Long-term consequences of diverse early-life stressful events

Life experiences mainly affect neurodevelopment during restricted time windows (i.e., critical periods), when the brain is more responsive to environmental stimuli. Positive experiences during critical periods are necessary for healthy brain wiring and proper skill development. Conversely, traumatic life experiences (e.g., physical/sexual abuse, prolonged hospitalization, and warfare) can damage brain structure and connectivity, increasing risk for neuropsychiatric disorders (e.g., personality disorders, depression, anxiety, and post-traumatic stress disorder). In this context, although the nature of traumatic life experiences possibly leading to poor behavioral outcomes later in life can vary largely, the consequent neuropsychiatric conditions suffered by the traumatized individuals are in a restricted number. Moreover, whether a correspondence between specific traumatic life experiences and the insurgence of certain neuropsychiatric traits exists, remains elusive, suggesting that a particular traumatic event can trigger different psychiatric consequences. In this framework, we examined the long-term behavioral consequences of adverse life experiences (predator odor exposure, underwater immersion, and maternal separation) in diverse developmental periods (infancy, childhood, adolescence, and young adulthood) in mice, thus developing proper experimental animal models. We found that the timing of trauma exposure influenced the dominance/aggressiveness, with adult mice stressed in infancy displaying a submissive/passive behavior and adult mice stressed during adolescence and young adulthood showing an aggressive/active behavior in the tube dominance test. Conversely, trauma exposure led to an anxiety- like behavior, irrespective of the stimulus nature and the age at which the trauma was experienced. Proteomic analysis of adult mice exposed to predator odor at diverse ages showed that subcortical regions (hypothalamus, amygdala, and hippocampus) were more sensitive to stress exposure in infancy and childhood, while the prefrontal cortex was mostly affected upon stress exposure in adolescence and young adulthood. We also identified differentially expressed proteins common to all ages of stress (mainly involved in metabolic and synaptic processes), and age-specific ones (involved in apoptosis for stress in infancy, in ribosomal function for stress in childhood, and mitochondrial function for stress in adolescence). Biochemical experiments revealed that predator odor exposure during infancy and adolescence differently affected adult brain connectivity and determined changes in chloride homeostasis, suggesting an alteration in GABAergic neurotransmission. Finally, we broadly profile our mouse models of earlier life trauma in their ability to cope with mild stress when adults by assessing their different behaviors in the Multivariate Concentric Square Field test. We found that the behavioral strategies adopted by adult animals exposed to stress during infancy or adolescence were different from the ones used by adult control animals, but similar to the ones used by naïve infant or adolescent mice, respectively. Taken together, our data revealed deficits at both behavioral and molecular levels in adult mice exposed to stressful events earlier in life. These alterations specifically related to the timing of trauma exposure highlight the existence of critical periods for stress-induced long term-consequences.