RESUMEN
The decline of microglia in the dentate gyrus is a new phenomenon that may explain the pathogenesis of depression, and reversing this decline has an antidepressant effect. The development of strategies that restore the function of dentate gyrus microglia in under stressful conditions is becoming a new focus. Lymphocyte-activating gene-3 (LAG3) is an immune checkpoint expressed by immune cells including microglia. One of its functions is to suppress the expansion of immune cells. In a recent study, chronic systemic administration of a LAG3 antibody that readily penetrates the brain was reported to reverse chronic stress-induced hippocampal microglia decline and depression-like behaviors. We showed here that a single intranasal infusion of a LAG3 antibody (In-LAG3 Ab) reversed chronic unpredictable stress (CUS)-induced depression-like behaviors in a dose-dependent manner, which was accompanied by an increase in brain-derived neurotrophic factor (BDNF) in the dentate gyrus. Infusion of an anti-BDNF antibody into the dentate gyrus, construction of knock-in mice with the BDNF Val68Met allele, or treatment with the BDNF receptor antagonist K252a abolished the antidepressant effect of In-LAG3 Ab. Activation of extracellular signal-regulated kinase1/2 (ERK1/2) is required for the reversal effect of In-LAG3 Ab on CUS-induced depression-like behaviors and BDNF decrease in the dentate gyrus. Moreover, both inhibition and depletion of microglia prevented the reversal effect of In-LAG3 Ab on CUS-induced depression-like behaviors and impairment of ERK1/2-BDNF signaling in the dentate gyrus. These results suggest that In-LAG3 Ab exhibits an antidepressant effect through microglia-mediated activation of ERK1/2 and synthesis of BDNF in the dentate gyrus.
Asunto(s)
Administración Intranasal , Antidepresivos , Antígenos CD , Factor Neurotrófico Derivado del Encéfalo , Depresión , Hipocampo , Proteína del Gen 3 de Activación de Linfocitos , Sistema de Señalización de MAP Quinasas , Estrés Psicológico , Animales , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Masculino , Antidepresivos/farmacología , Antidepresivos/administración & dosificación , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ratones , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Depresión/tratamiento farmacológico , Antígenos CD/metabolismo , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Anticuerpos/farmacología , Carbazoles/farmacología , Carbazoles/administración & dosificación , Transducción de Señal/efectos de los fármacos , Alcaloides IndólicosRESUMEN
Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder associated with abnormally elevated neuroinflammatory responses. Suppression of neuroinflammation is considered to be effective in ameliorating PTSD-like behaviors in rodents. Since pre-stimulation of microglia prior to stress exposure can prevent neuroinflammation, we hypothesized that pre-stimulation of microglia may prevent PTSD in animals. The results show that a single injection of a classical immune stimulant, lipopolysaccharide (LPS), at 50, 100 or 500, but not 10 µg/kg, one day before stress exposure, prevented the anxiety- and fear-like behaviors induced by modified single prolonged stress (mSPS). The time-dependent analysis shows that a single injection of LPS (100 µg/kg) either one or five, but not ten, days before stress prevented mSPS-induced anxiety- and fear-like behaviors. A second low-dose LPS injection 10 days after the first injection or a repeated LPS injection (4 × ) 10 days before stress induced tolerance to mSPS. Mechanistic studies show that a single injection of LPS one day before stress stimulation prevented mSPS-induced increases in levels of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and IL-6 mRNA in the hippocampus and medial prefrontal cortex. Inhibition of microglia by pretreatment with minocycline or depletion of microglia by PLX3397 abolished the preventive effect of low-dose LPS pre-injection on mSPS-induced anxiety- and fear-like behavior and neuroinflammatory responses. These results suggest that pre-stimulation of microglia may prevent the development of PTSD-like behaviors by attenuating the development of neuroinflammatory responses. This could help to develop new strategies to prevent the damaging effects of harmful stress on the brain.
