Individual differences in anxiety trait are related to spatial learning abilities and hippocampal expression of mineralocorticoid receptors

Although high levels of anxiety might be expected to negatively influence learning and memory, it remains to be shown whether individual differences in anxiety may influence spatial learning and memory in outbred rat populations. We have studied this possibility in male Wistar rats whose levels of anxiety were first characterized as either high (HA) or low (LA) according to their behavior in the elevated plus maze or in the open field test. Subsequently, their performance in the Morris water maze was studied, a task dependent on hippocampal activity. Interestingly, LA rats showed a faster acquisition and better memory in the water maze when compared to HA rats. Indeed, this difference in performance could mainly be attributed to the increase in thigmotactic behavior (swimming in circles close to the maze walls) displayed by HA rats during spatial navigation. Glucocorticoids are known to affect the state of anxiety and the hippocampus is the main target of glucocorticoids in the brain. Hence, we investigated whether the hippocampal expression of the two classical corticosteroid receptors, mineralocorticoid (MR) and glucocorticoid (GR) differed in the two groups of rats. We found that LA rats displayed higher hippocampal expression of MR but not GR than HA rats. Indeed, the expression levels for these receptors were positively correlated with the amount of time spent by the animals in the open arms of the elevated plus maze. Moreover, we present evidence that the levels of anxiety quantified in the first stages of our study constitute a trait rather than a state. Taken together, this study has generated evidence of a close interaction between the anxiety trait, hippocampal MR expression and the learning abilities of individuals in stressful spatial orientation tasks.

Psychobiological Vulnerability to Stress

Jorge Eduardo Castro Cifuentes, Maria del Carmen Sandi Perez

Several psychobiological factors are associated with vulnerability/resilience to stress-induced depression. Emerging evidence indicates behavioral traits, such as anxiety, can be related to depression-like symptoms after exposure to chronic stress. However, single traits cannot explain the variability observed in individual's vulnerability to stress, highlighting that a combination of behavioral traits might provide a better characterization of the individual's vulnerability to development of depression following prolonged stress. Hippocampal neurogenesis has been highlighted as a cellular mechanism involved in the reduction on hippocampal volume under conditions of stress and depression, suggesting that a lack of new cells and connections may underlie the cognitive and emotional symptoms of mood disorders, and modulating neurogenesis is regarded as a target/mechanism for antidepressants actions. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is expressed and potentially involved in cellular proliferation in the central nervous system. MIF was shown to induce cell cycle progression via activation of the extracellular signal-regulated kinase (ERK) cascade. Stress has been shown to alter the degree of activation of the multifunctional ERK 1/2 -as indicated by its phosphorylation (p) pERK1/2- and pharmacological manipulations of the ERK pathway affected anxiety and coping behavior. Nonetheless, other mediating mechanisms are involved in the course of both depression and antidepressant actions. Even though the amygdala has been related to the etiology and recovery of depression through imaging studies showing correlations between these mood conditions and amygdala's volume and functional activation, the number of studies devoted to this brain area is still scarce. We hypothesize here an essential role of the amygdala on depression and antidepressant actions based on the implication of the basolateral complex (BLA) in emotional arousal and stress-induced modulation of cognitive processes, and on recent data showing activation of corticotropin releasing factor receptors (CRFR1) as a substrate for stress-induced alterations. Interestingly, alterations in the functional connectivity between the amygdala, the hippocampus and frontal areas have been identified in individuals with genetic vulnerability to depression. Looking for such psychobiological interactions is particularly important today because of increasingly incidence of depression and stress related disorders'. Identifying and understanding psychobiological vulnerability to stress is crucial for best oriented and more effective prevention and intervention strategies. Therefore, the aim of this thesis was: i) to identify in rats behavioral traits capable of predicting differences in vulnerability/resilience to the behavioral, endocrine, neurogenic and brain activity effects of stress, ii) to explore the role of the amygdala and personality traits in the antidepressants' effects on depression-like behavior and hippocampal neurogenesis, and iii) to study the role of MIF expression in hippocampal neurogenesis and anxiety- and depression- like behaviors. Our first study indicates that both the direction and intensity of the impact of stress on behavior corresponds to different patterns of neurogenesis impairment and brain activity; moreover, these effects are dependent on the interaction between personality traits and the length of stress exposure. Chronic stress induced progressively depressive-like symptoms associated with an increase in cell proliferation and a decrease of cell survival in the hippocampus and with a decrease in ERK1/2 activity in the prefrontal cortex, the hippocampus and a U-shape effect in the amygdala. Personality-like profiles of high exploration seem to play a resilient role for the development of stress-induced depressive-like symptoms and the combination of high anxiety and low exploration seems to lead to higher vulnerability to develop depression-like behaviors. Whereas sub chronic stress increased cell proliferation in the combined profile of high anxiety and low exploration, profiles of low exploration showed a decrease in cell survival after exposure to chronic stress. Interestingly, ERK1/2 activity was decreased in control animals of the personality profile high anxiety and low exploration and subsequently increased after sub-chronic and chronic stress in the paraventricular nucleus, the amygdala and the hippocampus but not in the orbitofrontal cortex. The second study provides evidence for an important role for the amygdala on fluoxetine-stimulated cell proliferation and survival, as well as on the establishment of a link between cell proliferation and depression-like behavior. We also show an important role for anxiety in mediating the effects of basolateral amygdala and antidepressant activity on cell proliferation and survival. Chronic fluoxetine treatment had a positive effect on hippocampal cell survival only when the BLA was lesioned. Anxiety was related to hippocampal cell survival in opposite ways in sham- and BLA-lesioned animals (i.e., negatively in sham- and positively in BLA-lesioned animals). Both BLA lesions and low anxiety were critical factors to enable a negative relationship between cell proliferation and depression-like behavior. Therefore, our study highlights a role for the amygdala on fluoxetine-stimulated cell survival and on the establishment of a link between cell proliferation and depression-like behavior. It also reveals an important modulatory role for anxiety on cell proliferation involving both BLA-dependent and -independent mechanisms. The third study demonstrates the relevance of MIF expression for adult hippocampal neurogenesis. We identify MIF expression in neurogenic cells (in stem cells, cells undergoing proliferation and in newly proliferated cells undergoing maturation) in the subgranular zone of the rodent dentate gyrus. A causal role for MIF in cell proliferation was demonstrated using genetic and pharmacological approaches. Behaviorally, genetic deletion of MIF resulted in increased anxiety- and depression-like behaviors, as well as of impaired hippocampus-dependent memory. Together, our studies provide evidence supporting a pivotal role for MIF in both basal and antidepressant-stimulated adult hippocampal cell proliferation. Moreover, loss of MIF results in a behavioral phenotype that to a large extent corresponds with alterations predicted to arise from reduced hippocampal neurogenesis. These findings underscore MIF as a potentially relevant molecular target for the development of treatments linked to deficits in neurogenesis, as well as to problems related to anxiety, depression and cognition. Altogether the results presented support the idea of high anxiety trait individuals being a particularly prone phenotype and exposure to stressful life events as a requirement for individuals with this personality trait to develop depression.

