Age-Related changes in GABAergic influence on auditory corticothalamic projection

描述(由申请人提供)：听力损失是老年人口发病率和社会脱节的主要原因。不幸的是，助听器弥补了外周缺陷，但在现实世界中并不能充分提高语音的可理解性。这是因为与年龄相关的听力损失的一个主要原因是中枢机制的功能障碍，该机制允许大脑选择性地处理特定的听觉输入流。解释这种选择性注意过程崩溃的一个假设是，老化大脑中皮质抑制的特殊脆弱性。我们建议研究与年龄相关的抑制丧失在一个神经系统中的作用，该神经系统与选择性听觉注意有关：听觉皮质丘脑系统。我们之前已经证明，年轻成年小鼠的听觉皮质丘脑神经元处于实质性的抑制控制之下，并且皮质丘脑系统中存在多个不同的抑制微电路。我们假设，在这个抑制性微电路中，存在与年龄相关的特定元素的丢失。我们将在切片制备中使用笼养谷氨酸的激光扫描光刺激来研究已识别的听觉皮质丘脑神经元上抑制电路的年龄相关变化。具体地说，在我们以前工作的基础上，我们将研究三组特殊的抑制性输入：从第2/3层和第5层到第5层皮质丘脑神经元的GABA能输入，以及第6层派生的GABA能到第6层皮质丘脑神经元的GABA能输入。我们还将研究大脑皮质输入到丘脑神经元的功能映射中与年龄相关的变化。我们假设，皮层抑制的减少将导致丘脑细胞皮质输入的扩大，这可能是上述选择性听觉注意缺陷的原因。我们将记录来自单个丘脑神经元的听觉皮质丘脑切片的准备，并使用激光扫描光刺激构建皮质输入地图。MAP将在年轻和老年小鼠之间进行比较，预计老龄化将扩大这些输入。我们的长期目标是将这项工作扩展到体内准备工作，以将皮质丘脑标测图中潜在的年龄相关变化与特定的听觉注意缺陷联系起来。这项拟议的工作将有助于更好地理解与年龄相关的中枢听觉功能障碍的机制，并最终可能为改善这一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.