大脑中处理的。

DESCRIPTION (provided by applicant): The thalamus performs a critical role in processing sensory information, relaying it to key cortical sites, and regulating arousal and wakefulness. The lateral geniculate nucleus (LGN) of the thalamus is of chief interest, as it is the principal brain area resonisble for regulating visual information flow from the retina to visual cortical areas. Inhibitory interneurons in the LGN have a anatomical specializations enabling them to release neurotransmitter from their dendrites as well as their axon terminals. The intrinsic electrophysiological properties of these cells enables them to take advantage of these specializations for great flexibility in determining the spatial and temporal properties of inhibition onto thalamcortical (TC) cells, the principal output cells of the LGN. Currently, not much is known how neuromodulators, especially metabotropic glutamate receptors (mGluRs) interact with these intrinsic properties to shape inhibition onto TC cells. This proposal defines a course of action to determine the role of mGluR mediated modulation of this inhibition. First, the effect of mGluR activation on spontaneous and evoked inhibition onto TC cells will be quantified. We will explore the modulation of this inhibition due to single inputs, trains of inputs, and physiologically relevant patterns of inputs. We will also determine what other active conductances contribute to this modulation. Next, the effect of mGluR activation in LGN interneurons, and the relationship between interneuron output state and inhibition evoked onto TC cells will be defined. We will explore the mechanisms responsible for this change, chief among them, the altered properties of calcium dynamics associated with this neuromodulatory system. And lastly, we will relate the modulation evoked by mGluR activation to the actions of another neuromodulatory system-- muscarinic cholinergic modulation. We will define how these two different neuromodulators work synergistically to control interneuron output. PUBLIC HEALTH RELEVANCE: This study seeks to elucidate how the lateral geniculate nucleus of the thalamus processes visual information as it is routed from the eye to where it is decoded in higher brain regions. During the course of this research, as I define the parameters of this circuit, I will not only obtain information that may shed light on pathologies associated with vision defects, but I will also enhance our understanding of fundamental processes in neuroscience-- as circuit features found in the lateral genilculate nucleus are also repeated as modules throughout the nervous system. Understanding the mechanisms governing neuromodulation of feedforward inhibition, calcium-dependent regulation of intrinsic cellular physiology, and dynamic state-depedent output will not only help us to understand how visual information is processed in the thalamus, but will also help us to understand how information is processed throughout the brain.