Adolescent Stress Increases Depression-Like Behaviors and Alters the Excitatory-Inhibitory Balance in Aged Mice
Depression is a significant mental health issue that affects approximately 5% of elderly individuals. The etiology of depression in older adults may be linked to chronic stress exposure during critical neurodevelopmental periods, such as adolescence. Adolescence is a time of substantial brain reorganization, and stress during this period can have long-lasting effects on mental health. This study investigates the impact of chronic social stress during adolescence on depression-like behaviors and the excitatory-inhibitory (E/I) balance in aged mice, focusing on key brain regions involved in stress response.
The study utilized 64 adolescent male C57BL/6 mice, which were randomly assigned to either a stress group or a control group. The stress group underwent a 7-week social instability stress procedure, where cage mates were frequently changed to create an unstable social environment. The control group remained in stable housing conditions. At 15 months of age, behavioral tests were conducted to assess depression-like behaviors, anxiety-like behaviors, and sensorimotor gating. Following the behavioral tests, immunohistochemical analyses were performed to measure the density of parvalbumin (PV+)- and calretinin (CR+)-positive GABAergic interneurons and the expression levels of vesicular glutamate transporter-1 (VGluT1) and vesicular GABA transporter (VGAT) in the medial prefrontal cortex (mPFC), hippocampus, and amygdala.
Behavioral results indicated that adolescent chronic stress increased depression-like behaviors in aged mice. Specifically, stressed mice showed a significant decrease in sucrose preference, a measure of anhedonia, compared to control mice (54.96% ± 1.97% vs. 43.11% ± 2.85%). Additionally, stressed mice exhibited a reduced latency to immobility in the tail suspension test, indicative of behavioral despair (92.77 ± 25.08 seconds vs. 33.14 ± 5.95 seconds). However, adolescent stress did not affect anxiety-like behaviors or prepulse inhibition, suggesting a specific impact on depressive symptoms.
At the neurobiological level, adolescent stress led to significant changes in the E/I balance in stress-sensitive brain regions. In the mPFC and hippocampus, stress down-regulated the density of PV+ interneurons but did not affect CR+ interneurons. In the mPFC, PV+ interneuron density was significantly lower in stressed mice (F(1, 39) = 19.30, P < 0.001), and similar results were observed in the hippocampus (F(1, 42) = 5.823, P = 0.020). In contrast, in the amygdala, stress altered the density of CR+ interneurons, with an increase in the basolateral amygdala and a decrease in the central amygdala (F(1, 28) = 23.16, P < 0.001).
The expression levels of VGluT1 and VGAT were also affected by adolescent stress. The VGluT1/VGAT ratio, which reflects the E/I balance at the synaptic level, was decreased in all three brain regions (all F > 10.09, all P < 0.004). This reduction was primarily driven by a decrease in VGluT1 expression, suggesting stress-induced hypoexcitability in these regions. In the mPFC, VGluT1 expression was significantly lower in stressed mice (F(1, 39) = 16.45, P < 0.001), and similar findings were observed in the hippocampus (F(1, 39) = 7.702, P = 0.008) and amygdala (F(1, 26) = 10.09, P = 0.004).
The findings of this study demonstrate that chronic social stress during adolescence has long-term effects on depressive behaviors and the E/I balance in aged mice. The selective down-regulation of PV+ interneurons in the mPFC and hippocampus, along with the altered CR+ interneuron density in the amygdala, suggests that adolescent stress disrupts the developmental trajectory of GABAergic interneurons. The reduced VGluT1/VGAT ratio in stress-sensitive brain regions indicates a shift towards hypoexcitability, which may underlie the increased depression-like behaviors observed in aged mice.
These results highlight the importance of early-life stress in shaping mental health outcomes in later life. The adverse effects of adolescent stress on the E/I balance and depressive behaviors underscore the need for interventions during this critical developmental period. Future research should explore the mechanisms underlying these changes and investigate potential therapeutic strategies to mitigate the long-term impact of adolescent stress on mental health.
doi.org/10.1097/CM9.0000000000000313
Was this helpful?
0 / 0