Stress Impacts the Regulation Neuropeptides in the Rat Hippocampus and Prefrontal Cortex

Adverse life experience increases the lifetime risk to several stress-related psychopathologies, such as anxiety or depressive–like symptom following stress in adulthood. However, the neurochemical modulations triggered by stress have not been fully characterized. Neuropeptides play an important role as signaling molecules that contribute to physiological regulation and have been linked to neurological and psychiatric diseases. However, little is known about the influence of stress on neuropeptide regulation in the brain. Here, we have performed an exploratory study of how neuropeptide expression at adulthood is modulated by experiencing a period of multiple stressful experiences. We have targeted hippocampus and prefrontal cortex (PFC) brain areas, which have previously been shown to be modulated by stressors, employing a targeted Liquid Chromatography-Mass Spectrometry (LC-MS) based approach that permits broad peptide coverage with high sensitivity. We found that in the hippocampus, Met-enkephalin, Met-enkephalin-Arg-Phe and Met-enkephalin-Arg-Gly-Leu were up regulated, while Leu-enkephalin and Little SAAS were down regulated after stress. In the PFC area, Met-enkephalin-Arg-Phe, Met-enkephalin-Arg-Gly-Leu, peptide PHI-27, somatostatin-28 (AA1-12) and Little SAAS were all down regulated. This systematic evaluation of neuropeptide alterations in hippocampus and PFC suggests that stressor impact neuropeptides and that neuropeptide regulation is brain area specific. These findings suggest several potential peptide candidates, which warrant further investigations in terms of correlation with depression-associated behaviors.

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

Brain metabolic alterations in mice subjected to postnatal traumatic stress and in their offspring

Alberto Corcoba, João Miguel das Neves Duarte

Adverse environmental and social conditions early in life have a strong impact on health. They are major risk factors for mental diseases in adulthood and, in some cases, their effects can be transmitted across generations. The consequences of detrimental stress conditions on brain metabolism across generations are not well known. Using high-field (14.1 T) magnetic resonance spectroscopy, we investigated the neurochemical profile of adult male mice exposed to traumatic stress in early postnatal life and of their offspring, and of undisturbed control mice. We found that, relative to controls, early life stress-exposed mice have metabolic alterations consistent with neuronal dysfunction, including reduced concentration of N-acetylaspartate, glutamate and γ-aminobutyrate, in the prefrontal cortex in basal conditions. Their offspring have normal neurochemical profiles in basal conditions. Remarkably, when challenged by an acute cold swim stress, the offspring has attenuated metabolic responses in the prefrontal cortex, hippocampus and striatum. In particular, the expected stress-induced reduction in the concentration of N-acetylaspartate, a putative marker of neuronal health, was prevented in the cortex and hippocampus. These findings suggest that paternal trauma can confer beneficial brain metabolism adaptations to acute stress in the offspring.

Sage Publications Inc2017

Implication of individual differences in glucocorticoid responsiveness to stress in the development of psychopathology-like behaviour and underlying neurobiology

Sophie Elizabeth Walker

The period around puberty is a critical window in development. It is a time of neuroendocrine and neuroanatomical lability, rendering individuals highly sensitive to stress. Indeed, early adversity increases risk for psychopathology. The mechanisms via which this vulnerability is differentially translated between individuals are not yet understood. Wistar rats exposed to psychogenic stressors around puberty show increased psychopathology-like behaviors at adulthood. Like humans, not all rats exposed to this stress develop in the same way, particularly with regard to aggression. The actions of glucocorticoids, the end product of hypothalamic-pituitary-adrenal (HPA) axis activations, mediate some alterations induced by peripuberty stress (PPS). Here we thus focused on assessing if individual differences in glucocorticoid responsiveness to stress influenced outcome following stress. We exposed male rats to PPS and later measured socio-affective behaviors and brain structure with magnetic resonance imaging. By applying a profiling approach we discerned two distinct neurodevelopmental trajectories arising from PPS. One led to the development of pathological aggression and reduced mean diffusivity in infralimbic cortex, amygdala and hippocampus. The other led to increased anxiety-like behavior and reduced sociability, with no evidence of alterations in brain structure. We assessed glucocorticoid responsiveness to PPS across the protocol and found that impaired habituation was associated with a more aggressive profile. Impaired habituation of glucocorticoid responses, shown by â35% of people, is heritable and associated with self-report of psychopathology-related indices. Considering this and our findings, we asked if constitutive differences in habituation to repeated stress were implicated in vulnerability to psychopathology. To answer this question, we developed a new animal model. We selectively bred lines of rats, enriching for stress habituation (âlow-lineâ) and lack of stress habituation (âhigh-lineâ). Once the lines were established, we assessed socio-affective behaviors and neuroendocrine phenotype of the rats. High-line rats displayed more aggression, anxiety-like, and depression-like behaviors. High-line rats had a distinct neuroendocrine phenotype, with enhanced corticosterone reactivity to acute stress, but no evidence for general HPA axis hyperactivity, and altered expression of several HPA axis related genes. Finally, we studied the interaction of the two risk factors in the development of behavioral alterations. Low- and high-line rats were exposed to PPS, and socio-affective behaviors and basal activation of the brain were later assessed. Both factors enhanced levels of anxiety-like and aggressive behavior, as well as increasing activity across the prefrontal cortex in a manner that was associated with increased behavioral inhibition. PPS had a differential impact on the lines, enhancing aggression in the stress-habituating low-line but not in the already high-aggressive, high-line rats. In summary, we established incidence of differential neurobehavioral trajectories following PPS, trajectories associated with differential glucocorticoid responsiveness across the stress. Constitutively impaired stress habituation increased psychopathology-like behavior in its own right, and this was not enhanced by exposure to PPS. In contrast, constitutively strong habituation enhanced sensitivity to the programming effects of PPS.