Chronic stress-induced changes in the rat brain: Role of sex differences and effects of long-term tianeptine treatment

Highlights

• Sex-related dimorphisms were identified on FOS immunoreactivity, CREB phosphorylation and HPA activation.

• Chronic stress impaired neuroplasticity and HPA axis regulation in both sexes.

• Tianeptine attenuated stress-induced impairments in a sex-specific manner.

• Tianeptine modulated prefrontocortical activity in females and HPA axis activation in males.

Abstract

Growing evidence suggests neuroplasticity changes are pivotal in both the occurrence and treatment of affective disorders. Abnormal expression and/or phosphorylation of numerous plasticity-related proteins have been observed in depression, while prolonged antidepressant treatment has been associated with the attenuation of stress-mediated effects on dendritic remodeling and adult hippocampal neurogenesis in experimental animals. This study explores the neurobiological adaptations induced by chronic stress and/or long-term tianeptine treatment. Male and female rats were studied to determine the potential contributory role of sex differences on stress-induced pathology and antidepressant-mediated actions. Our results confirm chronic stress-induced HPA axis disturbance and neuroplasticity impairment in both sexes (i.e. reduced CREB phosphorylation and hippocampal BrdU labeling). Commonly ensuing neurobiological alterations were accompanied by unique sex-specific adaptations. When the antidepressant tianeptine was administered, HPA axis hyperactivity was attenuated and specific neuronal defects were ameliorated in both sexes. These findings provide novel insight into sex-related influences on the neurobiological substrates mediating chronic stress-induced actions on neuroplasticity and the mechanisms underlying tianeptine-mediated therapeutic effects.

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.