Social Isolation Induces Neuroinflammation And Microglia Overactivation, While Dihydromyricetin Prevents And Improves Them.

Abstract

Background: Anxiety disorders are the most prevalent mental illnesses in the U.S. and are estimated to consume one-third of the country's mental health treatment cost. Although anxiolytic therapies are available, many patients still exhibit treatment-resistance, relapse, or substantial side effects. Further, due to the COVID-19 pandemic and stay-at-home order, social isolation, fear of the pandemic, and unprecedented times, the incidence of anxiety has dramatically increased. Previously, we have demonstrated dihydromyricetin (DHM), the major bioactive flavonoid extracted from Ampelopsis grossedentata, exhibits anxiolytic properties in a mouse model of social isolation-induced anxiety. Because GABAergic transmission modulates the immune system in addition to the inhibitory signal transmission, we investigated the effects of short-term social isolation on the neuroimmune system.Methods: Eight-week-old male C57BL/6 mice were housed under absolute social isolation for 4 weeks. The anxiety like behaviors after DHM treatment were examined using elevated plus maze and open field behavioral tests. Gephyrin protein expression, microglial profile changes, NF-κB pathway activation, cytokine level, and serum corticosterone were measured. Results: Socially isolated mice showed increased anxiety levels, reduced exploratory behaviors, and reduced gephyrin levels. Also, a dynamic alteration in hippocampal microglia were detected illustrated as a decline in microglia number and overactivation as determined by significant morphological changes including decreases in lacunarity, perimeter, and cell size and increase in cell density. Moreover, social isolation also induced an increase in serum corticosterone level and activation in NF-κB pathway. Notably, DHM treatment counteracted these changes.Conclusion: The results suggest that social isolation contributes to neuroinflammation, while DHM has the ability to restore neuroinflammatory changes induced by anxiety.

Neuroinflammation and microglial expression in brains of social-isolation rearing model of schizophrenia

“…In contrast to Al-Omam et al (2022) , this study observed increased microglial count in the three brain regions of isolated male mice. Our finding is supported by a meta-analysis study that found an increase in microglia count in postmortem brains of patients with schizophrenia ( van Kesteren et al, 2017 ).…”

“…This study revealed that social isolation led to increased locomotor activity, depression, anxiety, and impaired prepulse inhibition function. Previous studies have shown these impairments ( Al Oman et al, 2022 ; Lander et al, 2017 ). Hence, social isolation used in this study was able to induce schizophrenia-related behaviours in both male and female mice.…”

“…However, their study did not report whether an increase in microglial count accompanied the increased expression. Another animal study reported a decrease in microglial count and microglial hyper-activation in the hippocampus ( Al Omam et al, 2022 ) though other brain regions were not considered. Thus, it is unknown whether this same effect occurs in other essential brain regions implicated in schizophrenia.…”

“…The open field chamber used has a dimension of 45 × 45 × 45 cm. The floor was segmented with 4 × 4 grid drawn to divide the floor into equal squares and an additional 20 × 20 cm square zone was drawn in the centre ( Al Omran et al, 2022 ). Animals were placed at this centre and were recorded for 6 min.…”

Thirty Risk Factors for Alzheimer’s Disease Unified by a Common Neuroimmune-Neuroinflammation Mechanism

“…Neuroinflammation is a definite immunological concomitant of the psychosocial problems inflicted by social isolation. In a study on eight-week-old male C57BL/6 mice, Al Omran et al showed that social isolation resulted in microglial activation and the release of pro-inflammatory cytokines [153]. Analogously, in a study with BALB/c mice, Ayilara and Owoyele demonstrated evidence of neuroinflammation manifesting as increased activated microglial count and elevated IL-1β and TNFα cytokine levels in a social isolation rearing model [154].…”