Asunto(s)
Ansiedad , Miedo , Lipopolisacáridos , Microglía , Enfermedades Neuroinflamatorias , Trastornos por Estrés Postraumático , Animales , Masculino , Trastornos por Estrés Postraumático/metabolismo , Trastornos por Estrés Postraumático/inmunología , Ratones , Lipopolisacáridos/farmacología , Microglía/metabolismo , Microglía/efectos de los fármacos , Miedo/efectos de los fármacos , Miedo/fisiología , Ansiedad/inmunología , Ansiedad/metabolismo , Enfermedades Neuroinflamatorias/inmunología , Inmunización/métodos , Modelos Animales de Enfermedad , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/inmunología , Conducta Animal/efectos de los fármacos , Estrés Psicológico/inmunología , Estrés Psicológico/metabolismo , Ratones Endogámicos C57BL , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Inflamación/metabolismo , Inflamación/inmunologíaRESUMEN
Introduction: Probiotics have been recognized for their various biological activities, including antioxidant and anti-inflammatory properties. This study investigates the therapeutic effect of a novel probiotic formula, BLLL, consisting of Bifidobacterium breve, Lactobacillus plantarum, Lactobacillus paracasei, and Lactobacillus helveticus, on chronic stress-induced depression-like behaviors in mice. Methods: The BLLL formula or phosphate-buffered saline (PBS) was given orally at a dose of 2, 4, or 8 × 1010 CFU/kg once daily for 10 days in mice treated with chronic unpredictable stress (CUS) treated or vehicle. Depression-like behaviors were assessed using the sucrose preference test (SPT), the forced swimming test (FST), and the tail suspension test (TST). The mRNA and/or protein expression of interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α), IL-4, IL-10, and chitinase-3-like protein 3 (CHI3L1, also known as Ym-1), as well as the concentration of nitrite, malondialdehyde (MDA), glutathione (GSH), and brain-derived neurotrophic factor (BDNF) in the hippocampus and medial prefrontal cortex were examined. Results: The BLLL formula treatment at a dose of 8 × 1010 CFU/kg, but not at a dose of 2 or 4 × 1010 CFU/kg, improved CUS-induced depression-like behaviors in mice, as shown by the decrease in immobility time in the TST and FST and the increase in sucrose intake in the SPT. Further analysis revealed that BLLL treatment suppressed the CUS-induced increase in IL-1ß, IL-6, and TNF-α mRNA and protein levels, as well as the CUS-induced decrease in IL-4, IL-10, and Ym-1 mRNA and/or protein levels in the hippocampus and medial prefrontal cortex. In addition, treatment with the BLLL formula countered the CUS-induced increase in nitrite and MDA levels and the CUS-induced decrease in GSH content and BDNF concentration in the hippocampus and medial prefrontal cortex. Conclusion: These results demonstrate that the novel probiotic formula BLLL ameliorates chronic stress-induced depression-like behavior in mice by suppressing neuroinflammation and oxido-nitrosative stress in the brain.
RESUMEN
It has been reported that pre-stimulation of the innate immune system in animals can prevent chronic stress-induced depression- and anxiety-like behaviors in animals, suggesting the possibility that innate immune stimulants may prevent the pathogenesis of neuropsychiatric disorders. Alcohol use, especially when it begins in adolescence, is a risk factor for the development of neuropsychiatric disorders in adulthood. Preventing the pathological changes induced by alcohol exposure in adolescence could be of great importance for improving human mental health. Here, we investigated whether pre-stimulation of the innate immune system can prevent the behavioral abnormalities in a disease model induced by adolescent intermittent alcohol exposure (AIE). The results showed that a single injection of lipopolysaccharide (LPS) injection (100 µg/kg) one day before alcohol exposure prevented the AIE-induced depression- and anxiety-like behaviors in the tail suspension test, forced swimming test, sucrose preference test, elevated pluz maze test, light-dark test, and open field test in adult mice. Single LPS injection (100 µg/kg) before alcohol exposure also transformed the AIE-induced neuroinflammatory responses in the hippocampus and prefrontal cortex in adult mice to an anti-inflammatory phenotype. Suppression of the innate immune response by minocycline pretreatment abolished the preventive effect of LPS on AIE-induced abnormalities and neuroinflammatory responses in the hippocampus and prefrontal cortex in adult mice. These results indicate that pre-stimulation of the innate immune system may prevent the AIE-induced depression- and anxiety-like behaviors in adult mice by preventing neuroinflammation. This may help to develop new strategies to prevent neuropsychiatric disorders induced by adolescent alcohol exposure.
