Deficits in sensory processing are a hallmark of schizophrenia. These deficits can be evaluated by surface recording of auditory evoked potential (AEPs) elicited in response to closely paired click stimuli. Normal individuals have a reduced, or gated, middle latency (P50) response to the second click as compared to the first, while schizophrenics are not able to gate their responses to the same stimuli. Fill delineation of the synaptic pathways and neurobiological mechanisms of sensory gating cannot be investigated in humans due to the invasive nature of the anatomical and physiological techniques involved. Although there is no animal model of schizophrenia available,, a model of sensory gating has been developed. Rats (both anesthetized and awake) show gating of a middle latency AEP (N40), in response to paired clicks; administration of psychogenic agents (amphetamine, PCP) produces a schizophrenia-like response pattern. This model permits inquiry into the neuronal circuitry and neurochemical basis of sensory gating which may be of heuristic value in indicating future directions for human investigations in other projects in the Center. In this project, the animal model will be used to further several areas of investigation. Intrinsic interanimal variability in gating will be used to evaluate the relative roles of catecholaminergic and cholinergic neurotransmission in the regulation of gating. Since recent data have indicated a role for the cholinergic system in the regulation of sensory gating in both humans and rats, the specific contribution of forebrain cholinergic pathways to sensory gating will be evaluated. In addition, the neuronal circuitry responsible for the regulation of septal modulation of gating will be identified through PHA-L tracing and immunohistochemical techniques. Finally, the specific role of the alpha-bungarotoxin binding site in gating will be assessed through acute hippocampal recordings of mice selectively bred for differing numbers of these binding sites.
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