A Comprehensive Overview on Stress Neurobiology: Basic Concepts and Clinical Implications

Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.

Adaptive goal-directed behavior involves monitoring of ongoing actions and performance outcomes, and subsequent adjustments of behavior and learning. We evaluate new findings in cognitive neuroscience concerning cortical interactions that subserve the recruitment and implementation of such cognitive control. A review of primate and human studies, along with a meta-analysis of the human functional neuroimaging literature, suggest that the detection of unfavorable outcomes, response errors, response conflict, and decision uncertainty elicits largely overlapping clusters of activation foci in an extensive part of the posterior medial frontal cortex (pMFC). A direct link is delineated between activity in this area and subsequent adjustments in performance. Emerging evidence points to functional interactions between the pMFC and the lateral prefrontal cortex (LPFC), so that monitoring-related pMFC activity serves as a signal that engages regulatory processes in the LPFC to implement performance adjustments.

This article presents a new formulation of the relationship between stress and the processes leading to disease. It emphasizes the hidden cost of chronic stress to the body over long time periods, which act as a predisposing factor for the effects of acute, stressful life events. It also presents a model showing how individual differences in the susceptibility to stress are tied to individual behavioral responses to environmental challenges that are coupled to physiologic and pathophysiologic responses. Published original articles from human and animal studies and selected reviews. Literature was surveyed using MEDLINE. Independent extraction and cross-referencing by us. Stress is frequently seen as a significant contributor to disease, and clinical evidence is mounting for specific effects of stress on immune and cardiovascular systems. Yet, until recently, aspects of stress that precipitate disease have been obscure. The concept of homeostasis has failed to help us understand the hidden toll of chronic stress on the body. Rather than maintaining constancy, the physiologic systems within the body fluctuate to meet demands from external forces, a state termed allostasis. In this article, we extend the concept of allostasis over the dimension of time and we define allostatic load as the cost of chronic exposure to fluctuating or heightened neural or neuroendocrine response resulting from repeated or chronic environmental challenge that an individual reacts to as being particularly stressful. This new formulation emphasizes the cascading relationships, beginning early in life, between environmental factors and genetic predispositions that lead to large individual differences in susceptibility to stress and, in some cases, to disease. There are now empirical studies based on this formulation, as well as new insights into mechanisms involving specific changes in neural, neuroendocrine, and immune systems. The practical implications of this formulation for clinical practice and further research are discussed.