Chronic stress-induced changes in the rat brain: Role of sex differences and effects of long-term tianeptine treatment
Introduction
Affective disorders, such as anxiety and depression, are among today's most common and disabling illnesses. Despite the great burden on afflicted individuals and society, the exact neurobiological mechanisms underlying disease pathophysiology as well as treatment remain scarcely understood. Numerous factors account for this lack of progress including poor understanding of sex-dependent adaptations to chronic stress and/or long-term pharmacotherapy. Curiously, although women are twice as likely as men to suffer from stress-related psychiatric disorders and constitute the majority of antidepressant recipients (Kessler et al., 1993), basic research has focused predominantly on male animals (Palanza, 2001).
Stress represents a major contributor to neuronal dysfunctions in brain structures important for emotional processing and stress response regulation (Price and Drevets, 2010). In the hippocampus, chronic stress has been linked to profound structural and functional changes in humans and experimental animals (Leuner and Gould, 2010) including reduced hippocampal volume (Lee et al., 2009, MacQueen and Frodl, 2011), dendritic remodeling of pyramidal neurons (Magarinos et al., 1997) and suppression of adult neurogenesis (Kuipers et al., 2006, Dagyte et al., 2009). Exposure to stress is not unequivocally predictive however of subsequent hippocampal pathology as stress-induced effects on neuroplasticity vary substantially depending upon stressor type, duration and severity. Since repeated exposure to severe physical (tailshock) and psychological (resident-intruder) stressors have failed to affect hippocampal neurogenesis (Hanson et al., 2011), this challenges the hypothesis that any stressor of sufficient intensity and duration has a negative impact upon neuroplasticity. Furthermore, another factor well-known to affect stress-mediated consequences is sex (McLaughlin et al., 2009). Chronic stress has been shown to impair neurogenesis in a sex-dependent manner, by reducing neurogenic rates in one sex without affecting the other (Westenbroek et al., 2004, Kuipers et al., 2006, Shors et al., 2007, Oomen et al., 2009). Moreover it seems to do so by differentially targeting the regulation of neurogenesis on the cellular level as it inhibits cell proliferation and increases neural stem cell quiescence in males and reduces newborn neuron survival in females (Barha et al., 2011, Hillerer et al., 2013).
In contrast to stress, antidepressants exert their therapeutic actions by stimulating synaptic plasticity and enhancing adult neurogenesis. Increased expression and phosphorylation of CREB, a transcription factor with a well-established role in learning-related synaptic plasticity (Carlezon et al., 2005), have been observed in response to prolonged administration of serotonin and/or noradrenaline reuptake inhibitors (Nibuya et al., 1996, Thome et al., 2000, Kuipers et al., 2006). Long-term pharmacotherapy has also been shown to attenuate stress-evoked dendritic remodeling (Magarinos et al., 1999) and impairments of hippocampal neurogenesis (Malberg et al., 2000, Czeh et al., 2001). In this regard, the antidepressant tianeptine has proven particularly effective in ameliorating stress-induced morphological sequelae in the hippocampus, prefrontal cortex and amygdala (Zoladz et al., 2008). More importantly, although structurally related to tricyclic agents, tianeptine illustrates unique pharmacological properties that challenge the hypothesis of direct monoaminergic modulation to promote antidepressant action and therefore, provides new insights into the neurobiological basis of depression and its treatment (Brink et al., 2006, McEwen et al., 2010). Tianeptine triggers a cascade of neuronal adaptations which include increased phosphorylation of different glutamate receptors subtypes (NMDA and AMPA). As a major excitatory neurotransmitter, glutamate controls neuronal excitability and neuroplasticity in most brain circuits and glutamatergic dysfunctions have been documented in depression (Paul and Skolnick, 2003, Zarate et al., 2003). Evidence suggests tianeptine ameliorates depressive symptoms and attenuates neuroplasticity impairments by modulating the glutamatergic system in key brain structures (McEwen et al., 2010).
This study explores the cellular and molecular changes associated with chronic stress and/or long-term tianeptine treatment in male and female Wistar rats. Although sex differences have been identified in responses to stress and pharmacotherapy, few studies have systematically evaluated the complex interplay between sex, stress and antidepressants in animal disease models. Here, patterns of c-fos, phosphorylated CREB and BrdU immunoreactivity were examined in specific cortical and limbic regions known to undergo structural changes in depression and marked neuroplastic adaptations in response to antidepressants (Duman and Monteggia, 2006). Visualization of FOS induction provides a valuable tool for functional mapping of neural circuits activated by stress and antidepressants (Veening et al., 1998, Martinez et al., 2002, Kovacs, 2008), while changes in phosphorylated CREB and BrdU labeling provide insight into the effects of drug treatment and aversive experience on neuroplasticity. The findings presented here provide evidence to support sex-dependent mechanisms underlying the deleterious consequences of chronic stress and the beneficial influences of tianeptine.
Section snippets
Animals
Use was made of 10-week old male (n = 24) and female (n = 25) Wistar rats. Animals were individually housed (cages 45 × 28 × 20 cm) with ad libitum access to food and tap water. They were maintained on a 12-h light/dark cycle (07:00 lights on), weighed and handled daily (09:00) and allowed 10 days to acclimatize to their new environmental conditions prior to onset of the experiment. This study was designed to minimize animal numbers and suffering, and performed in accordance with the European
Body weight gain
Throughout this experiment, body weight gain increased steadily in both sexes (time: F21,861 = 175.334, P < 0.001) with males gaining weight faster than females (time × sex: F21,861 = 35.612, P < 0.001) (Fig. 1a,b). In line with previous data, repeated footshock stress attenuated this time-dependent increase in body weight (time × stress: F21,861 = 7.631, P < 0.001), an effect which was sex-dependent (time × stress × sex: F21,861 = 6.356, P < 0.001) given the marked reduction of weight gain in
Discussion
The risk of developing affective disorders, particularly anxiety and depression, has a strong sex bias, marked by a greater incidence in women. The high female-to-male ratio, especially during the reproductive years, is one of the most replicated findings in epidemiology (Leibenluft, 1999) and various factors contribute to this differential prevalence. Gender-related dimorphisms naturally occur in brain anatomy, function and neurochemistry (Jazin and Cahill, 2010). Women are also more prone to
Conclusions
In this study, sex differences were observed in prefrontocortical FOS-ir patterns, HPA axis activity, hippocampal and amygdalar neuroplasticity following repeated stress and long-term tianeptine treatment. These structures represent key components of the stress response system. Females demonstrated enhanced prefrontocortical activation and HPA axis hyperactivity, suggesting sex-specific adaptations underlying negative emotional processing. These may represent susceptibility traits to account
Acknowledgments
This study was financially supported by University of Groningen. The technical assistance of T. Koch and F. Postema was greatly appreciated. The authors would like to thank Prof. Dr. I.P. Kema for the corticosterone analysis. We also would like to acknowledge the Bergen Medical Research Foundation (BMFS) for its support through the “Young Investigator Recruitment” grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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These authors contributed equally to the preparation of the manuscript.