Age-Related changes in GABAergic influence on auditory corticothalamic projection

描述（由申请人提供）：听力损失是老年人发病和社会脱离的主要原因。不幸的是，助听器，弥补周边缺陷，不足以提高语音在现实世界中的清晰度。这是因为与年龄相关的听力损失的主要原因是中枢机制的功能障碍，中枢机制允许大脑选择性地关注特定的听觉输入流。有一种假说可以解释这种选择性注意过程的崩溃，那就是衰老大脑中皮层抑制的特殊脆弱性。我们建议检查的作用，年龄相关的损失的抑制在一个神经系统，已牵连在选择性听觉注意：听觉皮质丘脑系统。我们以前已经表明，在年轻的成年小鼠的听觉皮质丘脑神经元大量的抑制控制和多个不同的抑制性微电路存在于皮质丘脑系统。我们假设，有一个与年龄相关的特定元素的这种抑制性微电路的损失。我们将研究年龄相关的变化，抑制电路到确定的听觉皮质丘脑神经元，使用激光扫描光刺激的笼状谷氨酸在切片制备。具体地说，基于我们以前的工作，我们将研究三组特定的抑制性输入：GABA能输入从第2/3层和第5层到第5层皮质丘脑神经元和第6层衍生的GABA能输入到第6层皮质丘脑神经元。我们也将探讨年龄相关的变化，在功能映射的皮质输入到丘脑神经元。我们假设，皮质抑制的减少将产生丘脑细胞的皮质输入的扩大，这可能是负责上述选择性听觉注意缺陷。我们将记录从个别丘脑神经元的听觉皮质丘脑切片制备和构建皮质输入地图，使用激光扫描光刺激。将在年轻和老年小鼠之间比较图谱，预计衰老将扩大这些输入。我们的长期目标是将这项工作扩展到体内制备，以将皮质丘脑映射中潜在的年龄相关变化与特定的听觉注意缺陷相关联。拟议的工作将导致更好地了解与年龄相关的中枢听觉功能障碍的机制，并可能最终为改善这种高度流行的疾病提供治疗靶点。

DESCRIPTION (provided by applicant): Hearing loss is a major cause of morbidity and social disengagement in the aging population. Unfortunately, hearing aids, which compensate for the peripheral deficits, do not adequately enhance the intelligibility of speech in real-world situations. This is because a major cause of age-relating hearing loss is the dysfunction of central mechanisms that allow the brain to selectively attend to particular streams of auditory input. One hypothesis to explain the breakdown in this selective attention process is the particular vulnerability of cortical inhibition in the aging brain. We propose to examine the role of age-related loss of inhibition in one neural system that has been implicated in selective auditory attention: the auditory corticothalamic system. We have previously shown that auditory corticothalamic neurons in young adult mice are under substantial inhibitory control and that multiple distinct inhibitory microcircuits exist within the corticothalamic system. We hypothesize that there is an age-associated loss of particular elements within this inhibitory microcircuitry. We will investigate age-related changes in the inhibitory circuitry onto identified auditory corticothalamic neurons using laser scanning photostimulation of caged glutamate in the slice preparation. Specifically, based on our previous work, we will study three particular sets of inhibitory inputs: GABAAergic inputs from layers 2/3 and 5 onto layer 5 corticothalamic neurons and layer 6-derived GABAAergic inputs onto layer 6 corticothalamic neurons. We will also investigate age-related changes in the functional mapping of cortical inputs onto thalamic neurons. We hypothesize that decreases in cortical inhibition will produce a broadening of cortical input onto thalamic cells, and that this may be responsible for the selective auditory attention deficits described above. We will record from individual thalamic neurons in the auditory corticothalamic slice preparation and construct cortical input maps using laser scanning photostimulation. Maps will be compared between young and aged mice and it is expected that aging will broaden these inputs. Our longer term goals are to extend this work to the in vivo preparation to correlate potential age-associated changes in corticothalamic mapping to particular auditory attention deficits. The proposed work will lead to a greater understanding of the mechanisms responsible for age-associated central auditory dysfunction, and may ultimately provide therapeutic targets for amelioration of this highly prevalent condition.