Ross S. Williamson, Ph.D - US grants

? DESCRIPTION (provided by applicant): Understanding how neural circuits process sensory information in order to drive behavior is a fundamental question in modern neuroscience. At early stages of the auditory pathway, function can often be inferred from patterns of connectivity and intrinsic electrical properties. This problem becomes far more difficult at higher levels, largely because neural responses no longer faithfully represent the features of the incoming sensory stimuli. Instead, responses can be readily modified by a host of non-sensory factors including attention, learning, and arousal. Thus, in order to understand the function of such circuits, it becomes crucial not only to isolate the functional identity of the cell types recorded from, but also to characterize how they contribute to acoustic signal processing while animals are engaged in purposeful behaviors. Recently, two cortical projection systems have been implicated as playing distinct roles in active listening behaviors. It has been suggested that subcortical feedback from auditory cortex to the inferior colliculus is critical in updating behaviorally relevant sensory representations in the midbrain. In contrast, the projection from auditory cortex to the striatum has been shown to encode the transformation between stimulus and action. However, in order to address the question of precisely how these projections are able to drive behavior, it is necessary to characterize their sensory tuning properties to understand exactly what information they are capable of carrying. Recent technical developments now make it possible to isolate specific neuron classes in vivo and document their specific contributions to auditory processing and sound-guided behavior. To this end, we will leverage these new techniques to identify and characterize the response properties of cortico-collicular and cortico-striatal neurons. We will then record from these neurons during task-engagement and employ optogenetic strategies to probe the role that these projections play in guiding auditory behaviors. Findings from the proposed studies will elucidate cortical contributions to behavior and will lay the foundation for a better understanding of the causes of neurological and behavioral disorders.

Project Summary The ability to both route and coordinate the propagation of sensory information to downstream areas is a critical feature of cognitive function. The deep layers of the auditory cortex (ACtx) give rise to a massive projection system that exerts influence over multiple downstream brain areas. Sub-cerebral projection neurons (SPNs) within layer 5b, with their elaborate dendritic processes and far-ranging axons, have long been regarded as canonical ?broadcast? neurons, pooling inputs from the upper cortical layers and transmitting signals to widespread downstream targets. Our recent work has shown that at least some SPNs that project to the midbrain also collateralize in the thalamus, striatum, and amygdala. Nevertheless, existing anatomical descriptions of this projection system are lacking, and the extent to which SPN populations broadcast information to several downstream targets simultaneously, as opposed to transmitting auditory signals to a single discrete region is not known. Despite their widespread influence, the neurons contributing to this corticofugal projection system have largely defied in vivo physiological characterization. Thus, the kind of sensory information that is routed to downstream targets remains to be established. Given that some SPN target regions reside within the limbic and reward systems of the brain, it is also important to assess how non- sensory factors related to internal state (such as arousal and locomotion) affect sensory processing in SPN populations that route information to distinct targets. Recent technical developments now make it possible to anatomically characterize the input/output circuitry of specific neuron classes in addition to being able to isolate these neurons in vivo to document their specific contributions to auditory processing. Here, we propose to use a battery of anatomical, optical, and viral approaches to elucidate the anatomical connectivity of SPN populations in mouse ACtx, to understand what information these SPN populations convey to downstream areas, and to describe how this information can be modulated by internal state. These data will provide a foundation for a subsequent R01 that will determine how different ACtx projections can influence perception and mediate behavior.