In the majority of mammalian brain regions, neurogenesis, migration and programmed cell death occur during a discrete time period that begins during gestation. In contrast, the dentate gyrus of the rat undergoes neuronal birth, migration and death throughout the postnatal period and well into adulthood. This neural region is an ideal system in which to study these processes in the absence of similar changes occurring in afferent or efferent neuronal populations. Since the dentate gyrus develops predominantly during the postnatal period, it is especially vulnerable to early environmental perturbations that may yield permanent effects on brain function. Identification of the factors that regulate the development of the dentate gyrus may elucidate the predisposing mechanisms underlying psychiatric conditions, such as depression and posttraumatic stress disorder, the etiologies of which are thought to involve early life experiences. Moreover, studying the cues that influence the birth, migration and survival of cells in the dentate gyrus may ultimately lead to an understanding of the factors that produce abnormal hippocampal development, as seen in schizophrenia, and potentially to the ability to reverse such developmental pathology by replacing aberrant neurons. The broad, long-term objectives of this proposal are to characterize neuronal birth, migration and survival in the developing dentate gyrus and to identify and study the factors that control these processes during the postnatal period and enable their occurrence in adulthood. Specifically, these experiments will examine the effects of adrenal steroids, excitatory input and cell death on neurogenesis, migration and cell survival in this system. A series of experiments assessing the effects of adrenalectomy or hormone administration, pharmacologic receptor blockade or stereotaxic lesions of afferent populations on the birth and migration of cells will be performed using in vivo 3H-thymidine autoradiography combined with Nissl staining and immunohistochemistry for neuronal and glial specific markers. These markers will also be used to assess the possibility that neuroblasts can be stimulated to divide by dying cells. In addition, the effects of adrenal hormones on the development of excitatory amino acid receptors and dendritic spines will be examined using autoradiography and single-section Golgi impregnation respectively. Collectively, these studies are designed to provide a thorough characterization of neuronal birth, migration and survival in this unusual brain region in order to understand the cues that permit these developmental processes to occur throughout the life of the animal.
| Shors, T J; Beylin, A V; Wood, G E et al. (2000) The modulation of Pavlovian memory. Behav Brain Res 110:39-52 |
