Understanding the Role of Oxidative Stress, Neuroinflammation and Abnormal Myelination in Excessive Aggression Associated with Depression: Recent Input from Mechanistic Studies
Abstract:Aggression and deficient cognitive control problems are widespread in psychiatric disorders, including major depressive disorder (MDD). These abnormalities are known to contribute significantly to the accompanying functional impairment and the global burden of disease. Progress in the development of targeted treatments of excessive aggression and accompanying symptoms has been limited, and there exists a major unmet need to develop more efficacious treatments for depressed patients. Due to the complex nature a… Show more
“…The present study demonstrated that chronic exposure to unpredictably alternating ultrasound frequencies, that are naturally emitted by rodents to communicate with conspecifics, is capable of inducing depressive syndrome in female mice, associated with systemic pro-inflammatory changes, and eliciting behavioral deficits in offspring. The present data are in accordance with earlier demonstrated findings in males that 21 days of exposure of BALB/c mice to unpredictably alternating frequencies of ultrasound between the ranges of 20-25 and 25-45 Hz led to decreased sucrose intake, a sign of anhedonia in rodents and increased anxiety-like behavior, as shown by decreased time spent in the center of the open field and open arms in the elevated plus maze [29,37]. Notably, here we demonstrated that ultrasound exposure causes pro-inflammatory changes locally in the hippocampus of dams and systemically in the blood, suggesting a profound pro-inflammatory effect of ultrasound stress.…”
Section: Discussionsupporting
confidence: 93%
“…Additionally, the overexpression of GSK-3β in the hippocampus, that we revealed in pregnant dams, is known to be a marker of distress and depressive syndrome [42]. In this paper, we report an over-expression of GSK-3β, IL-1β, and IL-6 mRNA in the hippocampus of ultrasound-exposed females, which is similar to the changes found in males [29,30,37].…”
Section: Discussionsupporting
confidence: 83%
“…The ultrasound exposure in male mice was associated with upregulated corticosterone level [30], activated hippocampal microglia, upregulated IL-1β and IL-6 locally in the hippocampus and in systemic circulation [30], and increased content of a marker of oxidative stress protein carbonyl in limbic structures [29]. Notably, ultrasound-exposed male mice developed prominent depressive-like and anxietylike behavioral changes [29][30][31]37,38] that were counteracted by chronic dosing with the classic antidepressant fluoxetine [39].…”
Neurodevelopmental disorders stemming from maternal immune activation can significantly affect a child’s life. A major limitation in pre-clinical studies is the scarcity of valid animal models that accurately mimic these challenges. Among the available models, administration of lipopolysaccharide (LPS) to pregnant females is a widely used paradigm. Previous studies have reported that a model of ‘emotional stress’, involving chronic exposure of rodents to ultrasonic frequencies, induces neuroinflammation, aberrant neuroplasticity, and behavioral deficits. In this study, we explored whether this model is a suitable paradigm for maternal stress and promotes neurodevelopmental abnormalities in the offspring of stressed females. Pregnant dams were exposed to ultrasound stress for 21 days. A separate group was injected with LPS on embryonic days E11.5 and E12.5 to mimic prenatal infection. The behavior of the dams and their female offspring was assessed using the sucrose test, open field test, and elevated plus maze. Additionally, the three-chamber sociability test and Barnes maze were used in the offspring groups. ELISA and qPCR were used to examine pro-inflammatory changes in the blood and hippocampus of adult females. Ultrasound-exposed adult females developed a depressive-like syndrome, hippocampal overexpression of GSK-3β, IL-1β, and IL-6 and increased serum concentrations of IL-1β, IL-6, IL-17, RANTES, and TNFα. The female offspring also displayed depressive-like behavior, as well as cognitive deficits. These abnormalities were comparable to the behavioral changes induced by LPS. The ultrasound stress model can be a promising animal paradigm of neurodevelopmental pathology associated with prenatal ‘emotional stress’.