Asunto(s)
Etanol , Lipopolisacáridos , Humanos , Animales , Ratones , Adolescente , Adulto , Lipopolisacáridos/efectos adversos , Etanol/farmacología , Ansiedad , Depresión , Hipocampo , Inflamación/inducido químicamente , Tolerancia InmunológicaRESUMEN
Depressed mice have lower numbers of microglia in the dentate gyrus (DG). Reversal of this decline by a single low dose of lipopolysaccharide (LPS) may have antidepressant effects, but there is little information on the molecular mechanisms underlying this effect. It is known that impairment of brain-derived neurotrophic factor (BDNF) signaling is involved in the development of depression. Here, we used a combination of neutralizing antibodies, mutant mice, and pharmacological approaches to test the role of BDNF-tyrosine kinase receptor B (TrkB) signaling in the DG in the effect of microglial stimulation. Our results suggest that inhibition of BDNF signaling by infusion of an anti-BDNF antibody, the BDNF receptor antagonist K252a, or knock-in of the mutant BDNF Val68Met allele abolished the antidepressant effect of LPS in chronically stressed mice. Increased BDNF synthesis in DG, mediated by extracellular signal-regulated kinase1/2 (ERK1/2) signaling but not protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling, was essential for the antidepressant effect of microglial stimulation. These results suggest that increased BDNF synthesis through activation of ERK1/2 caused by a single LPS injection and subsequent TrkB signaling are required for the antidepressant effect of hippocampal microglial stimulation.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Receptor trkB , Animales , Anticuerpos Neutralizantes/farmacología , Antidepresivos/metabolismo , Antidepresivos/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/metabolismo , Lipopolisacáridos/metabolismo , Lipopolisacáridos/farmacología , Sistema de Señalización de MAP Quinasas , Mamíferos/metabolismo , Ratones , Microglía/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor trkB/metabolismo , Receptor trkB/farmacología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
It has been reported that pre-stimulation of the innate immune system can prevent depressive and anxiogenic-like behaviors in chronically stressed male mice. However, it is unclear whether similar effects can be observed in female animals. In the present study, we investigated this question in female mice. Our results showed that a single injection of lipopolysaccharide (LPS; 100 µg/kg) one day before stress exposure prevented increased immobility time in the tail suspension test and forced swimming test and decreased sucrose intake in the sucrose preference test in chronic unpredictable stress (CUS)-treated female mice. The single LPS pre-injection (100 µg/kg) prevented the CUS-induced decrease in (i) time spent in open arms and number of entries into open arms in the elevated plus maze test, (ii) time spent in lit side in the light-dark test, and (iii) time spent in the central region of the open field in the open field test, along with no changes in locomotor activity. It was also found that the single LPS pre-injection in female mice prevented the CUS-induced increase in the expression levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 mRNA in the hippocampus and medial prefrontal cortex. Inhibition of innate immune system stimulation by minocycline pretreatment abrogated the preventive effect of LPS on CUS-induced depressive and anxiogenic-like behaviors and neuroinflammatory responses in the hippocampus and medial prefrontal cortex in female mice. These results suggest that pre-stimulation of the innate immune system by LPS injection may prevent the development of behavioral abnormalities in female mice.
Asunto(s)
Depresión , Lipopolisacáridos , Animales , Conducta Animal , Depresión/metabolismo , Modelos Animales de Enfermedad , Femenino , Hipocampo , Inmunidad Innata , Lipopolisacáridos/farmacología , Masculino , Ratones , Sacarosa/metabolismo , Sacarosa/farmacologíaRESUMEN
Our previous studies had reported that microglia activation one day before stress exposure prevented the behavioral abnormalities induced by chronic stress in adult mice, and a 10-day interval between microglia stimulation and stress exposure can abolish the prophylactic effect of LPS preinjection on the behavioral abnormalities induced by chronic stress, which, however, could be rescued by repeated LPS injection. This suggests that increased stimulation of microglia results in animals developing a strong ability to prevent deleterious stress stimuli. Because microglia in the adolescent brain exhibit flexible immunological plasticity, we hypothesize that a single low-dose LPS injection during adolescence may provide long-lasting protection against behavioral abnormalities induced by chronic stress in adult mice. As expected, our results showed that a single injection of LPS (100 µg/kg) at post-natal day 28 (PND 28) prevented the development of abnormal behaviors and shifted neuroinflammatory responses toward an anti-inflammatory phenotype in adult mice treated with CSDS at their different stages of the age (PND 56, 140, and 252). Moreover, pretreatment with minocycline or PLX3397 to inhibit microglial activation abolished the prophylactic effect of LPS preinjection after PND 28 on behavioral abnormalities and neuroinflammatory responses induced by CSDS in adult mice at their different stages of the age, PND 56, 140, and 252. These results indicate that stimulation of microglia in adolescence may confer long-lasting protection against neuroinflammatory responses and behavioral abnormalities induced by chronic stress in adult mice. This may offer the potential for the development of a "vaccine-like strategy" to prevent mental disorders.
