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.

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 proposed experiments will elucidate how one such cortical feedback circuit affects the processing of incoming auditory information.