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

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.

Role of the HPA axis in the long-term programming of social behaviors by peripuberty stress

Vandana Veenit

Stress during childhood and adolescence enhances the risk of psychopathology later in life. In fact, exposure to stress during this period is known to predispose individuals to the development of psychopathologies such as depression and anxiety disorders later in life. Similarly, individuals subjected to fearful experiences or abuse during childhood and puberty exhibit violent behaviors in adulthood, as revealed in both human literature and animal studies. Previous work from our laboratory has shown that exposing peripuberty rats to fear experiences (such as synthetic fox odor and exposure to an elevated platform) following an unpredictable schedule, on a range of 7 specific days across P28 to P42 in male Wistar rats leads to reduced sociability, increased aggression, anxiety- and depression-like behaviors in adulthood. The hypothalamic pituitary adrenal (HPA) axis is one of the main physiological stress systems and various components of the HPA axis like corticotropin releasing hormone (CRH), glucocorticoids are modulated in response to early life experience. We therefore sought to investigate the role of HPA axis in long term programming of social and emotional behaviors as a result of peripuberty stress(PPS). We addressed this by manipulating (i) glucocorticoid system by two approaches, and, (ii) corticotropin releasing hormone (CRH) system. First, using male Wistar rats, we evaluated the consequences of administration of corticosterone following the same experimental schedule as for stress administration in our peripuberty stress paradigm (without actual stress exposure) on play behavior on postnatal day 44 (P44) and on behavioral tests of anxiety, aggression, sociability and depression in adulthood. Corticosterone response to novelty was also measured in adulthood. Our results show that, as compared to vehicle-, corticosterone-treated animals exhibit higher aggressive play behavior during adolescence, and escalated aggressive behavior in adulthood, while reduced sociability and decreased corticosterone response to novelty in adulthood. No differences were observed between groups on anxiety- and depression-like behavior tested later in life. Next, we examined whether pharmacological blockade of glucocorticoid receptor 30 minutes prior to peripuberty stress would prevent the consequences of peripuberty stress on emotional, social behavior and dysregulated gene expression. Our findings showed that administration of glucocorticoid receptor antagonist on days of peripuberty stress prevents the effects of peripuberty stress on behaviors related to the domain of aggression and sociability in adulthood without producing any effect on anxiety- and depression-like behavior tested later in life. Interestingly, administration of GR antagonist in PPS animals also reversed the effects of PPS on increased expression of GR and Trpc5 genes in central nucleus of amygdala. We also observed increased Crhr1 expression in limbic areas in peripuberty stressed animals which was not reversed by administration of GR antagonist in peripuberty stressed animals. Subsequently, we sought to evaluate the consequences of counteracting CRHR1 activation during early post-stress period on long-term behavioral consequences of peripuberty stress in tests for anxiety- and depression-like behaviors. Our results showed that administration of CRHR1 antagonist post peripuberty stress rescued the effects of peripuberty stress on depression-like behavior and to some extent on anxiety- like behavior. Taken together, our studies show that corticosterone administration during peripuberty largely mimics the behavioral alterations observed in peripuberty stressed animals in social realm, administration of glucocorticoid receptor antagonist on days of peripuberty stress prevents the effects of peripuberty on social domain and on increased expression of GR and Trpc5 genes in central nucleus of amygdala, and administration of CRHR1 antagonist post peripuberty stress rescued the effects of PPS on depression-like behavior and to some extent on anxiety-like behavior.

EPFL2013

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

Constitutive differences in habituation of the glucocorticoid response to stress are related to variation in aggression and anxiety-related behaviors

Marie-Isabelle Guillot de Suduiraut, Maria del Carmen Sandi Perez, Sophie Elizabeth Walker, Olivia Zanoletti

Glucocorticoids coordinate responses that enable an individual to cope with stressful challenges and, additionally, mediate adaptation following cessation of a stressor. There are important individual differences in the magnitude of glucocorticoid responsiveness to stressors. However, whether individual differences in glucocorticoid responsiveness to stress are linked to different behavioral strategies in coping with social and non-social challenges is not easily studied, owing to the lack of appropriate animal models. To address this, we generated three lines of Wistar rats selectively bred for the magnitude of their glucocorticoid responses following exposure to a variety of stressors over three consecutive days at juvenility. Here, we present findings following observations of a high level of variation in glucocorticoid responsiveness to stress in outbred Wistar rats, and the strong response to selection for this trait over a few generations. When challenged with different stressful challenges, rats from the three lines differed in their coping behaviors. Strikingly, the line with high glucocorticoid responsiveness to stress displayed enhanced aggression and anxiety-like behaviors. In addition, these rats also showed alterations in the expression of genes within both central and peripheral nodes of the hypothalamic-pituitary-adrenal (HPA) axis and enhanced reactivity to acute stress exposure. Together, these findings strongly link differences in glucocorticoid responsiveness to stress with marked differences in coping styles. The developed rat lines are thus a promising model with which to examine the relationship between variation in reactivity of the HPA axis and stress-related pathophysiology and could be employed to assess the therapeutic potential of treatments modulating stress habituation to ameliorate psychopathology.

2017