Research has shown that immune activation outside the brain may produce changes within the brain and alter subsequent behavior, potentially rendering one more susceptible to stress reactivity and mental illness. Among the many behavioral effects of peripheral immune activation is the potential for a negative impact upon learning and memory processes. A particularly important question that has yet to be thoroughly explored is to what extent do immune-mediated inflammatory events during early development lead to long-term changes in behavior? The specific aims of this exploratory/developmental grant are designed to develop a mouse model of perinatal immune activation and long-term consequences of immune activation upon anxiety, activity, and learning behavior. From these initial exploratory studies, a significant body of research may come, in which key developmental windows (i.e., critical periods) during which the brain is particularly sensitive to immune-induced insult, as well as the key proteins involved in such disturbances, may be identified.
The specific aims i nclude: 1). Investigating the long-term effects of perinatal endotoxin (derived from the bacterium E. coil) injections in two commonly used inbred mouse strains on well-validated tests of anxiety and locomotor activity, 2). Investigating the developmental effects of perinatal endotoxin in two commonly used mouse strains on well-established tests of spatial and non-spatial learning and memory, 3). Ascertaining that observed effects of perinatal endotoxin on performance in a given learning paradigm are, in fact, effects on learning, as opposed to effects on performance due to other factors (e.g., increased stress reactivity, increased anxiety, decreased motor activity, etc.), 4). Explore limited parameters of dose, developmental timepoint, and strain-related aspects of the behavioral effects of neonatal endotoxin exposure, and 5). Verify and explore the effects of peripheral endotoxin exposure on proinflammatory cytokine (factors induced by endotoxin that promote inflammation) gene expression within the neonatal brain. These studies will enable us to test the hypothesis that inflammatory cytokines induced in brain following immune activation in the periphery may alter the developmental trajectory of mammals exposed to unusual immune activation during important periods of neural development. Ultimately, this work may contribute to our understanding of important new perinatal risk factors.
