Multiple studies have identified sensorimotor gating deficits in patients with schizophrenia, their first degree "unaffected" relatives, and in pharmacological and genetic mouse models of schizophrenia. These deficits in sensorimotor gating may serve as a hallmark endophenotype of the disorder. Here we propose to directly quantify the neurophysiological mechanisms that correspond with sensory gating in mice by implanting arrays of microelectrodes across 7 distinct brain areas comprising mesolimbic, mesocortical, and cortical-striatal-thalamic microcircuits and performing neurophysiological recordings as mice perform a classic sensorimotor gating task. We will then quantify the effect of the psychotomimetic agent PCP and the schizophrenia risk gene DISC1 on these circuit mechanisms. We believe that the insights derived from the current proposal into the distributed circuits that underlie normal sensorimotor gating, and the mechanisms whereby genetic and pharmacological manipulations disrupt these circuits, will provide a detailed network-level understanding of the neurophysiological alterations that may contribute to schizophrenia.

Public Health Relevance

Statement Multiple studies have identified sensorimotor gating deficits in patients with schizophrenia, their first degree unaffected relatives, and in pharmacological and genetic mouse models of schizophrenia. Here we intend to directly quantify the neurophysiological mechanisms that correspond with sensory gating in normal mice, and the gating deficits observed in pharmacological and genetic mouse models of schizophrenia. The resulting insights will lay the groundwork for a detailed network-level understanding of how genes which confer risk for schizophrenia diminish sensorimotor gating.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH099479-01A1
Application #
8582022
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Meinecke, Douglas L
Project Start
2013-07-15
Project End
2015-06-30
Budget Start
2013-07-15
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$228,660
Indirect Cost
$78,660
Name
Duke University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705