Structural imaging studies indicate reductions in gray matter volume localized to the auditory cortex of the superior temporal gyms in subjects with schizophrenia. Associated with these reductions are deficits in early, pre-attentive auditory sensory processing. In non-human primates, early cortical processing of auditory input occurs through hierarchically organized auditory core, lateral belt, and parabelt cortices of the superior temporal gyrus. Feedforward projections from auditory core to lateral belt, and from lateral belt to parabelt provide for rapid transfer of sensory information, facilitating pre-attentive behavioral responses. Our initial studies of auditory cortex in subjects with schizophrenia have found reductions in pyramidal cell size in a laminar pattern indicative of alterations of feedforward projections. These findings have led us to hypothesize that schizophrenia is associated with selective impairments of the feedforward projection neurons within the auditory core, lateral belt, and parabelt. We will test this hypothesis in a series of specific aims, capitalizing on the known organization of the primate auditory cortex and designed to examine the source cells, the terminations, and the post-synaptic targets of auditory cortieocortical feedforward projections. Selective involvement of feedforward projections will be tested by similarly examining the source cells, terminations, and post-synaptic targets of feedback projections. Specificity of findings for schizophrenia will be established by examining non-human primates exposed to chronic neuroleptic treatment, and by examining subjects with mood disorder. We will address the following questions: 1) Are reductions in gray matter volume in auditory cortex present in the cortical layers from which feedforward projections arise and in which they terminate? 2) Is mean pyramidal cell somal volume of the source cells for auditory feedforward projections reduced? 3) Is total axon length and axon terminal number reduced in the termination zones of auditory feedforward projections? 4) Are there post-synaptic reductions in dendritic spine density in the termination zones of auditory feedforward projections? Successful completion of these aims will establish whether impairments in auditory cortieocortical circuits in subjects with schizophrenia are selective for feedforward projections, identify which components of the feedforward circuits are impaired, and ascertain which impairments are specific for schizophrenia. This knowledge will guide the design of future investigations of auditory cortex pathology, and inform the interpretation of psychophysiology investigations and neural modeling of auditory processing in schizophrenia. ? ?
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