Renewed support is requested for MH53484, """"""""Cortico-striatal substrates of startle gating"""""""". Studies in MH 53484 have assessed the neural control of sensorimotor gating of the startle reflex in rats, focusing on the ventral hippocampus (VH) and medial prefrontal cortex (MPFC), and their interactions with the nucleus accumbens (NAC). Sensorimotor gating - measured by prepulse inhibition of startle (PPI) - is significantly reduced in schizophrenia patients;these PPI deficits are linked to both functional impairment and vulnerability genes in this disorder. In rats, PPI is reduced by specific manipulations of the VH and MPFC - limbic cortical regions strongly implicated in the pathophysiology of schizophrenia. The strategy of MH53484 is to use animal studies to understand the neural circuit basis for reduced PPI after disturbances within limbic cortex. By clarifying the basis for reduced PPI after alterations of the VH and MPFC, we will have powerful tools to explain the loss of PPI in schizophrenia, to develop new therapies to reduce functional impairment associated with this loss, and to predict the targets of genes that confer vulnerability to this disorder. New studies in this application focus on the neural interactions among the VH, MPFC and basolateral amygdala (BLA) in the regulation of PPI in rats. Studies in Aim 1 will use neuroanatomical tracing, fornix lesions and behavioral """"""""disconnection"""""""" strategies to map the serial flow of information from VH, through the MPFC and/or BLA Aim 2 will take a similar approach, focusing on the MPFC and its potential serial connections with the NAC and BLA.
Aim 3 will focus on the BLA and its potential interactions with the MPFC in the regulation of PPI, and will determine whether PPI is regulated by a serial circuit formed by the BLA and NAC.
Aim 4 will examine the impact of limbic cortical manipulations on ventral pallidal (VP) GABA release, and the role of these """"""""downstream"""""""" effects in the regulation of PPI.
Aim 5 will relate these limbic cortical substrates to broader models for schizophrenia pathophysiology, by assessing changes in sensitivity to the PPI-disruptive effects of limbic cortical manipulations in rats made """"""""vulnerable"""""""" via developmental (isolation rearing) or genetic (strain-related) variations. New information from these studies will be a foundation for innovative models of the pathophysiology of schizophrenia and other inherited neuropsychiatric disorders, and for prospective strategies for novel drug development.
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