“…The present study demonstrated that chronic exposure to unpredictably alternating ultrasound frequencies, that are naturally emitted by rodents to communicate with conspecifics, is capable of inducing depressive syndrome in female mice, associated with systemic pro-inflammatory changes, and eliciting behavioral deficits in offspring. The present data are in accordance with earlier demonstrated findings in males that 21 days of exposure of BALB/c mice to unpredictably alternating frequencies of ultrasound between the ranges of 20-25 and 25-45 Hz led to decreased sucrose intake, a sign of anhedonia in rodents and increased anxiety-like behavior, as shown by decreased time spent in the center of the open field and open arms in the elevated plus maze [29,37]. Notably, here we demonstrated that ultrasound exposure causes pro-inflammatory changes locally in the hippocampus of dams and systemically in the blood, suggesting a profound pro-inflammatory effect of ultrasound stress.…”
Section: Discussionsupporting
confidence: 93%
“…Additionally, the overexpression of GSK-3β in the hippocampus, that we revealed in pregnant dams, is known to be a marker of distress and depressive syndrome [42]. In this paper, we report an over-expression of GSK-3β, IL-1β, and IL-6 mRNA in the hippocampus of ultrasound-exposed females, which is similar to the changes found in males [29,30,37].…”
Section: Discussionsupporting
confidence: 83%
“…The ultrasound exposure in male mice was associated with upregulated corticosterone level [30], activated hippocampal microglia, upregulated IL-1β and IL-6 locally in the hippocampus and in systemic circulation [30], and increased content of a marker of oxidative stress protein carbonyl in limbic structures [29]. Notably, ultrasound-exposed male mice developed prominent depressive-like and anxietylike behavioral changes [29][30][31]37,38] that were counteracted by chronic dosing with the classic antidepressant fluoxetine [39].…”
Neurodevelopmental disorders stemming from maternal immune activation can significantly affect a child’s life. A major limitation in pre-clinical studies is the scarcity of valid animal models that accurately mimic these challenges. Among the available models, administration of lipopolysaccharide (LPS) to pregnant females is a widely used paradigm. Previous studies have reported that a model of ‘emotional stress’, involving chronic exposure of rodents to ultrasonic frequencies, induces neuroinflammation, aberrant neuroplasticity, and behavioral deficits. In this study, we explored whether this model is a suitable paradigm for maternal stress and promotes neurodevelopmental abnormalities in the offspring of stressed females. Pregnant dams were exposed to ultrasound stress for 21 days. A separate group was injected with LPS on embryonic days E11.5 and E12.5 to mimic prenatal infection. The behavior of the dams and their female offspring was assessed using the sucrose test, open field test, and elevated plus maze. Additionally, the three-chamber sociability test and Barnes maze were used in the offspring groups. ELISA and qPCR were used to examine pro-inflammatory changes in the blood and hippocampus of adult females. Ultrasound-exposed adult females developed a depressive-like syndrome, hippocampal overexpression of GSK-3β, IL-1β, and IL-6 and increased serum concentrations of IL-1β, IL-6, IL-17, RANTES, and TNFα. The female offspring also displayed depressive-like behavior, as well as cognitive deficits. These abnormalities were comparable to the behavioral changes induced by LPS. The ultrasound stress model can be a promising animal paradigm of neurodevelopmental pathology associated with prenatal ‘emotional stress’.
“…Brain tissue is extremely high in oxygen consumption and has weak antioxidant capacity. Brain cell membranes are abundant in lipid components, contain a large number of metal ions, and are important sites for oxidative stress 44,45 . An elevated TyG index significantly exacerbates oxidative stress, which produces large amounts of free radicals that can damage brain tissue, eventually leading to depression 46–48 .…”
Section: Discussionmentioning
confidence: 99%
“…Brain cell membranes are abundant in lipid components, contain a large number of metal ions, and are important sites for oxidative stress. 44,45 An elevated TyG index significantly exacerbates oxidative stress, which produces large amounts of free radicals that can damage brain tissue, eventually leading to depression. [46][47][48] In addition, oxidative stress can damage the structure and function of mitochondria, which subsequently leads to impairment of the mitochondrial respiratory chain, reduction of ATP synthesis, and disruption of cellular energy metabolism.…”
Growing evidence suggests that hypertensive individuals have a greater risk of developing depression, and depression can also increase the incidence of hypertension. In the hypertensive population, the association between triglyceride glucose (TyG) index and depression remains unclear. This study aimed to assess the association between TyG index and depression in hypertensive people through the cross‐sectional study of the National Health and Nutrition Examination Survey (2007–2018). To assess the relationship between TyG index and depression in hypertensive population, we conducted weighted multiple logistic regression models and used a generalized additive model to probe for nonlinear correlations. In addition, we employed a recursive algorithm to determine the inflection point and established a two‐piece linear regression model. This study enrolled 5897 individuals. In the model adjusted for all covariates, the ORs (95% CI) for the relationship between TyG index and depression in hypertensive population were 1.32 (1.12–1.54). A nonlinear association was found between TyG index and depression, with an inflection point at 8.7. After the inflection point, the ORs (95% CI) were 1.44 (1.15–1.79). Only the interaction with the obese population was statistically significant. Our study highlighted a nonlinear association between TyG index and depression in American hypertensive adults.
Aggression is a complex social behavior, critically involving brain serotonin (5-HT) function. The neurobiology of female aggression remains elusive, while the incidence of its manifestations has been increasing. Yet, animal models of female aggression are scarce. We previously proposed a paradigm of female aggression in the context of gene x environment interaction where mice with partial genetic inactivation of tryptophan hydroxylase-2 (Tph2+/− mice), a key enzyme of neuronal 5-HT synthesis, are subjected to predation stress resulting in pathological aggression. Using deep sequencing and the EBSeq method, we studied the transcriptomic signature of excessive aggression in the prefrontal cortex of female Tph2+/− mice subjected to rat exposure stress and food deprivation. Challenged mutants, but not other groups, displayed marked aggressive behaviors. We found 26 genes with altered expression in the opposite direction between stressed groups of both Tph2 genotypes. We identified several molecular markers, including Dgkh, Arfgef3, Kcnh7, Grin2a, Tenm1 and Epha6, implicated in neurodevelopmental deficits and psychiatric conditions featuring impaired cognition and emotional dysregulation. Moreover, while 17 regulons, including several relevant to neural plasticity and function, were significantly altered in stressed mutants, no alteration in regulons was detected in stressed wildtype mice. An interplay of the uncovered pathways likely mediates partial Tph2 inactivation in interaction with severe stress experience, thus resulting in excessive female aggression.
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