There is considerable evidence that perinatal glucocorticoid (GC) exposure, either from the administration of drugs or during periods of extreme perinatal stress, can produce neurodevelopmental deficits leading to permanent neuropsychlatric disorders. In our preliminary results, we have found that acute injections of GCs and exposure to neonatal stress can both produce an identical pattern of neural progenitor cell (NFC) apoptotic degeneration in the developing rodent cerebellum. Therefore, delineating the underlying mechanisms for this toxicity has the potential to provide important information for perinatal healthcare and basic mechanisms of neuredevelopment. While the cerebellum has traditionally been associated with neuromotor function, recent research has established that it plays a critical role in cognitive and affective behaviors. Therefore, this research may also suggest a role for GC induced cerebellar dysfunction in a variety of neuropsychlatric conditions. Consistent with this idea, prematurely born infants exposed to GCs have been found to develop cognitive and neuromotor deficits when compared to a saline control group. Of equal importance, exposure to perinatal stress has been associated with cognitive and affective dysfunction and has been implicated in a variety of neuropsychlatric conditions.
In Aim 1, the applicant will test the potential safener drug lithium for its ability to protect against GC induced NPC apoptosis and its long term effects in the cerebellum.
In Aim 2, the applicant will determine whether a perinatal stress paradigm associated with increased corticosterone release can produce apoptosis in cerebellar NPCs acutely and produce long term reductions in cerebellar granule cells. Finally, in Aim 3, the applicant will make use of the Cre/lox recombination system to selectively knockout GC receptors in the NPCs of the cerebellum in order to determine their role in this toxicity and cerebellar development. While conducting the proposed research plan the applicant will become trained in several areas critical for his career development including immunohistochemistry, pharmacokinetics, electron microscopy, stereology, the use of both knockout mice and conditional knockout mice, radioimmunoassay, and viral vector maintenance and use.
Currently, a large number of fetuses/neonates are exposed to GCs for either perinatal medical treatment or during the endogenous release associated with perinatal stress. Both of these conditions are known to produce permanent behavioral deficits yet little is known about how this occurs. Therefore, this research may provide key insights on the effects of exposure to GCs on perinatal health.
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