Research ReportDepression, anxiety-like behavior and memory impairment are associated with increased oxidative stress and inflammation in a rat model of social stress
Introduction
Stressful life events are believed to contribute to development of human psychopathologies including anxiety and depression (Kessler, 1997, Post, 1992), as well as cognitive impairment (Arnsten, 2009, Arnsten and Rubia, 2012, Burri et al., 2013, Ronnlund et al., 2013, Shansky and Lipps, 2013). Although there exists large body of evidence demonstrating the negative impact of stress on emotional symptoms including depression, anxiety (Millan et al., 2012) and cognitive impairment (Alzoubi et al., 2013a, Devilbiss et al., 2012, Jonsdottir et al., 2013, Ohman et al., 2007, Ronnlund et al., 2013, Schwabe et al., 2012), however, studies investigating role of stress in comorbid prevalence of anxiety, depression and cognitive impairment in humans (Andreotti et al., 2013, Millan et al., 2012), or co-occurrence of anxiety and depression-like behaviors as well as learning-memory impairment, in animals are limited (Gomez et al., 2013, Haridas et al., 2013). Although impressive mechanistic insights have been offered by several groups, with regards to co-occurrence of anxiety- and depression-like behaviors in animal models (Mineur et al., 2013, Roth et al., 2012, Venzala et al., 2012), studies addressing the underlying biology of stress-induced co-occurrence of depression, anxiety and cognitive impairment are scarce.
In the last few years, using variety of animal models, we have focused on examining the mechanistic basis for co-occurrence of anxiety, cognitive impairment and hypertension (Chugh et al., 2012, Salim et al., 2010a, Salim et al., 2010b, Salim et al., 2011, Vollert et al., 2011), More recently, we have reported that direct pharmacological induction of oxidative stress in rats caused anxiety-like behavior and learning and memory impairment while antioxidant treatment prevented these behaviors, suggesting causal role of oxidative stress in this co-occurrence (Allam et al., 2013). While these observations are interesting, an important question has emerged- whether induction of psychological stress is associated with the pathogenesis of depression. These behavioral and biochemical consequences are similar to those produced upon pharmacological induction of oxidative stress? Therefore, in the present study, we have examined behavioral and biochemical outcome of application of chronic stress in rats using the social defeat model. Social stress in rats is known to induce long-lasting, adverse physiological, behavioral and neuronal deficits, which seem to resemble certain human psychopathologies of depression and anxiety (Bartolomucci and Leopardi, 2009). An ethologically relevant animal model of social stress used for studying the link between stress and psychopathologies is the resident-intruder paradigm (Wood et al., 2010). This model involves intimidations and aggressive encounters by a large, aggressive male rat (resident) toward a smaller male rat (intruder) (Wood et al., 2010), and is regarded as one of the most robust models of post-traumatic stress disorder (PTSD), depression, and other stress-related illnesses (Berton et al., 2006, Krishnan et al., 2007), and hence is considered to be of translational relevance. Socially defeated animals reportedly demonstrate social avoidance for weeks after the last social defeat session, and also exhibit depression- and anxiety-like behavioral abnormalities (Berton et al., 2006, Krishnan et al., 2007) as well as cognitive impairment (Yu et al., 2011). Simultaneous occurrence of these behaviors in this model has never been examined.
Therefore, in the present study, using this animal model we have studied the effect of social defeat induced stress, on depression-like behavior, anxiety-like behavior and cognitive impairment as well as the status of oxidative stress in rats. Oxidative stress has been reported to modulate several behaviors including learning and memory function (Alzoubi et al., 2012, Alzoubi et al., 2013a, Alzoubi et al., 2013b), anxiety- (Allam et al., 2013, Hovatta et al., 2005, Masood et al., 2009, Salim et al., 2010a, Salim et al., 2011), depression- (Brocardo et al., 2012, Leonard and Maes, 2012, Pedreanez et al., 2011), mania- (Macedo et al., 2013), nociceptive- (Arcan et al., 2012) and schizophrenia- (Rao et al., 2012) like behaviors. We also measured the effect of social defeat-induced stress on oxidative stress within three critical brain areas, considered vital for depression, anxiety and cognition,namely, hippocampus, amygdala and prefrontal cortex (McEwen et al., 2012). Oxidative stress which is defined as the imbalance between production of reactive oxygen and nitrogen species (RONS) and their inefficient decomposition by the anti-oxidant system (Lau et al., 2011, Patki et al., 2009, Sies, 1997), has been implicated in the pathophysiology of depression, anxiety and other psychiatric disorders (Frey et al., 2006, Gibson et al., 2012, Kiecolt-Glaser et al., 2013, Maurer et al., 2001, Rezin et al., 2009). Actually, large consumption of oxygen, high amount of polyunsaturated fatty acids and iron content with diminished antioxidant enzymatic activity make brain a vulnerable target for oxidative stress (Evans, 1993) increasing its vulnerability to disease. Relevant to this, recently we have reported that hippocampus was most susceptible to oxidative stress-induced damage and also seemed to regulate the antioxidant pathway (Allam et al., 2013). Herein, we offer new mechanistic insights into the behavioral deficits observed in the social defeat model.
Section snippets
General parameters
Food intake during 7-day social defeat protocol was not different between control or socially defeated rats [Control vs SS (g/rat/day): 25.4±1.5 vs 25.9±1.9, t=0.172, df=18] (Fig. 1A). However, daily water intake increased with social defeat [Control vs SS (ml/rat/day): 31.4±2.4 vs 61.8± 3.2, t=6.122, df=18] rats (Fig. 1B). The socially defeated animals gained less weight during the 7-day social defeat protocol [Control vs SS (gain in body weight in g/7days): 18.0±3.9 vs 4.5±3.3, t=3.752, df
Discussion
In this study, we demonstrate that social defeat stress of 7 days in rats produces significant behavioral and biochemical alterations. Socially defeated rats exhibited heightened anxiety-like behavior, as indicated by reduced time spent in the light compartment of the LD box, decreased total and ambulatory activity and distance traveled as well as reduced time spent in the open arms of the EPM test. Moreover, socially defeated rats exhibited decreased sucrose preference, indicating anhedonia
Animals
Male Sprague Dawley (SD) rats (275–300 g) were used as controls or intruders, and male Long-Evans (LE) retired breeders (400–500 g) served as residents (Charles River, Wilmington, MA). Rats were singly housed with a 12-h light, 12-h dark cycle (lights on at 0600 h) in a climate-controlled room with ad libitum food and water. All experiments were conducted in accordance with the NIH guidelines using approved protocols from the University of Houston Animal Care Committee.
Screening of aggressor Long-Evans rats
Successful application of
Acknowledgments
Funding for this research was provided by NIH R15 G103327 grant awarded to S.S.
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