Inflammation plays a considerable role in the pathogenesis of many diseases, including neurodegenerative and psychiatric ones. Elucidation of the specific features of an immune response in various model organisms, and studying the relation of these features with the behavioral phenotype, can improve the understanding of the molecular mechanisms of many psychopathologies. In this work, we focused on BTBR mice, which have a pronounced autism-like behavioral phenotype, elevated levels of oxidative-stress markers, an abnormal immune response, several structural aberrations in the brain, and other unique traits. Although some studies have already shown an abnormal immune response in BTBR mice, the existing literature data are still fragmentary. Here, we used inflammation induced by low-dose lipopolysaccharide, polyinosinic:polycytidylic acid, or their combinations, in mice of strains BTBR T+Itpr3tf/J (BTBR) and C57BL6/J. Peripheral inflammation was assessed by means of a complete blood count, lymphocyte immunophenotyping, and expression levels of cytokines in the spleen. Neuroinflammation was evaluated in the hypothalamus and prefrontal cortex by analysis of mRNA levels of proinflammatory cytokines (tumor necrosis factor, Tnf), (interleukin-1 beta, Il-1β), and (interleukin-6, Il-6) and of markers of microglia activation (allograft inflammatory factor 1, Aif1) and astroglia activation (glial fibrillary acidic protein, Gfap). We found that in both strains of mice, the most severe inflammatory response was caused by the administration of polyinosinic:polycytidylic acid, whereas the combined administration of the two toll-like receptor (TLR) agonists did not enhance this response. Nonetheless, BTBR mice showed a more pronounced response to low-dose lipopolysaccharide, an altered lymphocytosis ratio due to an increase in the number of CD4+ lymphocytes, and high expression of markers of activated microglia (Aif1) and astroglia (Gfap) in various brain regions as compared to C57BL6/J mice. Thus, in addition to research into mechanisms of autism-like behavior, BTBR mice can be used as a model of TLR3/TLR4-induced neuroinflammation and a unique model for finding and evaluating the effectiveness of various TLR antagonists aimed at reducing neuroinflammation.

Chronic stress alters hypothalamic–pituitary–adrenal (HPA) axis function, affecting corticosterone regulation and adaptive responses. Understanding individual variability in stress adaptation requires identifying distinct HPA axis response patterns. Here, we assessed HPA axis sensitivity in male C57BL6 mice exposed to 30 days of chronic social defeat stress (CSDS). Negative feedback integrity was evaluated using the dexamethasone suppression test (DST), with corticosterone measured after saline or low-dose dexamethasone administration at days 10 and 30. Behavioral testing (open field, elevated plus maze, social interaction test, partition, social defeat, forced swimming test, sucrose preference test) and qPCR analysis of HPA-axis-related genes in the hypothalamus (Crh, Crhr1, Crhbp, Fkbp5, Nr3c1), pituitary (Pomc, Crhr1, Nr3c1, Nr3c2), and adrenal glands (Cyp11a1, Cyp11b1, Hsd11b1, Mc2r, Star, Fkbp5, Nr3c1) were performed. K-means cluster analysis identified three distinct response profiles differing in baseline and dexamethasone-suppressed corticosterone levels. Clusters also exhibited differences in behavioral phenotypes and HPA axis gene expression. Cluster 1 showed low basal corticosterone and an abnormal dexamethasone suppression response, without significant Crh or Crhbp dysregulation in the hypothalamus. Cluster 2 exhibited elevated basal corticosterone, a blunted dexamethasone response, anhedonia, and reduced immobility in the forced swim test; increased Crh and reduced Fkbp5 suggested enhanced glucocorticoid receptor sensitivity and sustained hypercortisolemia. Cluster 3, characterized by normal basal corticosterone and normal dexamethasone response, displayed upregulation of Crh and Crhbp, consistent with balanced and potentially adaptive HPA axis regulation under chronic stress. These results demonstrate that corticosterone response heterogeneity reflects distinct adaptive trajectories under chronic stress. Identifying behavioral and molecular markers of these strategies may advance understanding of stress vulnerability and resilience mechanisms, with implications for stress-related disorders.

Background: Depression is a severe disorder associated with hypothalamic–pituitary–adrenal (HPA) axis dysregulation and neuroinflammation, and which restrains the efficacy of conventional antidepressants. Vortioxetine is a multimodal antidepressant with potential immunomodulatory properties. Glycyrrhizic acid (GA) is a natural compound derived from licorice root that exhibits anti-inflammatory activity and modulates glucocorticoid signaling. We hypothesized that a supramolecular complex of vortioxetine with GA (Vort:Na₂GA) would exert synergistic effects on inflammatory and glucocorticoid pathways. Methods: Vortioxetine compositions with Na₂GA were prepared using a mechanochemical method. Cytotoxicity, anti-inflammatory property, and glucocorticoid receptor (GR) signaling pathway modulation of the complex were evaluated in vitro using SIM-A9 microglial cells. Additionally, a 7-day oral administration study in intact female C57BL/6 mice was conducted to evaluate the effects on peripheral blood cells. Results: The Vort:Na₂GA complex improves the solubility of the parent drug while increasing its stability and permeability. Furthermore, the resulting complex exhibits reduced cytotoxicity, particularly under glucocorticoid challenge. In SIM-A9 microglial cells, the Vort:Na₂GA complex upregulated expression of Nr3c1 and Nr1d1 genes without activating canonical GR target genes (Fkbp5 and Gilz) and partially reversed dexamethasone-induced glucocorticoid resistance. In vivo, the complex reduced the percentage of inflammatory Ly6C^high monocytes and preserved dexamethasone-induced Gilz expression in peripheral blood cells, indicating protection against stress-induced glucocorticoid resistance. Conclusions: The Vort:Na₂GA supramolecular complex enhances the physicochemical and pharmacological profile of vortioxetine, reduces inflammation-associated myeloid cell populations, and preserves glucocorticoid sensitivity. These findings support its further evaluation as a potential therapeutic agent for depressive disorders with inflammatory and HPA axis-related components.

