Stress and the Developing Hippocampus: A Double-Edged Sword?

Abstract

The mechanisms that regulate neuronal function are a sum of genetically determined programs and experience. The effect of experience on neuronal function is particularly important during development, because early-life positive and adverse experience (stress) may influence the still "plastic" nervous system long-term. Specifically, for hippocampal-mediated learning and memory processes, acute stress may enhance synaptic efficacy and overall learning ability, and conversely, chronic or severe stress has been shown to be detrimental. The mechanisms that enable stress to act as this "double-edged sword" are unclear. Here, we discuss the molecular mediators of the stress response in the hippocampus with an emphasis on novel findings regarding the role of the neuropeptide known as corticotropin-releasing hormone (CRH). We highlight the physiological and pathological roles of this peptide in the developing hippocampus, and their relevance to the long-term effects of early-life experience on cognitive function during adulthood. KeywordsCorticotropin-releasing hormone; CRH; CRF; stress; development; hippocampus; rat; learning and memory; excitotoxicity; neuroplasticity Input from the Environment Influences Neuronal and Circuit FunctionIn addition to intrinsic, genetically determined programs, inputs from the environment, or experience, regulate neuronal function. Thus, brain development and organization and the evolution of systems and circuits are governed by inherent, gene-dependent programs. Much has been unraveled about the genes that control neuronal fate, and differentiation and migration, and about the establishment and pruning of synaptic connectivity (1-3). These genetically determined programs provide a blueprint for the connectivity among neurons, the specificity of their input and responses, and the numerous other unresolved parameters that determine the function of the central nervous system (CNS) as a whole. Superimposed on this intricate, intrinsic blueprint, mechanisms that permit modulation by "experience" exist in the mammalian CNS. In other words, the CNS is designed with the capacity to be influenced, both immediately and long-term, by sensory input from within as well as the outside environment. This modulation, termed "plasticity," involves altered expression and function of specific neuronal genes in discrete regions, cells, and synapses in response to a wide range of signals. For example, short-term neuronal plasticity (e.g., synaptic Environment-Driven Neuroplasticity is Most Critical During DevelopmentThe effects of experience on neuronal activity are particularly important during development, when external stimuli may influence CNS function and interact with ongoing developmental programs to alter final neuronal "hard-wiring." Indeed, during the first postnatal weeks, neuronal birth, differentiation, and migration are still ongoing (6-8), and neuronal connectivity-for example, in the hippocampus-is incomplete (9-12). Do early life experiences, both "positive" (e.g., environmental enri...

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