EPFL2012

Personality traits in rats predict vulnerability and resilience to developing stress-induced depression-like behaviors, HPA axis hyper-reactivity and brain changes in pERK1/2 activity

Jorge Eduardo Castro Cifuentes, Maria Isabel Cordero Campana, Shanaz Diessler, Cristina Marquez Vega, Maria del Carmen Sandi Perez

Emerging evidence indicates that certain behavioral traits, such as anxiety, are associated with the development of depression-like behaviors after exposure to chronic stress. However, single traits do not explain the wide variability in vulnerability to stress observed in outbred populations. We hypothesized that a combination of behavioral traits might provide a better characterization of an individual's vulnerability to prolonged stress. Here, we sought to determine whether the characterization of relevant behavioral traits in rats could aid in identifying individuals with different vulnerabilities to developing stress-induced depression-like behavioral alterations. We also investigated whether behavioral traits would be related to the development of alterations in the hypothalamic-pituitary-adrenal axis and in brain activity - as measured through phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) - in response to an acute stressor following either sub-chronic (2 weeks) or chronic (4 weeks) unpredictable stress (CUS). Sprague-Dawley rats were characterized using a battery of behavioral tasks, and three principal traits were identified: anxiety, exploration and activity. When combined, the first two traits were found to explain the variability in the stress responses. Our findings confirm the increased risk of animals with high anxiety developing certain depression-like behaviors (e.g., increased floating time in the forced swim test) when progressively exposed to stress. In contrast, the behavioral profile based on combined low anxiety and low exploration was resistant to alterations related to social behaviors, while the high anxiety and low exploration profile displayed a particularly vulnerable pattern of physiological and neurobiological responses after sub-chronic stress exposure. Our findings indicate important differences in animals' vulnerability and/or resilience to the effects of repeated stress, particularly during initial or intermediate levels of stress exposure, and they highlight that the behavioral inhibition profile of an animal provides a particular susceptibility to responding in a deleterious manner to stress.

Elsevier2012

Long-term behavioral programming induced by peripuberty stress in rats is accompanied by GABAergic-related alterations in the amygdala

Maria del Carmen Sandi Perez, Stamatina Tzanoulinou, Vandana Veenit

Stress during childhood and adolescence is a risk factor for psychopathology. Alterations in γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain, have been found following stress exposure and fear experiences and are often implicated in anxiety and mood disorders. Abnormal amygdala functioning has also been detected following stress exposure and is also implicated in anxiety and social disorders. However, the amygdala is not a unitary structure; it includes several nuclei with different functions and little is known on the potential differences the impact of early life stress may have on this system within different amygdaloid nuclei. We aimed here to evaluate potential regional differences in the expression of GABAergic-related markers across several amygdaloid nuclei in adult rats subjected to a peripuberty stress protocol that leads to enhanced basal amygdala activity and psychopathological behaviors. More specifically, we investigated the protein expression levels of glutamic acid decarboxylase (GAD; the principal synthesizing enzyme of GABA) and of GABA-A receptor subunits α2 and α3. We found reduced GAD and GABA-A α3, but not α2, subunit protein levels throughout all the amygdala nuclei examined (lateral, basolateral, basomedial, medial and central) and increased anxiety-like behaviors and reduced sociability in peripubertally stressed animals. Our results identify an enduring inhibition of the GABAergic system across the amygdala following exposure to early adversity. They also highlight the suitability of the peripuberty stress model to investigate the link between treatments targeting the dysfunctional GABAergic system in specific amygdala nuclei and recovery of specific stress-induced behavioral dysfunctions.

Public Library of Science2014