Vol 8, No 4 - Stress
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I n  t h i s  i s s u e... It is empirical truth for most that stress is not good for us, and, further, we now recognize that stress comes in dif- ferent flavors and cannot be considered a unitary phe- nomenon. Nothing new there. What is new, however, is the recognition that the stress response is not simply an amplifier of behavioral and affective symptoms but is instead critical to their development and expression. What are the isomorphs between stress maladaptation and psy- chophathology, how does stress change how the brain learns, and what are the molecules and circuits of the stress response? In this issue of Dialogues in Clinical Neuroscience, these questions are answered by authors who both decompose the stress response, identifying its chemical and neural mediators, and demonstrate the centrality of stress adaptation to compromised as well as resilient psychological functioning. In the State of the art opening article, Bruce McEwen describes the brain as not only the director of the stress response, but also its target. The cumulative demands of everyday life combine with the efficiency of one’s man- agement of stressors to generate what Dr McEwen calls “allostatic overload,”the consequences of which include both chemical and structural remodeling of the brain. Current knowledge of this process is sufficient to argue for the implementation of societal policies to reduce allo- static overload. In the first Basic research article, Sean Smith and Wylie Vale deconstruct the stress response by first describing the pharmacology of its hormonal components, particularly the corticotropin-releasing factor (CRF) family of peptides, largely discovered through the work of Dr Vale and col- leagues. The authors then clearly and comprehensively describe the neuroendocrine and neuronal regulation of the hypothalamic-pitutary-adrenal (HPA) axis. With this back- ground, the diversity of the stress response becomes clear, as different stressors activate different neurocircuitry, with different behavioral and physiological consequences. In the second Basic research article, Steven Maier and colleagues, in a tour de force, describe the central role of the medial prefrontal cortex in the perception of control and in the subsequent inhibition of the adverse conse- quences of stress. Further, they demonstrate that the acti- vation of the medial prefrontal cortex, rather than the controllability of the stressor, is what determines both the acute response to stressor and the response to subse- quent stressors. These “behavioral immunization”studies provide a unique framework for understanding the devel- opment and expression of resilience or psychopathology in the face of repeated exposure to traumatic stressors. In the third Basic research article, Jay Schulkin redirects our attention from the prefrontal cortex to the amygdala. Known for years to be central to the fear response, the amygdala has increasingly been implicated in a variety of psychiatric disorders, including depression and post-trau- matic stress disorder (PTSD). Dr Schulkin first describes the anatomical complexity of the amygdala and the implica- tions of the differential “wiring.” He then suggests how stress-induced glucocorticoid secretion may, in the prop- er genetic context, increase corticotropin-releasing hor- mone (CRH) expression in the amygdala and, by so doing, result in exaggerated subsequent amygdala responses to stress, with concomitant alterations in both the percep- tion of and response to life events. Some of the ambiguities in stress research are explained in the fourth Basic research article by Vladimir and Alexandre Patchev, who systematically review existing ani- mal models for the stress response. These authors first describe the multitude of outcome measures that have been employed and then the variety of experimental approaches to stress induction .While no perfect model exists, appreciation of the major sources of variance per- mits the integration of what otherwise might be viewed as disparate findings. In the first Clinical research article, Marcus Ising and Flo- rian Holsboer review the heritability and genetic associa- tion studies of the stress response before arguing that the study of stress-related disorders—hypertension, coronary artery disease, and affective illness (bipolar and unipo- lar)—reveals genes relevant to the stress response that would not otherwise be identified. The authors describe how burgeoning technical capabilities must be dovetailed with clinical investigations that assess gene-gene and gene-environment interactions if we are to understand the role of genetic context in the etiopathogenesis of the stress response. In the second Clinical research article, J. Douglas Brem- ner uses brain imaging data to trace the neurocircuitry of the response to (and consequences of) traumatic stress in humans. The brain regions so identified are then exam-