This cross-species translational research project will use specific laboratory-based measures of gating and inhibitory functions to better understand the convergence and divergence of information-processing abnormalities in schizophrenia patients, and elucidate the clinical significance and neurobiological substrates of these abnormalities. The measures are: 1) prepulse inhibition of startle (PPI); 2) P50 (humans) and N40 (animals) event-related potential suppression; 3) startle habituation and 4) oculomotor antisaccade performance. Although groups of schizophrenia patients have deficits on each of these 4 measures, any single patient may exhibit deficits in some but not all of the measures. Similarly, in animals, pharmacological, neuroanatomical, and genetic manipulations have differential effects on these measures. Hence, 300 medicated, 100 non-medicated patients, and 200 normal subjects will be tested on all 4 inhibitory measures. The human research aims are to: 1) confirm and extend findings of inhibitory deficits in schizophrenia patients; 2) identify subgroups of schizophrenia patients based on patterns of deficits in the 4 inhibitory measures; 3) determine how subgroup membership and individual inhibitory deficits relate to clinical domains of demographic, symptom, neurocognitive, and functional status; 4) study patients over time to examine the stability and clinical importance of both subgroups and inhibitory measures. In animals, the project will assess similarities and differences among PPI, N40 suppression, and habituation measures, using parametric, pharmacological, and molecular biological manipulations in mice, rats, and marmosets. Simultaneous measures of PPI, N40 suppression, and/or habituation will be used in rats to assess the effects of psychotomimetic dopaminergic, serotonergic, and glutamatergic drugs. The role of specific receptors in the effects of antipsychotic drugs on inhibitory measures will be assessed in genetically engineered mice. Differential neural substrates of inhibitory measures will be identified using anatomically specific manipulations of the thalamus or ventral hippocampus in rats. Thus, this proposal is designed to """"""""parse"""""""" groups of schizophrenia patients according to convergence and divergence of inhibitory deficits, to examine both """"""""bottom up"""""""" applications (e.g. assessing the relationships of inhibitory measures to predict symptoms, neurocognitive deficits, functional status, and outcome) and """"""""top down"""""""" applications (e.g. applying these measures to understand the neural substrates of schizophrenia using lesion, pharmacological, and genetic manipulations) by using the interactive human and animal experiments.
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