social-threat-safety-test-uncovers-psychosocial-stress-related

Social Threat-Safety Test Uncovers Psychosocial Stress-Related Phenotypes

Social stress is a major cause of the development of mental disorders. To enhance the translational value of preclinical studies, social stress experience ...

Johannes Gutenberg University Medical Center

Leibniz-Institute for Resilience Research

Each year, more than half a billion people in the world are affected by stress-related health disorders. Consequently, there is an urgent need for new insights to guide interventions designed to increase stress resilience. Studies of humans and various animals have uncovered the process of stress inoculation, in which exposure to mild stressors enhances subsequent stress resilience. Here, we investigate whether stress inoculation-induced resilience in mice consistently occurs across a multiplicity of different stress contexts (tests). C57BL/6 J adult male mice were randomised either to stress inoculation training (n = 36) or to a non-inoculated, but handled control condition (n = 36). Thereafter, indications of coping and resilience were assessed during (i) acute social defeat in a context similar to that used for stress inoculation training, and (ii) fear conditioning and learned extinction in a novel context. Stress inoculation effects were also assessed during (iii) tail-suspension and (iv) open-field tests that each represent milder stressors. Stress-inoculated mice showed more active defence behaviour during acute social defeat, higher sociability before and after defeat, and greater indications of learned extinction of conditioned fear compared to non-inoculated control mice. Stress-inoculated mice also responded with diminished tail-suspension immobility and open-field defecation. Results suggest that stress inoculation protects against various stressors that differ in quality and relative intensity. Stress inoculation research in mice may serve as the basis for mechanistic studies of global resilience in humans.

Stress inoculation in mice induces global resilience.

Wheat amylase trypsin inhibitors (ATIs) represent a common dietary protein component of gluten-containing cereals (wheat, rye, and barley). They act as toll-like receptor 4 ligands, and are largely resistant to intestinal proteases, eliciting a mild inflammatory response within the intestine after oral ingestion. Importantly, nutritional ATIs exacerbated inflammatory bowel disease and features of fatty liver disease and the metabolic syndrome in mice. For Alzheimer's disease (AD), both inflammation and altered insulin resistance are major contributing factors, impacting onset as well as progression of this devastating brain disorder in patients. In this study, we evaluated the impact of dietary ATIs on a well-known rodent model of AD (5xFAD). We assessed metabolic, behavioral, inflammatory, and microbial changes in mice consuming different dietary regimes with and without ATIs, consumed ad libitum for eight weeks. We demonstrate that ATIs, with or without a gluten matrix, had an impact on the metabolism and gut microbiota of 5xFAD mice, aggravating pathological hallmarks of AD. If these findings can be translated to patients, an ATI-depleted diet might offer an alternative therapeutic option for AD and warrants clinical intervention studies.

Dietary Wheat Amylase Trypsin Inhibitors Impact Alzheimer's Disease Pathology in 5xFAD Model Mice.

Chronic social defeat (CSD) has been widely used as a psychosocial stress model in mice, with the magnitude of CSD-induced social avoidance as the major behavioral hallmark of the resilient and susceptible groups. Despite significant progress in the study of the neurobiology of resilient and susceptible mice, the nature and ethological relevance of CSD-induced social avoidance and social approach, particularly measured using a CD1 mouse, needs conceptual clarification. Based on the findings of a recent study revealing substantial individuality in genetically homogeneous inbred mice, we investigated whether certain baseline individual characteristics of male C57BL/6J mice predict the resilient outcome after CSD. We focused on two well-studied individual traits that seem to have heritable underpinnings-approach to novelty and avoidance of harm, which are essential for the expression of the exploratory drive. Our results showed that the exploration levels and the approach to novelty and harm were different before and after CSD in resilient and susceptible mice. Before the stress, resilient mice had higher horizontal activity in a novel environment, shorter approach latencies, and higher exploration times for social and non-social targets than susceptible mice. However, susceptible mice performed better in the passive avoidance task than resilient mice as they were more successful in learning to avoid potential adversity by suppressing the spontaneous exploratory drive. Our findings challenge the validity of the current selection criteria for the susceptible and resilient groups and encourage comprehensive assessment of both baseline and stress-induced individual behavioral signatures of mice.

Individual baseline behavioral traits predict the resilience phenotype after chronic social defeat.

Aberrant activity of local functional networks underlies memory and cognition deficits in Alzheimer's disease (AD). Hyperactivity was observed in microcircuits of mice AD-models showing plaques, and also recently in early stage AD mutants prior to amyloid deposition. However, early functional effects of AD on cortical microcircuits remain unresolved. Using two-photon calcium imaging, we found altered temporal distributions (burstiness) in the spontaneous activity of layer II/III visual cortex neurons, in a mouse model of familial Alzheimer's disease (5xFAD), before plaque formation. Graph theory (GT) measures revealed a distinct network topology of 5xFAD microcircuits, as compared to healthy controls, suggesting degradation of parameters related to network robustness. After treatment with acitretin, we observed a re-balancing of those network measures in 5xFAD mice; particularly in the mean degree distribution, related to network development and resilience, and post-treatment values resembled those of age-matched controls. Further, behavioral deficits, and the increase of excitatory synapse numbers in layer II/III were reversed after treatment. GT is widely applied for whole-brain network analysis in human neuroimaging, we here demonstrate the translational value of GT as a multi-level tool, to probe networks at different levels in order to assess treatments, explore mechanisms, and contribute to early diagnosis.

Acitretin reverses early functional network degradation in a mouse model of familial Alzheimer's disease.

