stress induction methods for establishing the chronic unpredictable mild stress rat model

Establishing and Validating a Chronic Unpredictable Mild Stress Rat Model

Major depressive disorder (MDD) is a prevalent mental illness, ranking as the third leading cause of disability globally and affecting over 300 million people1,2,3. Notably, it is estimated that at least half of the affected individuals do not receive adequate treatment4. Given this gap, animal models serve as a crucial tool for investigating the etiology of depression. To date, more than 20 different animal models for depression exist5. Among these, the chronic unpredictable mild stress (CUMS) model, refined by Paul Winer in 1987, is the most frequently utilized6. The CUMS model operates on the premise that exposing rodents to a diverse range of socio-environmental stressors leads to symptoms akin to anxiety, tension, and depression. The methodology involves exposing animals to various mild stressors over several weeks, culminating in a range of behavioral alterations, including anhedonia and depressive-like behaviors7,8. These changes are accompanied by shifts in endocrine and neurotransmitter profiles, such as a reduction in 5-HT9,10. These outcomes closely mirror those observed in humans diagnosed with MDD, thereby validating the model's utility. The CUMS model is particularly valued for its effectiveness in evaluating antidepressants, manifesting high levels of surface, structural, and predictive validity11,12. Unlike other models, CUMS is sensitive to the effects of chronic administration of monoaminergic antidepressants. For instance, selective serotonin reuptake inhibitors (SSRIs) such as citalopram, paroxetine, and fluoxetine have been shown to prevent and reverse anhedonia under conditions of chronic stress12,13. Additionally, new rapid-acting antidepressants, such as ketamine, have also demonstrated efficacy in this model14,15. In contrast, other tests like the forced swimming test (FST) and tail suspension test (TST) are less reliable for modeling long-term behavioral changes, often reflecting adaptations to acute stress rather than enduring symptoms of depression16. These characteristics underscore the robust validity of the CUMS model in depression research. One of the most salient features of the CUMS model, recognized for its high reliability in classical studies, is anhedonia-the incapacity to experience pleasure or interest in everyday activities17,18. This phenomenon is commonly evaluated using sucrose preference tests, and many antidepressants have been shown to reverse reduced sucrose consumption. Several other metrics are also commonly employed in the CUMS literature, including the open field test (OFT), which assesses voluntary motor behavior, exploratory tendencies, and tension, thereby gauging the severity of depression19. Other tests such as the elevated plus maze (EPM) evaluate anxiety-like behaviors, the Morris water maze test (MWM) examines cognitive functioning20, and the FST assesses susceptibility to negative emotions and behavioral despair20. Furthermore, the majority of stressors that impact humans are social in nature. Individuals with suboptimal social relationships, characterized by limited social activities, networks, and support, are at a heightened risk for various diseases21,22. This is also relevant in the case of rodents, who are social animals living in groups. For example, rats that are housed in isolation exhibit characteristics of what is termed isolation syndrome, which induces social stress and expedites the onset of depression23.
Mongolian medicine, a significant branch of Chinese medicine, posits that the onset of disease is a complex interplay between intrinsic and external factors. These external factors, referred to as the four auxiliary conditions, encompass climate change, diet, lifestyle, and sudden events such as infections, startling incidents, and psychological disorders. The disease process is conceptualized as an ongoing interaction between three elements-referred to as the three types of homors-and the Seven Bodily Constituents in concert with the four auxiliary conditions24. Mongolian medicine holds that the human body functions as an integrated entity, maintained by a relative balance among the three homors. A disruption in this balance is considered to be a precursor to illness24. Given the pivotal role of animal experimentation in bridging traditional and modern medicine, it is crucial to develop animal models that are relevant for research in the field of Mongolian medicine. Accordingly, we employed a 28-day isolation methodology coupled with CUMS to simulate these physiological and psychological stressors. We selected nine specific unpredictable stressors and sought to underpin this modeling method through the Three homors theory of Mongolian medicine. Establishing a robust animal model is fundamental for advancing basic research in Mongolian medicine and will contribute significantly to its foundational studies.

Author Spotlight: Establishing a Rodent Model for Investigating Depression Factors in Traditional Mongolian Medicine

Moğol tıbbına dayalı Sıçanlarda Kronik Öngörülemeyen Hafif Stres

Kronik Öngörülemeyen Hafif Stres Sıçan Modelinin Kurulması için Stres İndüksiyon Yöntemleri

Fareleri bir kontrole veya aleyhte ve modele veya moda, gruba ayırdıktan sonra, onları ayrı kafeslerde barındırın. Kuyruk kelepçesi yöntemi için, bir sıçanın kuyruğunu sabitleyin ve sıkıştırma süresini bir dakika boyunca ölçün. Su yoksunluğu yönteminde, biberonu kafesten çıkarın ve fareyi 24 saat boyunca kaydedin.Yiyecek yoksunluğu yöntemi için, yiyeceği kafesten çıkarın ve fareyi 24 saat boyunca kaydedin. Dört santigrat derecede soğuk stimülasyon için, bir kova soğuk suya bir fare koyun ve aktivitesini beş dakika boyunca izleyin. Daha sonra fareyi bir üfleyici ile kurulayın ve orijinal kafesine geri koyun.45 santigrat derece ısı stresi uygulamak için, fareyi bir fırına koyun ve beş dakika boyunca izleyin. Aydınlık-karanlık döngüsünün tersine çevrilmesi için, gündüz karanlığını uyarmak için kafesi bir saat boyunca siyah bir beze sarın. Ardından, gün ışığını taklit etmek için kafesi gece 12 saat aydınlatın ve verileri 24 saat boyunca kaydedin.Islak dolgu deneyi için, 100 gram dolgu içeren bir kafese 200 mililitre su dökün. Fareyi ıslak kafese yerleştirin ve 24 saat boyunca izleyin. Fareyi daha önce gösterildiği gibi kuruttuktan sonra, taze odun talaşı içeren bir kafese geri koyun.Kafes eğimi yönteminde, fareyi duvara karşı 45 derece açılı bir kafese yerleştirin ve 24 saat boyunca izleyin. Yüksek hızda çalkalamak için, fareyi 160 RPM'ye ayarlanmış mekanik çalkalayıcılara yerleştirin ve verileri 15 dakika boyunca kaydedin. Stres faktörlerini uyguladıktan sonra, mod grup kafesini CUMS odasından muhafaza odasına aktarın.

Research

JoVE Journal

Medicine

Stress Induction Methods for Establishing the Chronic Unpredictable Mild Stress Rat Model

Chronic Unpredictable Mild Stress in Rats based on the Mongolian medicine

Depression is a prevalent affective disorder and constitutes a leading cause of global disability. The limitations of current pharmacological ...

Tıp

Behavioral Tests for Assessing Depression-Related Behaviors in Rats

Sıçanlarda Depresyonla İlgili Davranışları Değerlendirmek için Davranış Testleri