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The Unpredictable Chronic Mild Stress Protocol for Inducing Anhedonia in Mice

Published: October 24th, 2018



1School of Behavioral Science, The Academic College Tel-Aviv-Yaffo, 2Department of Education and Psychology, Open University

Here we present the unpredictable chronic mild stress protocol in mice. This protocol induces a long-term depressive-like phenotype and enables to assess the efficacy of putative antidepressants in reversing the behavioral and neuromolecular depressive-like deficits.

Depression is a highly prevalent and debilitating condition, only partially addressed by current pharmacotherapies. The lack of response to treatment by many patients prompts the need to develop new therapeutic alternatives and to better understand the etiology of the disorder. Pre-clinical models with translational merits are rudimentary for this task. Here we present a protocol for the unpredictable chronic mild stress (UCMS) method in mice. In this protocol, adolescent mice are chronically exposed to interchanging unpredictable mild stressors. Resembling the pathogenesis of depression in humans, stress exposure during the sensitive period of mice adolescence instigates a depressive-like phenotype evident in adulthood. UCMS can be used for screenings of antidepressants on the variety of depressive-like behaviors and neuromolecular indices. Among the more prominent tests to assess depressive-like behavior in rodents is the sucrose preference test (SPT), which reflects anhedonia (core symptom of depression). The SPT will also be presented in this protocol. The ability of UCMS to induce anhedonia, instigate long-term behavioral deficits and enable reversal of these deficits via chronic (but not acute) treatment with antidepressants strengthens the protocol's validity compared to other animal protocols for inducing depressive-like behaviors.

Major depressive disorder (MDD) is a debilitating condition, that has been indicated as the 11th cause of global burden from disease1, with a lifetime prevalence of 11–16%2,3. MDD has been associated with severe impairments on patients' social and occupational functioning, diminished quality of life, numerous mental and physical disorders and increased risk for mortality4,5,6,7. There are several efficacious pharmacotherapies and psycholog....

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All methods described here have been approved by the Institutional Animal Care and Use Committee of the Academic College Tel-Aviv-Yaffo.

1. Animals

  1. Use pre-adolescent (i.e., 3 weeks old) Institute of Cancer Research (ICR) outbred male mice.
  2. Randomize mice to two equally sized stress group (UCMS vs. naïve). Use 15 mice per treatment group (e.g.: if there are 3 pharmacological treatment groups use 90 mice overall; 2 [UCMS vs. naïve] × 3 [tre.......

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In order to corroborate the efficacy of the UCMS procedure for inducing depressive-like deficits, a manipulation check was conducted. Male ICR outbred mice were randomly assigned to either UCMS or naïve conditions (4 weeks, as described in protocol 2.2). Subsequently, the SPT (6 days, as described in protocol 4) was administered to assess whether mice after undergoing UCMS demonstrated hedonic deficits. Shortly after, mice were sacrificed and the hippocampus was dissected o.......

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Insofar as MDD is a widespread highly debilitating disorder, only partially addressed by current therapeutic options, the scientific quest for better treatments is still a pressing issue. Along with innovations in psychological techniques, additional pharmacotherapies are required for the large portion of patients who do not respond to the existing drugs. Meticulous animal models for depression are the key element in this task. Such models facilitate screenings for innovative antidepressants and expand the understanding .......

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The authors would like to thank Gali Breuer for her assistance in the video production. This research was supported by the Israel Ministry of Science, Technology & Space (grant no. 313552), by the National Institute for Psychobiology in Israel (NIPI-208-16-17b) and by the Open University Foundation.


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Name Company Catalog Number Comments
Heating lamp Ikea AA-19025-3
Heating pillow Sachs EF-188B
Mice restrainer
Portable electronic balance (*.** g)
Standard rubber stopper, size 5 Ancare #5.5R To avoid spillage during SPT
Straight open drinking tube (2.5") Ancare OT-100 To avoid spillage during SPT (insert drinking tube into rubber stopper)
2% sucrose solution
50ml conical centrifuge tube For the SPT
Pre-adolescent (approximately 20-days old) ICR outbred mice Envigo Hsd:ICR (CD-1)

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