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

Abstract

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.

Keywords:

• Aggression
• anxiety
• gene-environment interaction
• HPA axis
• individual differences
• stress habituation

Acknowledgements

We thank Dr. Aurélie Papilloud and Damien Huzard for assistance in the performance of the stress protocol. We are additionally grateful to Dr. Alexandre Bacq and Yann Dubois for their assistance in digitalizing autoradiography images.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This project has been supported by grants from the Swiss National Science Foundation (31003A-152614 and 31003A-176206; and NCCR Synapsy, Grant No. 51NF40-158776), European Union’s Seventh Framework Program for research, technological development and demonstration under Grant Agreement No. 603016 (MATRICS), and intramural funding from the EPFL to CS. The funding sources had no additional role in study design, in the collection, analysis and interpretation of data, in the writing of the report or in the decision to submit the paper for publication. This paper reflects only the authors’ views and the European Union is not liable for any use that may be made of the information contained therein.