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Recent years have seen increased interest in psychopathologies related to trauma exposure. Specifically, there has been a growing awareness to posttraumatic stress disorder (PTSD) in part due to terrorism, climate change-associated natural disasters, the global refugee crisis, and increased violence in overpopulated urban areas. However, notwithstanding the increased awareness to the disorder, the increasing number of patients, and the devastating impact on the lives of patients and their families, the efficacy of available treatments remains limited and highly unsatisfactory. A major scientific effort is therefore devoted to unravel the neural mechanisms underlying PTSD with the aim of paving the way to developing novel or improved treatment approaches and drugs to treat PTSD. One of the major scientific tools used to gain insight into understanding physiological and neuronal mechanisms underlying diseases and for treatment development is the use of animal models of human diseases. While much progress has been made using these models in understanding mechanisms of conditioned fear and fear memory, the gained knowledge has not yet led to better treatment options for PTSD patients. This poor translational outcome has already led some scientists and pharmaceutical companies, who do not in general hold opinions against animal models, to propose that those models should be abandoned. Here, we critically examine aspects of animal models of PTSD that may have contributed to the relative lack of translatability, including the focus on the exposure to trauma, overlooking individual and sex differences, and the contribution of risk factors. Based on findings from recent years, we propose research-based modifications that we believe are required in order to overcome some of the shortcomings of previous practice. These modifications include the usage of animal models of PTSD which incorporate risk factors and of the behavioral profiling analysis of individuals in a sample. These modifications are aimed to address factors such as individual predisposition and resilience, thus taking into consideration the fact that only a fraction of individuals exposed to trauma develop PTSD. We suggest that with an appropriate shift of practice, animal models are not only a valuable tool to enhance our understanding of fear and memory processes, but could serve as effective platforms for understanding PTSD, for PTSD drug development and drug testing.

Sex differences and social context independently contribute to the development of stress-related disorders. However, less is known about how their interplay might influence behavior and physiology. Here we focused on social hierarchy status, a major component of the social environment in mice, and whether it influences behavioral adaptation to chronic stress in a sex-specific manner. We used a high-throughput automated behavioral monitoring system to assess social dominance in same-sex, group-living mice. We found that position in the social hierarchy at baseline was a significant predictor of multiple behavioral outcomes following exposure to chronic stress. Crucially, this association carried opposite consequences for the two sexes. This work demonstrates the importance of recognizing the interplay between sex and social factors and enhances our understating of how individual differences shape the stress response. Most people experience chronic stress at some point in their life, which may increase their chances of developing depression or anxiety. There is evidence that chronic stress may more negatively impact the well-being of women, placing them as higher risk of developing these mental health conditions. The biological factors that underlie these differences are not well understood, which leaves clinicians and scientists struggling to develop and provide effective treatments. The social environment has a powerful influence on how people experience and cope with stress. For example, a person’s social and socioeconomic status can change their perception of and reaction to everyday stress. Researchers have found differences in how men and women relate to their social standing. One way for scientists to learn more about the biological processes involved is to study the effect of social standing and chronic stress in male and female mice. Now, Karamihalev, Brivio et al. show that social status influences the behavior of stressed mice in a sex-specific way. In the experiments, an automated observation system documented the behavior of mice living in all female or male groups. Karamihalev, Brivio et al. determined where each animal fit into the social structure of their group. Then, they exposed some groups of mice to mild chronic stress and compared their behaviors to groups of mice housed in normal conditions. They found that both the sex and social status of each played a role in how they responded to stress. For example, subordinate males displayed more anxious behavior under stressful circumstances, while dominant females acted bolder and less anxious. More studies in mice are needed to understand the biological basis of these social- and sex-based differences in stress response. Learning more may help scientists understand why some individuals are more susceptible to the effects of stress and lead to the development of personalized prevention or treatment strategies for anxiety and depression.

