RESUMO
Increasing evidence indicates that prenatal cocaine exposure may result in many developmental and long-lasting neurological and behavioral effects. The behaviors of female animals are strongly associated with the estrous cycle. Estrogen receptors and oxytocin are important neuroendocrine factors that regulate social behavior and are of special relevance to females. However, whether prenatal cocaine exposure induces estrous cycle changes in offspring and whether neurobehavioral changes in estrus and diestrus offspring differ remains unclear. On gestational day 12, mice were administered cocaine once daily for seven consecutive days, then the estrous cycle was examined in adult female offspring, as well as locomotion, anxiety level, and social behaviors, and the expression of estrogen receptor alpha-immunoreactive and oxytocin-immunoreactive neurons were compared between estrus and diestrus offspring. Prenatal cocaine exposure resulted in the shortening of proestrus and estrus in the offspring. During estrus and diestrus, prenatally cocaine-exposed offspring showed increased anxiety levels and changed partial social behaviors; their motility showed no significant differences in estrus, but declined in diestrus. Prenatal cocaine exposure reduced estrogen receptor alpha-immunoreactive expression in the medial preoptic area, ventromedial hypothalamic nucleus, and arcuate nucleus and oxytocin-immunoreactive expression in the paraventricular nucleus in estrus and diestrus offspring. These results suggest that prenatal cocaine exposure induces changes in the offspring's estrous cycle and expression of estrogen receptor alpha and oxytocin in a brain region-specific manner and that prenatal cocaine exposure and the estrous cycle interactively change motility and partial social behavior. Estrogen receptor alpha and oxytocin signaling are likely to play important concerted roles in mediating the effects of prenatal cocaine exposure on the offspring.
Assuntos
Cocaína , Diestro , Receptor alfa de Estrogênio , Ciclo Estral , Estro , Ocitocina , Efeitos Tardios da Exposição Pré-Natal , Comportamento Social , Animais , Ocitocina/metabolismo , Feminino , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Gravidez , Receptor alfa de Estrogênio/metabolismo , Cocaína/farmacologia , Camundongos , Ciclo Estral/efeitos dos fármacos , Estro/efeitos dos fármacos , Diestro/efeitos dos fármacos , Diestro/metabolismo , Comportamento Animal/efeitos dos fármacos , Ansiedade/metabolismo , Masculino , Neurônios/metabolismo , Neurônios/efeitos dos fármacosRESUMO
Omeprazole, a drug of choice for the management of gastric hyperacidity, influences serotonergic neurotransmission in brain regions and its long-term use is known to cause stress-related behavioral deficits including anxiety. Aim of the current study was to explore the effects of omeprazole treatment on immobilization-induced anxiety in rats, specifically on the role of serotonin (5-HT). In view of the role of serotonin-1A (5-HT1A) autoreceptor in the availability of 5-HT in brain regions, mRNA expression of this autoreceptor was performed in raphe nuclei. Similarly, because of the role of hippocampal 5-HT neurotransmission in anxiety-like disorders, expression of the 5-HT1A heteroreceptors was determined in this region. We found that the treatment with omeprazole reduces anxiety-like behavior in rats, increases the expression of 5-HT1A autoreceptor in the raphe and decreases the hippocampal expression of 5-HT1A heteroreceptor. This suggests a role of 5-HT1A receptor types in omeprazole-induced behavioral changes. It also indicates a potential role of omeprazole in the management of serotonergic disorders.
Assuntos
Ansiedade , Modelos Animais de Doenças , Hipocampo , Omeprazol , Receptor 5-HT1A de Serotonina , Estresse Psicológico , Animais , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Omeprazol/farmacologia , Masculino , Ratos , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/tratamento farmacológico , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Ratos Wistar , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Serotonina/metabolismo , Núcleos da Rafe/metabolismo , Núcleos da Rafe/efeitos dos fármacos , RNA Mensageiro/metabolismo , Restrição Física , ImobilizaçãoRESUMO
Maternal immune activation (MIA) is reported to increase the risk of psychiatric disorders in the offspring. However, the underlying mechanism remains unclear. Methods: We constructed a MIA mouse model by intraperitoneal injection of LPS into pregnant mice and evaluated the behaviors and gene expression profiles in the brains of the female and male offspring, respectively. Results: We found that the MIA female offspring exhibited increased anxiety and a large number of differentially expressed genes (DEGs) in the brain, which were enriched with candidate gene sets of psychiatric disorders and immune functions. In contrast, the MIA male offspring exhibited no significant abnormal behaviors and only a small number of DEGs that were not enriched with disease genes and immune functions. Therefore, we further pursued the downstream study on the molecular mechanism underlying the increased anxiety in the female offspring. We identified the lncRNA AU020206-IRFs-STAT1-cytokine axis by integrating lncRNA-protein interaction data and TF-promoter interaction data, and verified the axis in vitro and in vivo. Conclusion: This study illustrates that MIA upregulates the AU020206-IRFs-STAT1 axis in controlling the brain immunity linked to abnormal behaviors, providing a basis for understanding the role of MIA in psychiatric disorders.
Assuntos
Encéfalo , Citocinas , Modelos Animais de Doenças , Fator de Transcrição STAT1 , Animais , Feminino , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/genética , Camundongos , Encéfalo/metabolismo , