experimentally determined in animals models, including for anhedonia [30], locomotor disturbances [29,42,44,53], anxiety [44,53], sleep pattern [29], and learning/memory [44,53]. Of main inter- est is the experimental evidence [30] that a shift in the circadian rhythm induced by overnight illumination is the single most important experimental factor influencing the intake of a sweetened solution, which is the currently accepted animal equivalent of evidence of anhedonia [54]. Further- more, Ilin and Richter-Levine [44] show that daily exposure to a stressful stimulus for three consecutive days at a juvenile age (named juvenile stress, JS), determines long-lasting behavioral and motivational effects in rats, i.e., increased anxiety, lower exploratory drive, and increased learned helplessness. On the contrary, housing JS rats in an enriched environment complete- ly abolished JS-induced behavioral effects. A similar ameliorating effect on stress coping has also been determined by Collins and coworkers [53], by exposing rats to a different form of environmental enrichment, i.e., home cage presence of a running wheel which induces in rodents spontaneous physical exercise. Exercised rats show increased behavioral coping and reduced anxiety and depression-like be- haviors in the open field test and in the forced swimming test when compared with sedentary rats. Molecular Neuroscience In the postgenomic era, high-throughput techniques allow the identification of genes overexpressed or downregulated in selected brain regions after chronic stress exposure or in MD. Following these observations, researchers now aim at translating omics evidences into experimentally based results (based on on purpose experimental designs). For example, the ‘‘sequenced treatment alternatives to relieve depression’’ (STAR*D) clinical trial identified several loci associated with response to anti- depressants and suicidal ideation in MD patients [55,56]. Among these is the gene encoding for a class of ionotropic glutamate receptors known as kainate receptors (KA). Hunter and coworkers [45] now report that KA1 subunit mRNA is selectively modu- lated by stress- and HPA-axis activity in the dentate gyrus and CA3 region of the hippocampal formation. Another fruitful approach follows the identification of potential biomarkers in postmortem brain tissue of MD patients. A recent study found in the prefrontal and parieto-occipital cortex of MD patients an altered level of the L1-cell adhesion molecule (L1-CAM) [57]. Ilin and Richter-Levin [44] firstly demonstrate that juvenile stress in rats is able to upregulate L1-CAM expression in the basolateral amygdala and the thalamus (in parallel with behavioral disturbances described above), and secondly they prove that environmental enrichment is able to reverse stress-induced alterations. A final example concerns the role of membrane glycoprotein M6a in stress and neuroplas- ticity. M6a mRNA was found to be upregulated in the hippocampus of both mice and tree shrews under chronic stress [58,59]. Cooper and coworkers [43] now establish for the first time that only a splice variant, M6a-Ib, is modulated in a region- ally dependent manner, i.e., downregulated in the dentate gyrus granule neurons and in CA3 pyramidal neurons while upregulated in the medial prefrontal cortex. According to the examples above, it can be concluded that changes in gene expres- sion and their association with behavioral traits or psychopathologies remain among the more powerful experimental tools to uncover the mechanisms leading to a brain disorders. In addition, recent find- ings demonstrate that complex ‘‘epigenet- ic’’ mechanisms, which regulate gene activity without altering the DNA code, have long-lasting effects within mature neurons [60]. An example of the former is presented by Collins and coworkers [53], who establish that histone (H3) phospho-acetylation and c-Fos immunore- activity increase in the dentate gyrus upon exposure to a novel environment or to forced swimming and that their expression is further augmented in exercised rats. Another fruitful research area in bio- logical psychiatry is the link between neural plasticity, MD, and antidepressants [9,13,32,61]. In particular, neurogenesis in the granular layer of the dentate gyrus is impaired by stress exposure and increased by other environmental factors including environmental enrichment or exercise [9,61]. Of main interest was the demon- stration that hippocampal neurogenesis is required for the beneficial effect of some but not all antidepressant classes [62–64]. Although impaired neurogenesis could not be confirmed in a human cohort of MD patients [65], the study of adult hippo- campal neurogenesis in MD has benefited tremendously from the attention it has received, and results will ultimately dem- onstrate its role in the etiology and/or treatment of MD [60]. Oomen and coworkers [46] now demonstrate that maternal deprivation in rats at postnatal day 3, which induces a transient increase of maternal care, also determines impaired neurogenesis in the dentate gyrus (DG) of Stress & Depression female rats, while increasing neurogenesis in male rats. Therefore, early environment may have a critical influence on establish- ing long-held sex differences in neural plasticity. This finding is particularly interesting because MD incidence in women is about twice that for men [66]. Metabolic Functions In addition to neuroanatomical chang- es, MD is also associated with severe vegetative and biological disturbances, including sleep and eating disorders, body weight changes, and neuroendocrine ab- normalities. The DSM-IV indicates as diagnostic criteria increased or diminished appetite/body weight which should repre- sent a change from pre-MD onset. Most animal models including several discussed in the present Collection [30,43–45] de- scribe stress-associated weight loss, which has long being considered a face-validity criterion for a valid animal model of MD [67]. Until recently there was a paucity of animal models of chronic stress-induced weight gain. Bartolomucci and coworkers [42] now report a mouse model of social subordination stress with behavioral de- pression-like responses and neuroendo- crine disturbances, which also determine hyperphagia, weight gain, and increased vulnerability to obesity. In addition, an- other study in the present Collection [46] reports that maternal deprivation deter- mined increased weight gain in juvenile rats when compared with undisturbed controls. These data offer new experimen- tal tools to investigate the link between mood disorders and metabolic functions. In this respect it is remarkable that obesity is often found in comorbidity with MD and particularly so with the atypical depression subtype [68], while clinical efficacy of antidepressants is reduced in obese individuals [69]. Accordingly, there is a great need to rule out the mechanism responsible for stress-induced positive or negative energy balance in different ani- mal models as well as in MD patients. ‘‘Stress-Induced Depression’’ (STRID): A New Depression Subtype? The notion that stress may cause depression has been an underlying con- cept in the choice of papers included in the PLoS ONE Collection discussed here. The link between stress and depression is not novel, and several authors have aimed at identifying new subtypes of depression based on their functional link with stress exposure (e.g., [70–72]). Of special interest PLoS ONE | www.plosone.org 3 January 2009 | Volume 4 | Issue 1 | e4265