Dynamic Regulation of Feedforward Inhibition in the Visual Thalamus

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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.