Chronic stress has been found to be a major risk factor for various human pathologies. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, which is tightly regulated via, among others, the glucocorticoid receptor (GR). The activity of the GR is modulated by a variety of proteins, including the co-chaperone FK506 binding protein 51 (FKBP5). Although FKBP5 has been associated with risk for affective disorders and has been implicated in GR sensitivity, previous studies focused mainly on peripheral blood, while information about basal distribution and induction in the central nervous system are sparse. In the present study, we describe the basal expression pattern of Fkbp5 mRNA in the brain of adult male mice and show the induction of Fkbp5 mRNA via dexamethasone treatment or different stress paradigms. We could show that Fkbp5 is often, but not exclusively, expressed in regions also known for GR expression, for example the hippocampus. Furthermore, we were able to induce Fkbp5 expression via dexamethasone in the CA1 and DG subregions of the hippocampus, the paraventricular nucleus (PVN) and the central amygdala (CeA). Increase of Fkbp5 mRNA was also found after restrained stress and 24 hours of food deprivation in the PVN and the CeA, while in the hippocampus only food deprivation caused an increase in Fkbp5 mRNA. Interestingly, regions with a low basal expression showed higher increase in Fkbp5 mRNA following induction than regions with high basal expression, supporting the hypothesis that GR sensitivity is, at least partly, mediated via Fkbp5. In addition, this also supports the use of Fkbp5 gene expression as a marker for GR sensitivity. In summary, we were able to give an overview of the basal expression of fkbp5 mRNA as well as to extend the findings of induction of Fkbp5 and its regulatory influence on GR sensitivity from peripheral blood to the brain.

Depressive disorders are the most burdensome psychiatric disorders worldwide. Although huge efforts have been made to advance treatment, outcomes remain unsatisfactory. Many factors contribute to this gridlock including suboptimal animal models. Especially limited study comparability and replicability due to imprecise terminology concerning depressive-like states are major problems. To overcome these issues, new approaches are needed. Here, we introduce a taxonomical concept for modelling depression in laboratory mice, which we call depression-like syndrome (DLS). It hinges on growing evidence suggesting that mice possess advanced socioemotional abilities and can display non-random symptom patterns indicative of an evolutionary conserved disorder-like phenotype. The DLS approach uses a combined heuristic method based on clinical depression criteria and the Research Domain Criteria to provide a biobehavioural reference syndrome for preclinical rodent models of depression. The DLS criteria are based on available, species-specific evidence and are as follows: (I) minimum duration of phenotype, (II) significant sociofunctional impairment, (III) core biological features, (IV) necessary depressive-like symptoms. To assess DLS presence and severity, we have designed an algorithm to ensure statistical and biological relevance of findings. The algorithm uses a minimum combined threshold for statistical significance and effect size ( p value ≤ 0.05 plus moderate effect size) for each DLS criterion. Taken together, the DLS is a novel, biologically founded, and species-specific minimum threshold approach. Its long-term objective is to gradually develop into an inter-model validation standard and microframework to improve phenotyping methodology in translational research.

The stress response is an essential mechanism for maintaining homeostasis, and its disruption is implicated in several psychiatric disorders. On the cellular level, stress activates, among other mechanisms, autophagy that regulates homeostasis through protein degradation and recycling. Secretory autophagy is a recently described pathway in which autophagosomes fuse with the plasma membrane rather than with lysosomes. Here, we demonstrate that glucocorticoid-mediated stress enhances secretory autophagy via the stress-responsive co-chaperone FK506-binding protein 51. We identify the matrix metalloproteinase 9 (MMP9) as one of the proteins secreted in response to stress. Using cellular assays and in vivo microdialysis, we further find that stress-enhanced MMP9 secretion increases the cleavage of pro-brain-derived neurotrophic factor (proBDNF) to its mature form (mBDNF). BDNF is essential for adult synaptic plasticity and its pathway is associated with major depression and posttraumatic stress disorder. These findings unravel a cellular stress adaptation mechanism that bears the potential of opening avenues for the understanding of the pathophysiology of stress-related disorders. Glucocorticoids are associated with stress. Here, the authors show that high levels of glucocorticoid stress promote secretory autophagy of matrix metalloproteinase 9 via a stress responsive chaperone, increasing brain-derived neurotrophic factor processing and potentially altering adult synaptic plasticity.

