Project Summary: Prepulse inhibition (PPI) represents a powerful method for understanding a fundamental component of information-processing, sensorimotor gating. PPI refers to the diminution of the startle response when a sudden startling stimulus is preceded 30-500 ms by a barely detectable prestimulus. This basic form of startle plasticity, seen across species from rodents to primates, has been studied extensively as an exemplar of preattentional sensory 'filters' that defend cognitive processes against the information inundation of our sensory world. A prominent theory holds that dysfunction in these filtering systems represents a core endophenotype manifested in schizophrenia, obsessive compulsive disorder, tic disorders, and possibly attention deficit hyperactivity disorder and post traumatic stress disorder. Patients suffering from this diverse range of illnesses share the common feature of an inability to screen out sensory, motor, or cognitive information, and display markedly deficient PPI. Because PPI deficits can be studied across species, PPI has become well-established as a crucial paradigm with which to study deficient sensorimotor gating in animal models of these psychiatric disorders. Much information has accrued regarding the neurochemical systems and circuits underlying PPI, particularly regarding the role of the dopamine and serotonin systems. Nevertheless, there is a striking gap in knowledge about the role of the norepinephrine (NE) system in regulating PPI. Our preliminary evidence indicates that this catecholamine plays a fundamental role in the ability of phencyclidine-like drugs (potent psychotomimetics in humans) to disrupt PPI in rodent models and the unique ability of atypical antipsychotic medications to reverse these PPI deficits. In addition, we have recently discovered that pharmacologically activating the locus coeruleus (LC), the major source of forebrain norepinephrine, markedly disrupts PPI. These data indicate that the LC-NE system represents a critical, yet almost completely overlooked central modulator of PPI. The experiments outlined in this proposal are designed to systematically characterize the role of the LC and its NE-innervated forebrain targets in regulating PPI, and in mediating the actions of psychotomimetic and antipsychotic drugs on PPI. These data may provide insights into novel circuitries underlying the regulation of PPI, and be of great relevance to understanding the neurobiology of the large set of psychiatric disorders of which dysfunctional sensorimotor gating is a central feature. Relevance to Public Health: Information-processing deficits are a major part of several psychiatric illnesses such as schizophrenia. When totaled, these illnesses represent a staggering 9-10% of the United States population. This proposal will study the neurobiology of the information-processing deficits seen in illnesses like schizophrenia in order to ultimately develop new treatments for these diseases. [unreadable] [unreadable] [unreadable]