National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital/Institute of Mental Health) and the Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing 100191, China.
The Sixth People's Hospital of Hebei Province, Baoding, Hebei 071000, China.
Chin Med J (Engl). 2019 Jul 20;132(14):1689-1699. doi: 10.1097/CM9.0000000000000313.
Depression affects approximately 5% of elderly people and its etiology might be related to chronic stress exposure during neurodevelopmental periods. In this study, we examined the effects of adolescent chronic social stress in aged mice on depressive behaviors and the excitatory-inhibitory (E/I) balance in stress-sensitive regions of the brain.
Sixty-four adolescent, male C57BL/6 mice were randomly assigned to either the 7-week (from post-natal days 29 to 77) social instability stress (stress group, n = 32) or normal housing conditions (control group, n = 32). At 15 months of age, 16 mice were randomly selected from each group for a series of behavioral tests, including two depression-related tasks (the sucrose preference test and the tail suspension test). Three days following the last behavioral test, eight mice were randomly selected from each group for immunohistochemical analyses to measure the cell density of parvalbumin (PV)- and calretinin (CR)-positive gamma-aminobutyric-acid (GABA)ergic inhibitory inter-neurons, and the expression levels of vesicular transporters of glutamate-1 (VGluT1) and vesicular GABA transporter (VGAT) in three stress-sensitive regions of the brain (the medial pre-frontal cortex [mPFC], hippocampus, and amygdala).
Behaviorally, compared with the control group, adolescent chronic stress increased depression-like behaviors as shown in decreased sucrose preference (54.96 ± 1.97% vs. 43.11 ± 2.85%, t(22) = 3.417, P = 0.003) and reduced latency to immobility in the tail suspension test (92.77 ± 25.08 s vs. 33.14 ± 5.95 s, t(25) = 2.394, P = 0.025), but did not affect anxiety-like behaviors and pre-pulse inhibition. At the neurobiologic level, adolescent stress down-regulated PV, not CR, inter-neuron density in the mPFC (F(1, 39) = 19.30, P < 0.001), and hippocampus (F(1, 42) = 5.823, P = 0.020) and altered the CR, not PV, inter-neuron density in the amygdala (F(1, 28) = 23.16, P < 0.001). The VGluT1/VGAT ratio was decreased in all three regions (all F > 10.09, all P < 0.004), which suggests stress-induced hypoexcitability in these regions.
Chronic stress during adolescence increased depression-like behaviors in aged mice, which may be associated with the E/I imbalance in stress-sensitive brain regions.
抑郁症影响约 5%的老年人，其病因可能与神经发育过程中慢性应激暴露有关。在这项研究中，我们研究了青少年慢性社会压力对老年小鼠的影响，以观察其对大脑中应激敏感区域的抑郁行为和兴奋-抑制（E/I）平衡的影响。
64 只雄性 C57BL/6 青少年小鼠被随机分配到 7 周（从出生后第 29 天到第 77 天）的社会不稳定应激（应激组，n=32）或正常饲养条件（对照组，n=32）。在 15 个月大时，从每组中随机选择 16 只小鼠进行一系列行为测试，包括两项与抑郁相关的任务（蔗糖偏好测试和悬尾测试）。在最后一次行为测试后的第三天，从每组中随机选择 8 只小鼠进行免疫组织化学分析，以测量三个应激敏感脑区（内侧前额叶皮质[mPFC]、海马体和杏仁核）中 PV-和 CR-阳性 GABA 能抑制性中间神经元的细胞密度，以及谷氨酸转运体 1（VGluT1）和 GABA 转运体（VGAT）的囊泡转运蛋白的表达水平。
在行为上，与对照组相比，青少年慢性应激增加了抑郁样行为，表现为蔗糖偏好度降低（54.96±1.97% vs. 43.11±2.85%，t(22)=3.417，P=0.003）和悬尾测试中不动时间延长（92.77±25.08 s vs. 33.14±5.95 s，t(25)=2.394，P=0.025），但不影响焦虑样行为和前脉冲抑制。在神经生物学水平上，青少年应激下调了 mPFC（F(1, 39)=19.30，P<0.001）和海马体（F(1, 42)=5.823，P=0.020）中 PV 而不是 CR 中间神经元的密度，并改变了杏仁核中 CR 而不是 PV 中间神经元的密度（F(1, 28)=23.16，P<0.001）。所有三个区域的 VGluT1/VGAT 比值均降低（所有 F>10.09，所有 P<0.004），提示这些区域存在应激诱导的兴奋性降低。
青少年时期的慢性应激增加了老年小鼠的抑郁样行为，这可能与应激敏感脑区的 E/I 失衡有关。
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