FK506 binding protein 51 (FKBP51) is an Hsp90 co-chaperone and regulator of the glucocorticoid receptor, and consequently of stress physiology. Clinical studies suggest a genetic link between FKBP51 and antidepressant response in mood disorders; however, the underlying mechanisms remain elusive. The objective of this study was to elucidate the role of FKBP51 in the actions of antidepressants, with a particular focus on pathways of autophagy. Established cell lines, primary neural cells, human blood cells of healthy individuals and patients with depression, and mice were treated with antidepressants. Mice were tested for several neuroendocrine and behavioral parameters. Protein interactions and autophagic pathway activity were mainly evaluated by co-immunoprecipitation and Western blots. We first show that the effects of acute antidepressant treatment on behavior are abolished in FKBP51 knockout (51KO) mice. Autophagic markers, such as the autophagy initiator Beclin1, were increased following acute antidepressant treatment in brains from wild-type, but not 51KO, animals. FKBP51 binds to Beclin1, changes decisive protein interactions and phosphorylation of Beclin1, and triggers autophagic pathways. Antidepressants and FKBP51 exhibited synergistic effects on these pathways. Using chronic social defeat as a depression-relevant stress model in combination with chronic paroxetine (PAR) treatment revealed that the stress response, as well as the effects of antidepressants on behavior and autophagic markers, depends on FKBP51. In human blood cells of healthy individuals, FKBP51 levels correlated with the potential of antidepressants to induce autophagic pathways. Importantly, the clinical antidepressant response of patients with depression (n = 51) could be predicted by the antidepressant response of autophagic markers in patient-derived peripheral blood lymphocytes cultivated and treated ex vivo (Beclin1/amitriptyline: r = 0.572, p = 0.003; Beclin1/PAR: r = 0.569, p = 0.004; Beclin1/fluoxetine: r = 0.454, p = 0.026; pAkt/amitriptyline: r =  -0.416, p = 0.006; pAkt/PAR: r =  -0.355, p = 0.021; LC3B-II/PAR: r = 0.453, p = 0.02), as well as by the lymphocytic expression levels of FKBP51 (r = 0.631, p<0.0001), pAkt (r =  -0.515, p = 0.003), and Beclin1 (r = 0.521, p = 0.002) at admission. Limitations of the study include the use of male mice only and the relatively low number of patients for protein analyses. To our knowledge, these findings provide the first evidence for the molecular mechanism of FKBP51 in priming autophagic pathways; this process is linked to the potency of at least some antidepressants. These newly discovered functions of FKBP51 also provide novel predictive markers for treatment outcome, consistent with physiological and potential clinical relevance. Please see later in the article for the Editors' Summary.

Severe stress exposure increases the risk of stress-related disorders such as major depressive disorder (MDD). An essential characteristic of MDD is the impairment of social functioning and lack of social motivation. Chronic social defeat stress is an established animal model for MDD research, which induces a cascade of physiological and behavioral changes. Current markerless pose estimation tools allow for more complex and naturalistic behavioral tests. Here, we introduce the open-source tool DeepOF to investigate the individual and social behavioral profile in mice by providing supervised and unsupervised pipelines using DeepLabCut-annotated pose estimation data. Applying this tool to chronic social defeat in male mice, the DeepOF supervised and unsupervised pipelines detect a distinct stress-induced social behavioral pattern, which was particularly observed at the beginning of a novel social encounter and fades with time due to habituation. In addition, while the classical social avoidance task does identify the stress-induced social behavioral differences, both DeepOF behavioral pipelines provide a clearer and more detailed profile. Moreover, DeepOF aims to facilitate reproducibility and unification of behavioral classification by providing an open-source tool, which can advance the study of rodent individual and social behavior, thereby enabling biological insights and, for example, subsequent drug development for psychiatric disorders. Accurate phenotyping is key to deciphering behavior. Here, authors show the utility of the software package DeepOF in supervised and unsupervised identification of distinct individual and social behavioral patterns following chronic social stress.