The IntelliCage systems offer the possibility to conduct long-term behavioral experiments on mice in social groups without human intervention. Although this setup provides new findings, only about 150 studies with the IntelliCage system have been published in the last two decades, which is also caused by the challenging problems of processing and handling the large and heterogeneous amounts of captured data. This application note introduces the Python-GUI IntelliPy, especially designed for users not very experienced in using programming languages. IntelliPy allows users to quickly analyze the IntelliCage output in a user-friendly way, thus making the systems more accessible to a broader audience.

IntelliPy: a GUI for analyzing IntelliCage data.

β-Site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) is the major described β-secretase to generate Aβ peptides in Alzheimer's disease (AD). However, all therapeutic attempts to block BACE1 activity and to improve AD symptoms have so far failed. A potential candidate for alternative Aβ peptides generation is the metalloproteinase meprin β, which cleaves APP predominantly at alanine in p2 and in this study we can detect an increased meprin β expression in AD brain. Here, we report the generation of the transgenic APP/lon mouse model of AD lacking the functional Mep1b gene (APP/lon × Mep1b). We examined levels of canonical and truncated Aβ species using urea-SDS-PAGE, ELISA and immunohistochemistry in brains of APP/lon mouse × Mep1b. Additionally, we investigated the cognitive abilities of these mice during the Morris water maze task. Aβ1-40 and 1-42 levels are reduced in APP/lon mice when meprin β is absent. Immunohistochemical staining of mouse brain sections revealed that N-terminally truncated Aβ2-x peptide deposition is decreased in APP/lon × Mep1b mice. Importantly, loss of meprin β improved cognitive abilities and rescued learning behavior impairments in APP/lon mice. These observations indicate an important role of meprin β within the amyloidogenic pathway and Aβ production in vivo.

Meprin β knockout reduces brain Aβ levels and rescues learning and memory impairments in the APP/lon mouse model for Alzheimer's disease.

 Δ-Tetrahydrocannabinol (THC) acts as an agonist at cannabinoid receptors. Its chronic intake affects many behaviors, including cognitive processes. The aims of this study in rats are to assess the chronic effects of THC on impulsivity and on regional brain glucose uptake.  For the determination of "waiting impulsivity," a total of 20 male Lister Hooded rats were trained to perform a reaction time task, followed by a baseline test of impulsivity and baseline glucose uptake measurements with [F]-fluoro-2-deoxy-D-glucose and positron emission tomography (PET). Then, 10 rats each received 3 mg/kg THC or vehicle injected intraperitoneally daily for 21 days. Subsequently, a second behavioral test and PET measurements were performed, and blood THC concentrations were determined. Analyses of variance of brain regions of the impulsivity network with the parameter "standardized uptake value" regarding glucose uptake and correlation analyses of the collected parameters were carried out.  After chronic THC treatment, decreased glucose uptake (-values <0.05) was found in cingulate cortex, hippocampus, amygdala, thalamus, and cerebellar cortex, as compared with vehicle-treated rats. The number of correct no-go responses (increased waiting time) significantly increased (<0.05) in THC-treated rats. Furthermore, correct no-go responses correlated positively and strongly with the THC blood concentrations (Spearman's =0.79, <0.01).  These findings reflect a specific reduction in impulsive behavior after chronic THC treatment, showing a functionally relevant influence of THC on "waiting impulsivity" with reduced selective glucose uptake at the same time.

Chronic Administration of Δ-Tetrahydrocannabinol Alters Brain Glucose Uptake and Improves Waiting Impulsivity in the Rat.

Consistent evidence from human data points to successful threat-safety discrimination and responsiveness to extinction of fear memories as key characteristics of resilient individuals. To promote valid cross-species approaches for the identification of resilience mechanisms, we establish a translationally informed mouse model enabling the stratification of mice into three phenotypic subgroups following chronic social defeat stress, based on their individual ability for threat-safety discrimination and conditioned learning: the , characterized by successful social threat-safety discrimination and extinction of social aversive memories; the , showing aversive response generalization and resistance to extinction, in line with findings on susceptible individuals; and the  displaying impaired aversive conditioned learning. To explore the neurobiological mechanisms underlying the stratification, we perform transcriptome analysis within three key target regions of the fear circuitry. We identify subgroup-specific differentially expressed genes and gene networks underlying the behavioral phenotypes, i.e., the individual ability to show threat-safety discrimination and respond to extinction training. Our approach provides a translationally informed template with which to characterize the behavioral, molecular, and circuit bases of resilience in mice.

Article	Year
Stress inoculation in mice induces global resilience. Translational psychiatry\| PubMed ID: 32561821	2020
Dietary Wheat Amylase Trypsin Inhibitors Impact Alzheimer's Disease Pathology in 5xFAD Model Mice. International journal of molecular sciences\| PubMed ID: 32878020	2020
Individual baseline behavioral traits predict the resilience phenotype after chronic social defeat. Neurobiology of stress\| PubMed ID: 33457472	2021
Acitretin reverses early functional network degradation in a mouse model of familial Alzheimer's disease. Scientific reports\| PubMed ID: 33758244	2021
IntelliPy: a GUI for analyzing IntelliCage data. Bioinformatics (Oxford, England)\| PubMed ID: 34601559	2021
Meprin β knockout reduces brain Aβ levels and rescues learning and memory impairments in the APP/lon mouse model for Alzheimer's disease. Cellular and molecular life sciences : CMLS\| PubMed ID: 35235058	2022
Chronic Administration of Δ-Tetrahydrocannabinol Alters Brain Glucose Uptake and Improves Waiting Impulsivity in the Rat. Cannabis and cannabinoid research\| PubMed ID: 36800226	2023
Fear circuit-based neurobehavioral signatures mirror resilience to chronic social stress in mouse. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 37068238	2023

Ulrich Schmitt

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