Differential effects of chronic stress in young-adult and old female mice: cognitive-behavioral manifestations and neurobiological correlates

Abstract

Stress-related psychopathology is highly prevalent among elderly individuals and is associated with detrimental effects on mood, appetite and cognition. Conversely, under certain circumstances repeated mild-to-moderate stressors have been shown to enhance cognitive performance in rodents and exert stress-inoculating effects in humans. As most stress-related favorable outcomes have been reported in adolescence and young-adulthood, this apparent disparity could result from fundamental differences in how aging organisms respond to stress. Furthermore, given prominent age-related alterations in sex hormones, the effect of chronic stress in aging females remains a highly relevant yet little studied issue. In the present study, female C57BL/6 mice aged 3 (young-adult) and 20-23 (old) months were subjected to 8 weeks of chronic unpredictable stress (CUS). Behavioral outcomes were measured during the last 3 weeks of the CUS protocol, followed by brain dissection for histological and molecular end points. We found that in young-adult female mice, CUS resulted in decreased anxiety-like behavior and enhanced cognitive performance, whereas in old female mice it led to weight loss, dysregulated locomotion and memory impairment. These phenotypes were paralleled by differential changes in the expression of hypothalamic insulin and melanocortin-4 receptors and were consistent with an age-dependent reduction in the dynamic range of stress-related changes in the hippocampal transcriptome. Supported by an integrated microRNA (miRNA)-mRNA expression analysis, the present study proposes that, when confronted with ongoing stress, neuroprotective mechanisms involving the upregulation of neurogenesis, Wnt signaling and miR-375 can be harnessed more effectively during young-adulthood. Conversely, we suggest that aging alters the pattern of immune activation elicited by stress. Ultimately, interventions that modulate these processes could reduce the burden of stress-related psychopathology in late life.

Brain targeting of 9c,11t-Conjugated Linoleic Acid, a natural calpain inhibitor, preserves memory and reduces Aβ and P25 accumulation in 5XFAD mice

“…The test was performed using the Ethovision 10 system, providing fully computerized, blinded and unbiased measurement. Normal animals tent to explore the new object longer than the old one, indicating normally long-term recognition memory 55 .…”

AVPR1A main effect and OXTR-by-environment interplay in individual differences in depression level

“…In the present study we reported the association of rs3803107 A-allele and higher depression score in one ethnic group (Russians), which seems to be congruent with published data on association between lower AVPR1A level and reduced anxiety ( Barrett et al., 2013 ) and the presence of rs3803107 GG genotype ( Zhang et al., 2019 ). According to the literature, miR-375 is relevant to psychiatric conditions and psychological phenotypes ( Bhinge et al., 2016 ; Dulcis et al., 2017 ), while chronic unpredictable stress can cause miR-375 increase thus affecting expression of relevant genes ( Lotan et al., 2018 ). In turn, the role of miR-186 in synaptic scaling as a degree of stable neuronal activity affected by developmental processes was demonstrated ( Silva et al., 2019 ).…”

Distinctive stress sensitivity and anxiety-like behavior in female mice: Strain differences matter

“…Following the NIH directive of the use of females in biomedical studies (NOT-OD-15-102, NIH, 2015) there has been an steady increase in the number of studies comparing male and females, where many report differential responses between sexes (for a recent review see Bolea-Alamanac et al, 2018 ). The literature on anxiety and depression considering female individuals as the target population are still a minority, but they point to the importance of studying female response to different stressors, since their impact seems drastically different ( Zhu et al, 2014 ; Lotan et al, 2017 ).…”