A Systematic Review of the Effect of Stress in Animals During Adolescence, and Its Long-Term Consequences during Adulthood: Focus on Hippocampal Neurogenesis, Cognitive Function and Behavioural Outcomes

Abstract

Adolescence represents a critical period for the programming of future adult behaviours. Neurogenesis is particularly active during adolescence, with increased number of granule cells and increased hippocampal volume both in animals and humans. Among the factors which can affect neurogenesis during adolescence, stress is considered a major one. Indeed, adolescence is known to be a particularly stressful period in life, with some adolescents suffering from mood disorders and anxiety. While there is increasing interest on the neurogenic changes occurring during the adolescent period, evidence is sparse. We conducted a systematic review summarising changes in hippocampal neurogenesis, neuroplasticity and hippocampal-dependent cognitive functions and behavioural outcomes in stress-induced adolescent animal models of depression, and investigating long-term stress effects on the same outcomes assessing the same animals in adulthood. Overall, the results show a significant reduction in hippocampal cell proliferation, and a concomitant increase in depressive-like behaviours in adolescent animals exposed to stress challenges, however reduction in the number of surviving neurons was accompanied by no changes in both cognition and behaviour. Studies also observed altered neuroplasticity, including a stress-induced decrease in markers of pre- and post-synaptic plasticity, dendritic spine length and density, and long-term potentiation. These changes in neuroplasticity were accompanied by cognitive impairments and depressive-like behaviours. Overall, some of the negative effects observed during adolescence, especially on cell proliferation, neuroplasticity, cognition and behaviour either persisted or worsened during adulthood. Interestingly, treatment during adolescence with antidepressants, glutamate receptor inhibitors, glucocorticoid antagonists, or a healthy diet consisting of omega-3 fatty acids and vitamin A, were able to reverse or prevent these detrimental effects. Future research should aim to investigate the translational impact of these preclinical findings, developing novel tools for the measurement of hippocampal neurogenesis directly in depressed adolescents, and subsequently assessing neurogenic changes in response to stress as well as pharmacological and non-pharmacological interventions.