Dynamic Regulation of Feedforward Inhibition in the Visual Thalamus

描述（申请人提供）：丘脑在处理感觉信息，将其传递到关键皮质部位以及调节觉醒和清醒方面发挥关键作用。丘脑的外侧膝状核（LGN）是主要的兴趣，因为它是负责调节从视网膜到视觉皮质区域的视觉信息流的主要脑区。LGN中的抑制性中间神经元具有解剖学上的特化，使它们能够从树突和轴突末端释放神经递质。这些细胞固有的电生理特性使它们能够利用这些特化的优势，在确定对丘脑皮质（TC）细胞（LGN的主要输出细胞）的抑制的空间和时间特性方面具有很大的灵活性。目前，人们对神经调节剂，特别是代谢性谷氨酸受体（mGluRs）如何与这些内在特性相互作用以形成对TC细胞的抑制知之甚少。该建议定义了一个行动过程，以确定mGluR介导的这种抑制的调节作用。首先，mGluR激活对TC细胞自发抑制和诱发抑制的影响将被量化。我们将探讨由于单一输入、输入序列和输入的生理相关模式而引起的这种抑制的调制。我们还将确定哪些其他有源电导有助于这种调制。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对TC细胞的抑制之间的关系。我们将探索导致这种变化的机制，其中主要是与这种神经调节系统相关的钙动力学特性的改变。最后，我们将把mGluR激活引起的调节与另一个神经调节系统的作用联系起来——毒蕈碱胆碱能调节。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中间神经元的输出。

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.