Chronic stress alters hypothalamic-pituitary-adrenal (HPA) axis function, influencing corticosterone regulation and adaptive responses. Identifying distinct response patterns can provide insight into individual variability in stress adaptation. This study is aimed to assess variability in HPA axis sensitivity following chronic social defeat stress. Male C57BL6 mice were exposed to chronic social defeat stress (CSDS) for 30 days. In order to evaluate integrity of negative feedback loop of HPA axis dexamethasone suppression test (DST) was used. Corticosterone levels were measured following saline or low-dose dexamethasone administration at 10 and 30 days. K-means clustering by corticosterone levels after saline and dexamethasone administration was applied to identify distinct response profiles. Behavioral testing (open field, elevated plus maze, social interaction test, partition, social defeat, forced swimming test, sucrose preference test) and qPCR analysis of HPA axis-related genes in hypothalamus (Crh, Crhr1, Crhbp, Fkbp5, Nr3c1), pituitary gland (Pomc, Crhr1, Nr3c1, Nr3c2), and corticosterone synthesis genes in adrenal glands (Cyp11a1, Cyp11b1, Hsd11b1, Mc2r, Star, Fkbp5, Nr3c1) was performed. Cluster analysis identified 3 distinct response profiles differing in baseline and dexamethasone-suppressed corticosterone levels. Clusters also exhibited differences in behavioral phenotypes and HPA axis gene expression. Cluster 1 showed low basal corticosterone and an abnormal dexamethasone suppression response, without significant Crh or Crhbp dysregulation in the hypothalamus. Cluster 2 exhibited elevated basal corticosterone, a blunted dexamethasone response, anhedonia, and reduced immobility in the forced swim test; increased Crh and reduced Fkbp5 suggest enhanced glucocorticoid receptor sensitivity and sustained hypercortisolemia. Cluster 3, characterized by normal basal corticosterone and normal dexamethasone response, showed upregulation of Crh and Crhbp, consistent with balanced and potentially adaptive HPA axis regulation under chronic stress. Corticosterone response heterogeneity reflects distinct adaptive trajectories under chronic stress. Identifying behavioral markers of these strategies may improve understanding of stress vulnerability and resilience mechanisms, with implications for stress-related disorders.

This study investigated how prolonged aggression in male CD1 mice alters responses to chronic LPS-induced inflammation. Aggression experience induced pathological aggression in 36% of mice. Following LPS, aggressors resolved systemic inflammation within five days—evidenced by normalized locomotor activity, WBC, and lymphocyte counts—while controls remained inflamed. LPS did not alter established aggression or anxiety. Furthermore, aggressors demonstrated accelerated inflammation resolution in the brain, showing a higher proportion of resting microglia and a lower percentage of activated microglia following LPS-induced inflammation compared to control animals. Gene expression analysis revealed a more pronounced inflammatory response in the hypothalamus than in the nucleus accumbens. Aggressive mice exhibited a profile associated with inflammation resolution, indicated by increased expression of the Trem2 gene. These differential immune responses may be modulated by the dopaminergic system. Elevated Drd1 gene expression in the hypothalamus likely enhances anti-inflammatory signaling, while changes in nucleus accumbens dopaminergic activity, involving D2 receptor activation, appear linked to the development of pathological aggression. Thus, this study demonstrates that prolonged aggression induces persistent changes in behavioral, neuroimmune, and neuroendocrine systems in male CD1 mice. Aggressive animals develop a distinct neuroimmune phenotype characterized by accelerated resolution of both systemic and brain inflammation following LPS challenge.

This study investigated how prolonged aggression in male CD1 mice alters responses to chronic LPS (lipopolysaccharide)-induced inflammation. Experience of aggression induced pathological aggression in 36% of mice. Following LPS, aggressors resolved systemic inflammation within five days—evidenced by normalized locomotor activity, WBC (white blood cells), and lymphocyte counts—while controls remained inflamed. LPS did not alter established aggression or anxiety. Furthermore, aggressors demonstrated accelerated inflammation resolution in the brain, showing a higher proportion of resting microglia and a lower percentage of activated microglia following LPS-induced inflammation compared to control animals. Gene expression analysis revealed a more pronounced inflammatory response in the hypothalamus than in the nucleus accumbens. Aggressive mice exhibited a profile associated with inflammation resolution, indicated by increased expression of the Trem2 gene. These differential immune responses may be modulated by the dopaminergic system. Elevated Drd1 gene expression in the hypothalamus could possibly contribute to the anti-inflammatory signaling, while changes in nucleus accumbens dopaminergic activity, involving D2 receptor activation, appear linked to the development of pathological aggression. Thus, this study demonstrates that prolonged aggression induces persistent changes in behavioral, neuroimmune, and neuroendocrine systems in male CD1 mice. Aggressive animals develop a distinct neuroimmune phenotype characterized by accelerated resolution of both systemic and brain inflammation following LPS challenge.