A prominent hypothesis for the development of psychiatric diseases, such as schizophrenia, is the two-hit hypothesis. Recent evidence suggests that maternal immune activation may represent the first hit, whereas subsequent stressors to the offspring serve as additional secondary precipitants (second hit) of disease onset. Much of this evidence is for innate immune responses. Therefore, in the present set of studies, it is proposed to determine whether T cell activation in pregnant mice will serve as an initial sensitizing agent in the developing embryo;this may render future stressors in the postpartum and postpubertal periods more destabilizing to maintenance of normal behavior. Induction of T cell activation will involve the use of bacterial T cell superantigens (SAgs), such as Staphylococcal enterotoxins A and B (SEA;SEB), which activate T cells in vivo and induce high levels of cytokines. In addition, they activate the hypothalamic-pituitary-adrenal (HPA) axis, cortical and limbic brain regions, and alter cognitive and emotional behaviors. The study will encompass a single specific aim, which will investigate the immunologic effects of SEA in pregnant mice, and determine whether this exerts an influence on cognitive and sensorimotor behavioral functions of male and female offspring. Furthermore, postpubertal conditions of chronic psychogenic stress (the second hit) will also be imposed on subsets of male and female offspring from SEA or Saline-injected mothers. Cognitive functions to be assessed will include (i) spatial navigation learning in the Morris water maze (MWM), that will include a working memory component, and (ii) an operant learning task of response-inhibition. In addition, mice will be subjected to a test of prepulse inhibition (PPI), which measures sensorimotor gating, a neural mechanism deficient in schizophrenia. Finally, to probe for anxiety-related and depression-like behavioral changes, mice will be tested for open field behavior, the elevated plus maze (EPM), and sucrose consumption (to test anhedonia). These studies will contribute to an understanding of T cell mediated effects on brain development in the intrauterine environment, and the risk this represents for normal neurobehavioral development and behavioral adaptation to psychogenic stressors.
The early life origins of psychiatric diseases, such as schizophrenia, may represent a compounding of different environmental influences that alter the course of normal brain and behavioral development. Immunological responses of the pregnant female to infectious agents, and behavioral maladaptation of the offspring to psychological stressors, figure prominently in this conceptualization. Therefore, understanding how intrauterine immune responses shape the future neurodevelopmental progress of the offspring may reveal important approaches to predicting, and reversing, early-life psychiatric disease.
|Ye, Xuan; Feng, Tuancheng; Tammineni, Prasad et al. (2017) Regulation of Synaptic Amyloid-? Generation through BACE1 Retrograde Transport in a Mouse Model of Alzheimer's Disease. J Neurosci 37:2639-2655|