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The calm mouse: an animal model of stress reduction.

ABSTRACT: Chronic stress is associated with negative health outcomes and is linked with neuroendocrine changes, deleterious effects on innate and adaptive immunity, and central nervous system neuropathology. Although stress management is commonly advocated clinically, there is insufficient mechanistic understanding of how decreasing stress affects disease pathogenesis. Therefore, we have developed a "calm mouse model" with caging enhancements designed to reduce murine stress. Male BALB/c mice were divided into four groups: control (Cntl), standard caging; calm (Calm), large caging to reduce animal density, a cardboard nest box for shelter, paper nesting material to promote innate nesting behavior, and a polycarbonate tube to mimic tunneling; control exercise (Cntl Ex), standard caging with a running wheel, known to reduce stress; and calm exercise (Calm Ex), calm caging with a running wheel. Calm, Cntl Ex and Calm Ex animals exhibited significantly less corticosterone production than Cntl animals. We also observed changes in spleen mass, and in vitro splenocyte studies demonstrated that Calm Ex animals had innate and adaptive immune responses that were more sensitive to acute handling stress than those in Cntl. Calm animals gained greater body mass than Cntl, although they had similar food intake, and we also observed changes in body composition, using magnetic resonance imaging. Together, our results suggest that the Calm mouse model represents a promising approach to studying the biological effects of stress reduction in the context of health and in conjunction with existing disease models.

SUBMITTER: Gurfein BT

PROVIDER: S-EPMC3388136 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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The calm mouse: an animal model of stress reduction.

Gurfein Blake T BT Stamm Andrew W AW Bacchetti Peter P Dallman Mary F MF Nadkarni Nachiket A NA Milush Jeffrey M JM Touma Chadi C Palme Rupert R Di Borgo Charles Pozzo CP Fromentin Gilles G Lown-Hecht Rachel R Konsman Jan Pieter JP Acree Michael M Premenko-Lanier Mary M Darcel Nicolas N Hecht Frederick M FM Nixon Douglas F DF

Molecular medicine (Cambridge, Mass.) 20120509

Chronic stress is associated with negative health outcomes and is linked with neuroendocrine changes, deleterious effects on innate and adaptive immunity, and central nervous system neuropathology. Although stress management is commonly advocated clinically, there is insufficient mechanistic understanding of how decreasing stress affects disease pathogenesis. Therefore, we have developed a "calm mouse model" with caging enhancements designed to reduce murine stress. Male BALB/c mice were divided ...[more]

PMID: 22398685

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Project description:Endoplasmic reticulum (ER) stress refers to a condition of accumulation of unfolded or misfolded proteins in the ER lumen, which is known to activate an intracellular stress signaling termed Unfolded Protein Response (UPR). A number of pharmacologic reagents or pathophysiologic stimuli can induce ER stress and activation of the UPR signaling, leading to alteration of cell physiology that is associated with the initiation and progression of a variety of diseases. Non-alcoholic steatohepatitis (NASH), characterized by hepatic steatosis and inflammation, has been considered the precursor or the hepatic manifestation of metabolic disease. In this study, we delineated the toxic effect and molecular basis by which pharmacologic ER stress, induced by a bacterial nucleoside antibiotic tunicamycin (TM), promotes NASH in an animal model. Mice of C57BL/6J strain background were challenged with pharmacologic ER stress by intraperitoneal injection of TM. Upon TM injection, mice exhibited a quick NASH state characterized by hepatic steatosis and inflammation. An increase in hepatic triglycerides (TG) and a decrease in plasma lipids, including plasma TG, plasma cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL), were observed in the TM-treated mice. In response to TM challenge, cleavage of sterol responsive binding protein (SREBP)-1a and SREBP-1c, the key trans-activators for lipid and sterol biosynthesis, was dramatically increased in the liver. Consistent with the hepatic steatosis phenotype, expression of some key regulators and enzymes in de novo lipogenesis and lipid droplet formation was up-regulated, while expression of those involved in lipolysis and fatty acid oxidation was down-regulated in the liver of mice challenged with TM. Moreover, TM treatment significantly increased phosphorylation of NF-?B inhibitors (I?B), leading to the activation of NF-?B-mediated inflammatory pathway in the liver. Our study not only confirmed that pharmacologic ER stress is a strong "hit" that triggers NASH, but also demonstrated crucial molecular links between ER stress, lipid metabolism, and inflammation in the liver in vivo.

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The calm mouse: an animal model of stress reduction.

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The calm mouse: an animal model of stress reduction.

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