Many mood and psychological disorders develop during adolescence; however, the relationship between adolescent stress-related neurogenesis and psychiatric illnesses during this period remains unclear.
A new paper in the journal Molecular Psychiatry presents a systematic review of studies involving changes in the hippocampus and behavior following acute stress exposure in adolescent mice, as well as the chronic effects of this type of stress once these mice reach adulthood.
Study: Acute and long-term effects of adolescence stress exposure on rodent adult hippocampal neurogenesis, cognition, and behaviour. Image Credit: polya_olya / Shutterstock.com
Introduction
Behavioral changes characteristic of adolescence include higher social tendencies, more risky behavior, greater impulsivity, as well as improved social and executive cognitive functions. Previous studies have indicated that these behavioral changes may be attributed to the maturation of the hippocampus and other areas that are key to memory and learning.
The hippocampus during adolescence is bigger than in both rodent and human adults. More specifically, the adolescent hippocampus is characterized by neurogenesis, during which new neurons are formed in the subgranular zone of the dentate gyrus (DG) to become part of the granule cell layer. These cells are relatively numerous in the adolescent as compared to adults.
Some studies have reported that neurogenesis is crucial for certain cognitive functions, such as pattern separation, which is the ability to distinguish threats from non-threatening situations and between different situations that have some similarities.
In mice, stress inhibits hippocampal neurogenesis. This type of stress could be due to intruders, intermittent feeding rather than constant feeding, isolation, and a lack of communication, all of which result in worse memory, learning, and dysregulated emotions.
Stress-induced inflammation may reduce hippocampal neurogenesis by reduced neurogenitor cell pools coupled with increased neuronal apoptosis of already mature cells, both of which could affect cognitive functions. Stress can also interfere with the ability of the hippocampus to recall certain emotional memories, which may ultimately lead to personality differences and future adult mental traits.
The current study examines how the hippocampus is related to stress in adolescence and the effects of interventions on stress-linked adverse effects on the hippocampus and resulting cognitive, behavioral, and neuroplasticity functions.
What did the study show?
A total of 37 studies were reviewed in an effort to determine whether stress during adolescence impacts neurogenesis in the hippocampus, as well as neuroplasticity, cognitive functions mediated by the hippocampus, and behavior.
Of these 37 studies, seven reported reduced cell proliferation in the hippocampus. Two papers reported that stressed rodents were more likely to exhibit depressive-like behavior, whereas three studies reported that stressed animals exhibited fewer new neurons but no cognitive or behavioral changes.
In 16 studies, mice exposed to chronic stress during adolescence exhibited adverse effects on the hippocampus, including reduced hippocampal neuroplasticity markers of synaptophysin and post-synaptic density 95. These changes occur before or after the synapses, respectively, and were associated with depressive-like behavior, irrespective of the type of stress exposure.
Other effects included changes in the length and density of dendritic spines, as well as dysfunction in post-stress long-term potentiation (LTP) and long-term depression (LTD). Poor dendrite formation or altered density and morphology of dendrites were associated with dysfunctional memory and depressive-like symptoms.
LTP changes were independent of acute or chronic stress exposure and associated with impaired memory function. Notably, these effects were reversed by capsaicin, which has antidepressant properties.
In 11 of the 16 studies that reported reduced neuroplasticity, mice exhibited poor cognition and increased depressive-like behavior.
Reduced neurogenesis occurred irrespective of the type of stress, duration, or time of biopsy. Conversely, depressive-like symptoms were more likely to be observed in studies where cortisol administration or social defeat stress were used as compared to those that used social instability as the stressor.
The presence of depressive-like symptoms was consistent regardless of the time of behavioral testing. Moreover, the duration of stress was associated with depressive-like responses.
Among adult mice exposed to stress during adolescence, seven studies reported variable effects following the aforementioned negative stress-related effects on the hippocampus. Two studies reported reduced dendritic spine density over time, as well as normal or consistently decreased levels of brain-derived neurotrophic factor (BDNF), which supports cell proliferation, growth, and survival.
In previous human studies, long-term cognitive impairment and depressive symptoms have been recorded in children who have undergone cancer treatment or adolescents who are undergoing brain radiation, the latter of which abolishes hippocampal neurogenesis.
When adolescent mice were administered a range of therapies, from antidepressants, glutamate receptor inhibitors, glucocorticoid antagonists, or a diet rich in omega-3 fatty acids and vitamin A, negative effects were either prevented or corrected. Importantly, supplements only prevented cognitive changes.
These medications successfully reversed stress-linked effects by promoting neuronal survival and increased neuroplasticity, which was independent of stress type, duration, or length of treatment.
What are the implications?
Together, these studies found that detrimental effects on neuroplasticity, cognitive functions and behaviour can either persist or develop in adulthood as a consequence of stress exposure during adolescence, and demonstrate the beneficial role of nutritional interventions in preventing these effects.”
The current review only discussed preclinical studies; therefore, further studies are needed to understand the utility of these findings in clinical settings.
Newer neuroimaging tools are crucial for assessing human hippocampal neurogenesis in vivo to allow researchers to determine how stress affects neurogenesis and how this is reflected in human beings. These studies will also enable researchers to evaluate the impact of any potential therapeutic intervention.
Journal reference:
- Borsini, A., Giacobbe, J., Mandal, G., & Boldrini, M. (2023). Acute and long-term effects of adolescence stress exposure on rodent adult hippocampal neurogenesis, cognition, and behaviour. Molecular Psychiatry. doi:10.1038/s41380-023-02229-2.