Asunto(s)
Lipopolisacáridos , Microglía , Animales , Antiinflamatorios/farmacología , Encéfalo , Humanos , Inflamación/tratamiento farmacológico , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Minociclina/farmacologíaRESUMEN
Chronic stress exposure is a risk factor that can induce the development of depression-like behaviors by impairing the hippocampal cyclic adenosine monophosphate-response element binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling, but its underlying mechanisms remain largely unknown. We identified an orphan receptor that can suppress the activity of CREB, nuclear receptor sub-family 6, group A, member 1 (NR6A1), in mouse brain neurons. Given the critical role of the impaired CREB-BDNF signaling in depression, we speculate that the neuronal NR6A1 may mediate the pathogenesis of depression. Results showed that chronic unpredictable stress (CUS) markedly increased the expression levels of hippocampal NR6A1 protein, which reduced hippocampal CREB phosphorylation and BDNF protein expression. Overexpression of hippocampal NR6A1 in stress-naïve mice simulated chronic stress, inducing depression-like behaviors in the tail suspension test, forced swimming test, and sucrose preference test, and impairing the hippocampal CREB-BDNF signaling cascade. Genetic knockdown of hippocampal NR6A1 did not affect mouse behaviors but prevented the CUS-induced depression-like behaviors in mice and impairment in hippocampal CREB-BDNF signaling. Furthermore, genetic knockdown of hippocampal CREB or BDNF abrogated the preventive effect of hippocampal NR6A1 down-regulation on CUS-induced depression-like behaviors in mice. Collectively, these results for the first time identified a nuclear expression of NR6A1 in mouse brain neurons, and showed that the abnormally increased NR6A1 protein in the hippocampus in mice treated with or without chronic stress can impair the CREB-BDNF signaling cascade and lead to the development of depression-like behaviors. Hippocampal NR6A1 could be a novel target for the development of antidepressants.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Depresión , Miembro 1 del Grupo A de la Subfamilia 6 de Receptores Nucleares/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Depresión/metabolismo , Modelos Animales de Enfermedad , Hipocampo , Ratones , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismoRESUMEN
Anxiety is a common psychological disease which can induce severe social burdens. Searching methods that prevent the onset of anxiety is of great significance for ameliorating the social and individual problems induced by this type of disease. In this study, we investigated how innate immune pre-stimulation influences the anxiety-like behaviors in chronically stressed mice. Our results showed that a single injection of an innate immune stimulant lipopolysaccharide (LPS) at the dose of 50, 100, and 500 µg/kg 1 day before stress exposure prevented chronic social defeat stress (CSDS)-induced anxiety-like behaviors in mice. A single injection of LPS (100 µg/kg) 5 days before stress exposure produced similar preventive effects on CSDS-induced anxiety-like behaviors, while similar effects were not observed at the condition of 10-days interval between LPS injection and stress exposure. A second LPS injection 10 days after the first LPS injection or a 4 × LPS injection 10 days before stress exposure also prevented CSDS-induced anxiety-like behaviors. Moreover, a single injection of LPS (100 µg/kg) 1 day before stress exposure prevented the production of pro-inflammatory cytokines in the hippocampus and prefrontal cortex of CSDS mice. Suppression of innate immune stimulation by minocycline pretreatment simultaneously abrogated the preventive effect of LPS pre-injection (100 µg/kg) on CSDS-induced anxiety-like behaviors and pro-inflammatory cytokine production in the brain. Our results demonstrated that the pre-stimulation of the innate immune system can prevent the development of anxiety-like behaviors and the progression of the neuroinflammatory responses in the brain in chronically stressed mice.