Adolescent stress increases depression-like behaviors and alters the excitatory-inhibitory balance in aged mice

Abstract

Background: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.Methods: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).Results: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.Conclusions: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.

Parvalbumin interneuron alterations in stress-related mood disorders: A systematic review

“…(2018) Mouse (C57/BL6) Adolescent-adult Adult ♂ CSIS 7 weeks. After stress, mice housed individually for 1 year Prelimbic cortex IHC PV cell density decreased [179] Wang et al. (2019) Rat (Sprague-Dawley) Early postnatal Juvenile ♂ MS 4h/day Prelimbic cortex IHC; Western blot PV cell density; PV protein content no change [19] Brenhouse and Andersen (2011) Rat (Sprague-Dawley) Early postnatal Adolescent ♂ MS 4h/day Prelimbic cortex IHC; Western blot PV cell density; PV protein content decreased protein and density [19] Brenhouse and Andersen (2011) Rat (Sprague-Dawley) Early postnatal Adolescent ♂♀ MS 4h/day Prelimbic cortex Western blot PV protein content decreased in males [35] do Prado et al.…”

“…(2018) Mouse (C57/BL6) Adolescent-adult Adult ♂ CSIS 7 weeks. After stress, mice housed individually for 1 year Infralimbic cortex IHC PV cell density decreased [179] Wang et al. (2019) Rat (Sprague-Dawley) Early postnatal Adolescent ♂♀ MS 4h/day Infralimbic cortex Western blot PV protein content decreased in males [35] do Prado et al.…”

“…(2018) Mouse (C57/BL6) Adolescent-adult Adult ♂ CSIS 7 weeks. After stress, mice housed individually for 1 year Anterior Cingulate cortex IHC PV cell density decreased [179] Wang et al. (2019) Degu Early postnatal Juvenile ♂ MS 3 × 1h/day Precentral Medial cortex IHC PV cell density no change [66] Helmeke et al.…”

“…(2017) Mouse (C57/BL6) Adolescent-adult Adult ♂ CSIS 7 weeks. After stress, mice housed individually for 1 year Dentate Gyrus IHC PV cell density decreased [179] Wang et al. (2019) Mouse (C57/BL6) Early postnatal Adult ♂ MSEW: MS 4h/day from P2–P5, then 8h/day from P6–P16.…”

“…(2017) Mouse (C57/BL6) Adolescent-adult Adult ♂ CSIS 7 weeks. After stress, mice housed individually for 1 year CA1 IHC PV cell density decreased [179] Wang et al. (2019) Rat (Sprague-Dawley) Early postnatal Juvenile ♂♀ MS 4h/day 19 days CA1 IHC 8-oxo-dG + fraction of PV cells; PV + cell 8-oxo-dG intensity; PV cell number; PV intensity increased 8-oxo-dG + fraction; increased PV+ 8-oxo-dG in females vs males and increased PV intensity in males vs females [159] Soares et al.…”