Disturbances of the excitation/inhibition (E/I) balance in the brain were recently suggested as potential factors underlying disorders like autism and schizophrenia resulting in associated behavioral alterations including changes in social and emotional behavior as well as abnormal aggression. Neuronal cell adhesion molecules (nCAMs) and mutations in these genes were found to be strongly implicated in the pathophysiology of these disorders. Neuroligin2 (nlgn2) is a postsynaptic cell adhesion molecule, which is predominantly expressed at inhibitory synapses and required for synapse specification and stabilization. Changes in the expression of nlgn2 were shown to result in alterations of social behavior as well as altered inhibitory synaptic transmission, hence modifying the E/I balance. In our study, we focused on the role of nlgn2 in the dorsal hippocampus in the regulation of emotional and social behaviors. To this purpose, we injected an AAV construct overexpressing nlgn2 in the hippocampus of rats and investigated the effects on behavior and on markers for the E/I ratio. We could show an increase in GAD65, a GABA-synthesizing protein in neuronal terminals, and furthermore, reduced exploration of novel stimuli and less offensive behavior. Our data suggest nlgn2 in the hippocampus to be strongly implicated in maintaining the E/I balance in the brain and thereby modulating social and emotional behavior.

Disturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, metabolic, and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), the main driver of HPA axis regulation, and FKBP5 polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. We here demonstrate that the deletion of Fkbp5 in Sim1+ neurons dampens the acute stress response and increases GR sensitivity. In contrast, Fkbp5 overexpression in the PVN results in a chronic HPA axis over-activation, and a PVN-specific rescue of Fkbp5 expression in full Fkbp5 KO mice normalizes the HPA axis phenotype. Single-cell RNA sequencing revealed the cell-type-specific expression pattern of Fkbp5 in the PVN and showed that Fkbp5 expression is specifically upregulated in Crh+ neurons after stress. Finally, Crh-specific Fkbp5 overexpression alters Crh neuron activity, but only partially recapitulates the PVN-specific Fkbp5 overexpression phenotype. Together, the data establish the central and cell-type-specific importance of Fkbp5 in the PVN in shaping HPA axis regulation and the acute stress response.

Dysregulation of the corticotropin-releasing hormone (CRH) system has been implicated in stress-related psychopathologies such as depression and anxiety. Although most studies have linked CRH/CRH receptor 1 signaling to aversive, stress-like behavior, recent work has revealed a crucial role for distinct CRH circuits in maintaining positive emotional valence and appetitive responses under baseline conditions. Here we addressed whether deletion of CRH, specifically from GABAergic forebrain neurons (CrhCKO-GABA mice) differentially affects general behavior under baseline and chronic stress conditions. Expression mapping in CrhCKO-GABA mice revealed absence of Crh in GABAergic neurons of the cortex and limbic regions including the hippocampus, central nucleus of the amygdala and the bed nucleus of the stria terminals, but not in the PVN. Consequently, conditional CRH knockout animals exhibited no alterations in circadian and stress-induced corticosterone release compared to controls. Under baseline conditions, absence of Crh from forebrain GABAergic neurons resulted in social interaction deficits but had no effect on other behavioral measures including locomotion, anxiety, immobility in the forced swim test, acoustic startle response and fear conditioning. Interestingly, following exposure to chronic social defeat stress, CrhCKO-GABA mice displayed a resilient phenotype, which was accompanied by a dampened, stress-induced expression of immediate early genes c-fos and zif268 in several brain regions. Collectively our data reveals the requirement of GABAergic CRH circuits in maintaining appropriate social behavior in naïve animals and further supports the ability of CRH to promote divergent behavioral states under baseline and severe stress conditions.