The coronavirus disease 2019 (COVID-19) pandemic has generated a lot of stress and anxiety among not only infected patients but also the general population across the globe, which disturbs cerebral immune homeostasis and potentially exacerbates the SARS-CoV-2 virus-induced neuroinflammation, especially among people susceptible to neuropsychiatric disorders. Here, we used a chronic unpredictable mild stress (CUMS) mouse model to study its effects on glia-mediated neuroinflammation and expression of SARS-CoV2 viral receptors. We observed that female mice showed depressive-like behavior after CUMS, whereas male mice showed enhanced anxiety and social withdrawal. Interestingly, CUMS led to increased amounts of total and MHCII⁺ microglia in the hippocampi of female mice but not male mice. mRNA levels of SARS-CoV-2 viral receptors angiotensin-converting enzyme 2 (Ace2) and basigin (Bsg) were also upregulated in the prefrontal cortices of stressed female mice but not male mice. Similarly, sex-specific changes in SARS-CoV-2 viral receptors FURIN and neuropilin-1 (NRP1) were also observed in monocytes of human caregivers enduring chronic stress. Our findings provided evidence on detrimental effects of chronic stress on the brain and behavior and implied potential sex-dependent susceptibility to SARS-CoV-2 infection after chronic stress.

In GWAS studies, the neural adhesion molecule encoding the neuronal growth regulator 1 (NEGR1) gene has been consistently linked with both depression and obesity. Although the linkage between NEGR1 and depression is the strongest, evidence also suggests the involvement of NEGR1 in a wide spectrum of psychiatric conditions. Here we show the expression of NEGR1 both in tyrosine- and tryptophan hydroxylase-positive cells. Negr1^−/− mice show a time-dependent increase in behavioral sensitization to amphetamine associated with increased dopamine release in both the dorsal and ventral striatum. Upregulation of transcripts encoding dopamine and serotonin transporters and higher levels of several monoamines and their metabolites was evident in distinct brain areas of Negr1^−/− mice. Chronic (23 days) escitalopram-induced reduction of serotonin and dopamine turnover is enhanced in Negr1^−/− mice, and escitalopram rescued reduced weight of hippocampi in Negr1^−/− mice. The current study is the first to show alterations in the brain monoaminergic systems in Negr1-deficient mice, suggesting that monoaminergic neural circuits contribute to both depressive and obesity-related phenotypes linked to the human NEGR1 gene.

Many studies have demonstrated significant mouse-strain-specific differences in behavior and response to pathogenic and pharmacological agents. This study seeks to characterize possible differences in microglia activation and overall severity of neuroinflammation in two widely used mouse strains, C57BL/6NTac (Bl6) and 129S6/SvEvTac (129Sv), in response to acute lipopolysaccharide (LPS) administration. Locomotor activity within the open field arena revealed similar 24 h motor activity decline in both strains. Both strains also exhibited significant bodyweight loss due to LPS treatment, although it was more severe in the Bl6 strain. Furthermore, LPS induced a hypothermic response in Bl6 mice, which was not seen in 129Sv. We found that 24 h LPS challenge significantly increased the inflammatory status of microglia in 129Sv mice. On the other hand, we observed that, under physiological conditions, microglia of Bl6 seemed to be in a higher immune-alert state. Gene and protein expression analysis revealed that LPS induces a significantly stronger upregulation of MHC-I-pathway-related components in the brain of Bl6 compared to 129Sv mice. The most striking difference was detected in the olfactory bulb, where we observed significant LPS-induced upregulation of MHC-I pathway components in Bl6 mice, whereas no alterations were observed in 129Sv. We observed significant positive correlations between bodyweight decline and expressions of MHC-I components in the olfactory bulbs of Bl6 mice and the frontal cortex of 129Sv, highlighting different brain regions most affected by LPS in these strains. Our findings suggest that the brains of Bl6 mice exist in a more immunocompetent state compared to 129Sv mice.

Different inbred mouse strains vary substantially in their behavior and metabolic phenotype under physiological and pathological conditions. The purpose of this study was to extend the knowledge of distinct coping strategies under challenging events in two differently adapting mouse strains: C57BL/6NTac (Bl6) and 129S6/SvEvTac (129Sv). Thus, we aimed to investigate possible similarities and differences in the body weight change, behavior, and several metabolic variables in Bl6 and 129Sv strains in response to high-fat diet (HFD) using the AbsoluteIDQ p180 kit. We found that 9 weeks of HFD induced a significant body weight gain in 129Sv, but not in Bl6 mice. Besides that, 129Sv mice displayed anxiety-like behavior in the open-field test. Metabolite profiling revealed that 129Sv mice had higher levels of circulating branched-chain amino acids, which were even more amplified by HFD. HFD also induced a decrease in glycine, spermidine, and t4-OH-proline levels in 129Sv mice. Although acylcarnitines (ACs) dominated in baseline conditions in 129Sv strain, this strain had a significantly stronger AC-reducing effect of HFD. Moreover, 129Sv mice had higher levels of lipids in baseline conditions, but HFD caused more pronounced alterations in lipid profile in Bl6 mice. Taken together, our results show that the Bl6 line is better adapted to abundant fat intake.

Objective: Neuronal growth regulator 1 (Negr1) is a GPI-anchored neuronal cell adhesion molecule of the IgLON superfamily associated with multiple psychiatric disorders. This study aimed to investigate behavioral and molecular adaptations to social isolation (SI) stress in Negr1-deficient (Negr1^−/−) mice. Methods: Male and female Negr1^−/− and wild-type (Wt) mice (n = 10 per group) were exposed to two weeks of SI or group housing (Ctl). Behavioral assays assessed exploratory and anxiety-like behavior. Gene expression analyses in the prefrontal cortex and hippocampus were performed using RT-qPCR, focusing on GABAergic, neurotrophic, and IgLON family genes. Results: SI-induced weight loss in Negr1^−/− mice compared to Wt was evident in both sexes but more pronounced in males. Behaviorally, SI Wt males showed stress-induced hyperactivity compared to Ctl Wt, whereas SI Negr1^−/− males exhibited blunted exploratory behavior relative to SI Wt in the open field test (OFT). Negr1^−/− females showed reduced exploration in the elevated plus maze (EPM), suggesting increased anxiety. Hippocampal Pvalb was downregulated in SI Negr1^−/− mice of both sexes compared to Wts, with a stronger decrease in males, indicating heightened male vulnerability in GABAergic interneuron function. In males, SI reduced hippocampal Bdnf in both genotypes, whereas Ntrk2 (TrkB) upregulation occurred only in Negr1^−/− mice, suggesting a genotype-specific compensatory response. Hippocampal expression of Fgfr2 and IgLON members (Ntm1a/1b, Lsamp1a/1b) was increased in SI Negr1^−/− males compared to SI Wt, with minimal changes in females. Conclusions: Negr1 deficiency leads to sex-specific behavioral and molecular adaptations to social isolation stress, highlighting the role of Negr1 in modulating neurotrophic and GABAergic signaling pathways under adverse environmental conditions.