Abstract

Mounting evidence shows that chronic stress can affect both the structure and function of the brain resulting in decreased synaptic plasticity and cognitive dysfunction. Although several studies have indicated that aged brains are more vulnerable to chronic stress, it remains unknown how to prevent stress-induced memory deficits in aged animals. Neuroinflammation plays an important role in the pathogenesis of chronic stress-related brain dysfunction. Receptor-interacting protein 1 (RIP1) is a key molecule that can modulate inflammation, apoptosis, and necroptosis. Here, we investigated whether inhibiting RIP1 using necrostatin-1 during chronic stress could improve chronic stress-related brain dysfunction in D-galactose-induced aging mice. The stressed mice underwent restraint stress for 14 days. Necrostatin-1 (6.25 mg/kg) or vehicle was administered intraperitoneally once every 3 days during the stress period. Locomotor activity was tested using the open field test and cognitive function was assessed using the novel object recognition and Barnes maze tests. The hippocampus was collected to assess neuroinflammation (Iba1, IL-1α, IL-1β, TNF-α, and C1q), necroptosis [RIP1, RIP3, mixed lineage kinase domain-like (MLKL), and NF-κB], neuroplasticity (doublecortin, NR1, NR2A, NR2B, GluA1, and GluA2), and the expression of glucocorticoid and mineralocorticoid receptors. Blood samples were collected to quantify the levels of corticosterone. We found that chronic stress induced obvious memory impairment and neuroinflammation, decreased neurogenesis and GluA2 expression, and increased the expression of RIP1 and NF-κB. Inhibiting RIP1 by necrostatin-1 during chronic stress rescued the memory impairment and alleviated the pathological changes induced by stress. These suggest that inhibiting RIP1 using necrostatin-1 improves chronic stress-related brain dysfunction in D-galactose-induced aging mice. The potential mechanisms include limitation of neuroinflammation and the rescue of neurogenesis and GluA2 expression.

Highlights

  • Chronic stress causes serious health problems in humans (Lupien et al, 2018)

  • These results suggested that necrostatin-1 alleviated the impairment of learning and memory induced by chronic stress in D-galactose-induced aging mice

  • We investigated the effects of chronic restraint stress on cognitive impairments in D-galactose-induced aging mice, and sought to determine whether inhibiting Receptor-interacting protein 1 (RIP1) using necrostatin-1 could mitigate any observed effects of stress

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Summary

Introduction

Chronic stress causes serious health problems in humans (Lupien et al, 2018). It is closely associated with brain dysfunction, including impairments of learning and memory (Sindi et al, 2017), depression (Mahar et al, 2014), anxiety (Herbison et al, 2017), and antisocial behaviors (Tielbeek et al, 2018). Activation of the hypothalamic–pituitary– adrenocortical (HPA) axis is the critical response during stress (Cacioppo et al, 2015). Targeting HPA axis has obvious side effects during the prevention and treatment of chronic stress-related brain impairments. It is more reasonable to target non-HPA axis mechanisms in order to prevent chronic stress-related impairments

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