Long term programming of psychopathology-like behaviors in male rats by peripubertal stress depends on individual’s glucocorticoid responsiveness to stress

Experience of adversity early in life and dysregulation of hypothalamus–pituitary–adrenocortical (HPA) axis activity are risk factors often independently associated with the development of psychopathological disorders, including depression, PTSD and pathological aggression. Additional evidence suggests that in combination these factors may interact to shape the development and expression of psychopathology differentially, though little is known about underlying mechanisms. Here, we studied the long-term consequences of early life stress exposure on individuals with differential constitutive glucocorticoid responsiveness to repeated stressor exposure, assessing both socio-affective behaviors and brain activity in regions sensitive to pathological alterations following stress. Two rat lines, genetically selected for either low or high glucocorticoid responsiveness to repeated stress were exposed to a series of unpredictable, fear-inducing stressors on intermittent days during the peripuberty period. Results obtained at adulthood indicated that having high glucocorticoid responses to repeated stress and having experience of peripuberty stress independently enhanced levels of psychopathology-like behaviors, as well as increasing basal activity in several prefrontal and limbic brain regions in a manner associated with enhanced behavioral inhibition. Interestingly, peripuberty stress had a differential impact on aggression in the two rat lines, enhancing aggression in the low-responsive line but not in the already high-aggressive, high-responsive rats. Taken together, these findings indicate that aberrant HPA axis activity around puberty, a key period in the development of social repertoire in both rats and humans, may alter behavior such that it becomes anti-social in nature.

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.

EPFL2016

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

Peripubertal stress-induced heightened aggression: modulation of the glucocorticoid receptor in the central amygdala and normalization by mifepristone treatment

Jocelin Grosse, Orbicia Riccio Wicht, Maria del Carmen Sandi Perez, Stamatina Tzanoulinou, Vandana Veenit, Olivia Zanoletti

Despite the enormous negative impact of excessive aggression for individuals and societies, there is a paucity of treatments. Here, using a peripubertal stress model of heightened aggression in rats, we investigated the involvement of the glucocorticoid system and tested the effectiveness of antiglucocorticoid treatment to normalize behavior. We assessed peripubertal stress-induced changes in glucocorticoid (GR) and mineralocorticoid (MR) gene expression in different amygdala nuclei and hippocampus, and report a specific increase in GR mRNA expression in the central amygdala (CeA). Administration of mifepristone (10 mg/kg), a GR antagonist, before stressor exposure at peripuberty prevented the habituation of plasma corticosterone responses observed throughout the stress protocol. This treatment also prevented the increase in aggression and GR expression in the CeA observed in peripubertally stressed rats at adulthood. Viral downregulation of CeA GR expression at adulthood led to reduced aggression. Subsequently, we showed that a brief, 3-day, treatment with mifepristone at adulthood was effective to normalize the abnormal aggression phenotype in peripubertally stressed rats. Our results support a key role for GR actions during peripubertal stress for the long-term programming of heightened aggression. Strikingly, they also support the translational interest of testing the effectiveness of mifepristone treatment to diminish reactive aggression in early adversity-related human psychopathologies.

2019