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脱离社会的主要原因。不幸的是，助听器，弥补外围缺陷，不能充分提高语音的可理解性在现实世界的情况下。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，该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，即大脑皮层在衰老过程中特别容易受到抑制。我们建议研究与年龄相关的抑制丧失在一个与选择性听觉注意有关的神经系统中的作用：听觉皮质丘脑系统。我们之前已经表明，年轻成年小鼠的听觉皮质丘脑神经元受到实质性的抑制性控制，并且皮质丘脑系统中存在多个不同的抑制性微回路。我们假设在这种抑制性微电路中存在与年龄相关的特定元素的丢失。我们将利用激光扫描光刺激笼中的谷氨酸来研究已识别的听觉皮质丘脑神经元抑制回路的年龄相关变化。具体而言，基于我们之前的工作，我们将研究三组特定的抑制性输入：来自第2/3层和第5层的gabaergic输入到第5层皮质丘脑神经元，以及来自第6层的gabaergic输入到第6层皮质丘脑神经元。我们还将研究皮层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，皮质抑制的减少会产生皮层对丘脑细胞输入的扩大，这可能是上述选择性听觉注意缺陷的原因。我们将记录单个丘脑神经元在听觉皮质丘脑切片制备中的情况，并利用激光扫描光刺激构建皮层输入图。将比较年轻和年老小鼠之间的图谱，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准备，以将皮质丘脑映射的潜在年龄相关变化与特定的听觉注意缺陷联系起来。这项工作将有助于更好地理解与年龄相关的中枢性听觉功能障碍的机制，并可能最终为改善这种高度普遍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.