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 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 improve neuroinflammation induced by anxiety.

Social Isolation Stress Modulates Pregnancy Outcomes and the Inflammatory Profile of Rat Uterus

“…When rats are deprived of physical social interactions during SIS rearing, while maintaining regular olfactory, auditory, and visual contact with their counterparts [ 28 , 29 ], they experience mild psychosocial stress [ 30 , 31 ]. Consequences of SIS include functional, morphological, and neurochemical alterations in distinct brain areas, HPA axis changes, disrupted inflammatory responses, and altered behaviour in adult offspring [ 16 , 31 , 32 , 33 , 34 , 35 , 36 ]. While the effects of SIS have been reported in the literature, little is known about its effects on pregnancy outcomes.…”

Dihydromyricetin improves social isolation-induced cognitive impairments and astrocytic changes in mice

“…In our previous studies with socially isolated mice, we reported that DHM reversed the reduced levels of adenine triphosphate (ATP) and gephyrin, a scaffolding protein that supports and stabilizes the clustering of post-synaptic GABA A receptors 13 . We also recently demonstrated that DHM ameliorated GABA A R-mediated currents, microglia, and neuroinflammation in the same mice model 13 , 43 . GABA A Rs are highly expressed in astrocytes and allow them to sense and respond to their environment 44 , 45 .…”

Standards-Based UPLC-Q-Exactive Orbitrap MS Systematically Identifies 36 Bioactive Compounds in Ampelopsis grossedentata (Vine Tea)

“…The flavonoids, however, can be further classified into two subtypes: one was flavone; while another was flavonol (including flavonol glucoside). Interestingly, the parent skeleton of flavone was actually noreugenin (22), while the parent skeleton of flavonol was 3,5,7-trihydroxychromone (9). This means that the plant A. grossedentata may utilize two chromones as parents to biosynthesize the corresponding flavones and flavonols.…”