cytokines and growth factors with MD [13,20,21]. On the other hand, hypotha- lamo–pituitary–adrenocortical (HPA)-axis dysregulation is confirmed to be an important parameter for treatment out- come in MD by Schu¨ le and coworkers [19], although dysfunction of the HPA system as determined by the classical dexamethasone (DEX)/corticotrophin re- leasing hormone (CRH) test as well as with other neuroendocrine assays, seems to be neither a necessary nor a sufficient deter- minant for acute treatment response. Of interest from a biological perspective, Cze´h and coworkers [22] recently ob- served that chronic tianeptine treatment may reverse neurobiological alterations associated with chronic psychosocial stress in male tree shrews without an improve- ment in HPA functions (see also [23]). Genetic Predisposition Although no single gene could be responsible for a complex and multifacto- rial disorder like MD, association and pharmacogenetic studies identified a num- ber of loci associated with vulnerability to MD or antidepressant efficacy [8,10,24– 26]. In parallel, increasing evidences report gene6environment (G6E) effect in MD, with stress often representing the key environmental trigger of MD onset in vulnerable individuals [27]. Preclinical studies are ongoing to elucidate specific genes and environmental context that could precipitate psychopathologies [28]. An alternative approach by Touma and coworkers [29] is described here: They selected for seven generations of mice based on their corticosterone reactivity to an environmental challenge. They dem- onstrate that individuals selected to be high responders show blunted circadian rhythmicity of HPA-axis hormones, be- havioral hyperactivity, and changes in rapid eye movement (REM) and non- REM sleep, as well as slow wave activity, indicative of reduced sleep efficacy. Con- sidering the incidence of disturbed HPA axis and sleep disorders in MD patients, these selected mouse lines may offer a new important experimental tool. G6E effects are easily accessible for preclinical investigations, and the elevated number of inbred strains of mice (i.e., animals showing almost heterozygosis) available offers a powerful experimental tool. In this respect, Schweizer and coworkers [30] further clarify how differ- ent inbred strains of mice can have very different vulnerabilities to the chronic mild stress model of depression in both behav- ioral and physiological parameters, thus offering an invaluable tool to understand- ing G6E interaction in stress-induced disturbances. A Biological Pathogenesis: The Stress Model and HPA Axis Activity Stress is usually defined as a state of disturbed homeostasis inducing somatic and mental adaptive reactions, globally defined as ‘‘stress response,’’ aiming to reconstitute the initial homeostasis or a new level of homeostasis after successful adaptation, i.e., allostasis [31–34]. There is wide consensus and support from preclinical and clinical data that stress exposure conceivably plays a causal role in the etiology of MD and depression-like disorders [11,27,31,34]. However, no spe- cific mechanism linking stress exposure and stress response to the occurrence of MD has yet been fully elucidated. Grow- ing evidence indicates several classical candidates, including neurotransmitters and neuropeptides, as well as conceptually novel immune and inflammatory media- tors, as likely intermediate links between stress exposure, depressive symptoms, and MD [9,21,34–38]. Related to the latter, A˚sberg and coworkers [18] discuss in their paper in this Collection a potential role for some inflammatory mediators in a cohort of patients under prolonged psychosocial stress, providing further epidemiological support (results discussed above in this Overview). One of the hallmarks of the stress response has long been considered the activation of the HPA axis. Hypothalamic CRH activation is a pivotal signaling molecule in the regulation of the HPA axis in particular and of the stress response in general. Therefore, comprehension of the mechanism responsible for the nega- tive feedback regulation of CRH is of paramount importance. In the present Collection, van der Laan and coworkers [39] demonstrate that the timing of glucocorticoid receptors (GR) activation determines the effective repression of the cAMP-induced transcription of the CRH gene, thus clarifying that in vivo a critical time window may exist for effective repression of the CRH gene and HPA axis by glucocorticoids. Knowledge on the functioning of the HPA axis under acute or chronic chal- lenge is also a key to understanding the intimate link between stress response and the pathogenesis of depression [40]. In- deed, in all MD syndromes, a certain degree of HPA-axis disturbance is often present, visible either at the baseline or Stress & Depression with functional tests. Despite the fact that observed changes of HPA regulation are so far not specific for the diagnosis of depression or for any of its clinical syndromes [8], altered HPA-axis parame- ters are considered important biomarkers, particularly in preclinical studies. In- creased circulating hormones such as adrenocorticotropic hormone (ACTH) and cortisol/corticosterone or increased adrenal gland weight are considered biomarkers of stress response in preclinical models [41], including in several papers in this Collection [19,29,42–46]. Despite the bulk of data available, surprisingly current knowledge has not yet been developed to a point where HPA-axis reactivity can be rationally exploited for targeted drug treatment, as opposed to the major achievements of drugs targeting the CRH receptors [47]. Present data offer reliable experimental tools to stimulate future drug discovery programs [48]. Behavioral Neuroscience The DSM-IV identifies specific behav- ioral and cognitive diagnostic criteria for MD patients. Among these, depressed mood, anhedonia, locomotor disturbanc- es, and anxiety are accessible for preclin- ical investigation, while others such as feelings of worthlessness and thoughts of death or suicide cannot be reliably mim- icked in animal models. A number of animal models have been developed and validated [11,38,49–51]. In particular, models involving a chronic (i.e., continu- ous exposure to a threatening stimulus for a significant amount of time, usually weeks) or intermittent (i.e., daily short exposure to a threat for subsequent days) exposure to negative stressful events can be considered the most effective in mod- eling MD-associated behavioral and phys- iological disturbances (but see [52]). In line with this conclusion, the preclinical papers included in the Special Collection of PLoS ONE make use of chronic or intermittent models of stress [30,42–45]. Furthermore, papers in the Collection also describe animal models that are increasingly being regard- ed as the most promising to model etiological factors and key features of MD patients, i.e., i) models in which the threatening stimulus is social in nature [42,46], ii) models in which exposure to stressful stimuli occurs in the early post- natal or juvenile age [44,46]. From a nosological point of view, original research presented in the Collection further clarifies that at least some behav- ioral disturbances present in MD diagnos- tic criteria can be reliably induced and PLoS ONE | www.plosone.org 2 January 2009 | Volume 4 | Issue 1 | e4265