Prepulse inhibition (PPI) of the acoustic startle reflex refers to the ability of a weak stimulus preceeding a startling stimulus to inhibit the response to that stimulus. PPI is an operational measure of sensorimotor gating that is amenable to cross-species comparisons. Deficits in PPI have been reported repeatedly in patients with schizophrenia and other psychiatric disorders characterized by abnormalities in sensory, cognitive, or motor gating. Because some forms of schizophrenia appear to be attributable to early developmental insults such as prenatal infection or birth complications, many animal studies have examined the influences of specific developmental manipulations on behaviors and neural circuitry relevant to schizophrenia. Isolation rearing of rats and mice from weaning is a non-pharmacological manipulation that leads to deficits in prepulse inhibition of startle. Similar deficits in PPI are produced in rats'exposed to a prenatal immune challenge. The current proposal will extend and integrate studies of isolation rearing into the broader framework of neurodevelopmental insults, based on the conceptual and empirical connections between social isolation, chronic stress, and immune/inflammatory activation. To clarify the biological underpinnings of this integrated model, the aims of this grant are to examine the mechanistic role of alterations in the endogenous NMDA receptor antagonist, kynurenic acid (KYNA), and the stress-related neuropeptide, corticotropin releasing factor (CRF) in isolation- and immune-mediated developmental models of sensorimotor gating deficits. Recently the endogenous NMDA receptor antagonist kynurenic acid has been shown to disrupt PPI in rats. Hence, Aim 1 studies will assess the contribution of KYNA and its metabolites 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) to isolation rearing-induced PPI deficits in rats. Based on the observation that schizophrenia may be associated with a prenatal immune insult (e.g. exposure to a virus), Aim 2 studies will further characterize the effects of prenatal immune challenge on PPI and examine the contribution of KYNA to these immune-related effects on PPI. The anxiety-like phenotype and exaggerated stress responses in isolation-reared rats are consistent with alterations in the brain's CRF system. Hence, Aim 3 studies will test the hypothesized differential roles of specific CRF receptors in mediating isolation rearing-induced deficits in PPI in mice, using CRF-R1 and CRF-R2 null mutant mice.
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