The proposed research will explore interactions between the immune system and learning/memory processes by examining IL-1 beta?s 1) site of action, 2) source of action, and 3) mechanisms of action that mediate hippocampal dependent contextual fear impairments. To determine whether IL-1beta is acting at the dorsal hippocampus to produce memory impairments, contextual fear will be tested in rats which receive an (a) LPS (peripheral) or (b) IL-1 beta (central) injection while endogenous dorsal hippocampal IL-1 beta is being inhibited with IL-I receptor antagonist (IL-1ra). To determine whether the source of brain-derived IL-l beta is neuronal and/or glial, (a) single- and (b) double-label immunohistochemical studies will be conducted to detect cell type and cell content in hippocampus following a peripheral injection of LPS. To explore whether IL- l beta impairs contextual fear by altering dorsal hippocampal glutamate release, in vivo microdialysis studies will be conducted to measure (a) unstimulated and (b) KCl-stimulated glutamate release following a peripheral injection of LPS. If LPS induces alterations in glutamate release, IL-1ra will be infused into the sampling region to determine whether such alterations are mediated specifically by IL-1 beta. These studies will answer some important questions about where and how pro-inflammatory cytokines may act to impair hippocampal-dependent memory processes.
