Integration of ascending and descending input to auditory cortex

描述（由申请人提供）：感官知觉是由先前的经验和期望形成的，这些自上而下和自下而上的信息流的整合增强了我们在嘈杂环境中识别刺激的能力，并加快了感觉运动的整合。这种能力的缺陷在自闭症、精神分裂症和注意力缺陷多动障碍等神经疾病中很常见。有证据表明，大脑皮层中的反馈回路对这种依赖经验的感知信息调制至关重要，但涉及的神经机制尚不清楚。在麻醉诱导的催眠和慢波睡眠中，这一过程的选择性丧失表明了这一过程对意识的重要性。在此，我们建议研究听觉皮层中这一整合过程的细胞和电路机制以及全身麻醉对其的调节。基于上升和下降传入信号的层流分离，以及具有不同树突状树突的细胞类型，我们认为上升和下降传入信号的整合将是细胞类型特异性的。由上升和下降输入激活的细胞的层流位置和时间序列，以及这些输入的突触生理学，对理解柱状整合至关重要，但对包括听觉皮层在内的任何皮质区域的理解都很差。我们预测下行输入将改变由上行输入引起的时空活动模式，而这一过程的动态将取决于上行和下行传入的突触生理学以及局部抑制过程的参与。我们将使用钙成像、电生理学和初级听觉皮层（A1）脑切片的解剖学来检验这些假设。将讨论三个具体目标。我们将研究第2/3层和第5层锥体细胞的上升和下降输入的整合，我们将表征下降传入事件对时空激活模式的调节，我们将研究催眠剂对A1上升和下降输入的影响。了解皮层回路如何整合来自外部和内部来源的信息是理解感觉加工和感觉意识的神经基础的基础，并且具有重要和实际的临床意义。传统的观点认为，自下而上的加工和收敛只在皮层层次的最高水平受到挑战的研究表明，自上而下的影响在所有层次，并强调初级感觉区域的知觉现象的重要性。了解麻醉引起的意识丧失的皮质机制将有助于研究催眠药物的设计，这些药物对血流动力学和其他中枢神经系统以外的现象的不良影响较小，并且还将进一步了解感觉意识的神经基础。感知是由先前的经验和期望形成的，这些自上而下和自下而上的信息流的整合增强了我们在嘈杂环境中识别刺激的能力，并加快了感觉运动整合的速度。这种能力的缺陷在自闭症、精神分裂症和注意力缺陷多动障碍等神经疾病中很常见。有证据表明，大脑皮层中的反馈回路对这种依赖于经验的传入感觉信息的调节至关重要，但涉及的神经机制尚不清楚。这些实验将阐明一个这样的皮质反馈回路是如何影响传入听觉信息的处理的。

DESCRIPTION (provided by applicant): Sensory perceptions are shaped by prior experience and expectation, and integration of these top-down and bottom-up information streams enhances our ability to identify stimuli in noisy environments and speeds sensorimotor integration. Deficits in this ability are common in neuropathologies such as autism, schizophrenia and attention deficit hyperactivity disorder. Evidence suggests that feedback circuits in cerebral cortex are critical for this experience-dependent modulation of incoming sensory information, but the neural mechanisms involved are poorly understood. The importance of this process for awareness is suggested by its selective loss upon anesthetic-induced hypnosis and during slow-wave sleep. Here, we propose to investigate the cellular and circuit mechanisms of this integrative process in auditory cortex and its modulation by general anesthetics. Based on the laminar segregation of ascending and descending afferents to a column and of cell types with distinct dendritic arborization, we suggest that integration of ascending and descending inputs will be cell-type specific. The laminar position and temporal sequence of cells activated by ascending and descending inputs, as well as these inputs' synaptic physiology, are critical to understanding columnar integration, but are poorly understood for any cortical area, including auditory cortex. We predict that descending inputs will alter the spatiotemporal activity pattern induced by ascending inputs to the column, and that the dynamics of this process will depend on the synaptic physiology of ascending and descending afferents and the engagement of local inhibitory processes. We will use calcium imaging, electrophysiology, and anatomy in brain slices of primary auditory cortex (A1) to test these hypotheses. Three specific aims will be addressed. We will investigate the integration of ascending and descending inputs in pyramidal cells of layer 2/3 and layer 5, we will characterize the modulation of spatiotemporal activation patterns by descending afferents, and we will investigate the effects of hypnotic agents on ascending and descending inputs to A1. Understanding how cortical circuits integrate information from external and internal sources is fundamental to understanding the neural basis of sensory processing and sensory awareness, and has important and practical clinical implications. Traditional views that have focused on bottom-up processing and convergence only at the highest levels of the cortical hierarchy are challenged by studies showing top-down influences at all levels of the hierarchy and highlighting the importance of primary sensory regions for perceptual phenomena. Understanding cortical mechanisms of anesthetic-induced loss of consciousness will benefit research into the design of hypnotic drugs that have fewer undesirable effects on hemodynamics and other phenomena outside the CNS, and will additionally provide insight into the neural basis of sensory awareness. Perceptions are shaped by prior experience and expectation, and integration of these top-down and bottom-up information streams enhances our ability to identify stimuli in noisy environments and speeds sensorimotor integration. Deficits in this ability are common in neuropathologies such as autism, schizophrenia and attention deficit hyperactivity disorder. Evidence suggests that feedback circuits in cerebral cortex are critical for this experience- dependent modulation of incoming sensory information, but the neural mechanisms involved are poorly understood. The proposed experiments will elucidate how one such cortical feedback circuit affects the processing of incoming auditory information.