Developmental disorders are one of several disorders that interrupt normal development in childhood. These disorders may affect only one or several different areas of development, including language, motor, social and learning skills. Learning disabilities in particular are one of the most common forms of developmental disorders and are typically diagnosed early in children. Notably, learning disabilities and developmental disorders, in general, are more often diagnosed in boys than in girls and it is thought, at least in part, to e the result of immune activation during early brain development. Despite these theories, the underlying etiologies of many developmental disorders are not well understood, particularly in the context of peripheral immune function, microglial function, and sex. The purpose of the proposed experiments is two-fold. First, we will seek to understand normal hippocampal development of microglia and the developmental expression of synaptic plasticity molecules during the onset of hippocampal dependent contextual fear learning in juvenile male and female rats. Second, we will examine how activation of the developing immune system in males and females may result in subsequent delays in microglial development, the expression of synaptic plasticity molecules in the hippocampus, and developmental delays in hippocampal dependent learning in a sex-dependent manner. The results of these experiments will significantly increase our understanding of the interactions between intrinsic factors (such as sex) and environmental factors (such as immune activation) that perturb the normal development of brain and behavior from the juvenile period and into adulthood. In addition, these experiments will identify new molecular targets of neuronal and glial interactions that are likely disrupted throughout development as a result of early-life immune activation, providing potential targets for future therapeutic interventions.
Learning disabilities are one of the most common forms of developmental disorders (affecting 7.66% of children in the U.S.) and are typically diagnosed very early in childhood. Neuroscientists do not yet fully understand just how the maturation of certain structures in the brain allows for the emergence of specific behaviors, such as learning, at specific ages. In addition, researchers know even less about how these developing neural systems are perturbed by early-life events that are known to cause developmental disorders, such as early-life immune activation or immune dysregulation. Importantly, males are twice as likely as females to be diagnosed with a number of developmental disorders and more specifically males have a higher prevalence of ADHD, autism, stuttering, and general learning disabilities than females. Thus, sex is a critical factor that must be considered when examining the etiology of developmental delays in learning. We hypothesize that sex differences in the developing immune system or microglia increases the vulnerability of males to early-life immune activation which subsequently results in immune dysregulation, the disruption of normal hippocampal development, and developmental delays in learning specifically in males. These hypotheses will be directly examined in the current proposal. Thus the proposed experiments will expand our understanding of the factors, both intrinsic (sex) and extrinsic (immune activation), that disrupt or delay the maturation of neural circuits important for learning.
