The focus of this proposal is to study how the limbic-hypothalamo- pituitary-adrenal (LHPA) axis changes as a function of developmental events, genetic predisposition and exposure to repeated stress, and how these factors contribute to individual differences in stress responsiveness throughout life, including during the aging process. Exactly when and how the stress exposure takes place may lead to different consequences on the endocrine, molecular, neuronal and behavioral functioning of the animal. Understanding the """"""""plasticity"""""""" of the LHPA axis is important in helping us describe how the system maintains optimal responsiveness to stress, and how it incorporates past experience into the coping process. Thus we shall explore these issues via 3 interrelated sets of studies: 1) In a series of developmental studies, we shall examine the neuronal bases of the stress hyporesponsive period (SHRP) in the rat and the mechanisms associated with the animal's emergence from it into stress responsiveness. We shall look at the consequences of 4 models of early stress (maternal deprivation with various timing, and changes in litter size) on the duration of the SHRP, and on stress responsiveness in adult life, focusing on relating changes in the brain circuits to alterations in endocrine profiles and in learning, memory and response to novelty; 2) In studies focused on aging, we shall examine some of the determinants of individual differences in stress responsiveness in aged animals in order to understand why some animals are impaired and others are not as they age. We shall study the effect of genetic predisposition on the aging process by contrasting two strains of rats, Fisher and Lewis, which are known to have different stress response profiles. We shall also study how events taking place during development may impact on the aging process, by studying the consequences of the developmental models as the animals age, including effects on stress responsiveness, brain responsiveness and learning and memory; 3) In studies focused on young adult animals, we shall investigate the neuronal mechanisms of sensitization and habituation to repeated stressors. In particular, we shall focus on the role of specific brain structures (e.g., the suprachiasmatic nucleus, and the prefrontal cortex) in contributing to this type of plasticity. Finally, we shall begin to investigate the potential role of NMDA receptors in these plastic processes. This combination of studies should provide us with a better understanding of how the stress axis is modified throughout the life of the animal, and how this contributes to individual differences in stress responsiveness and coping.
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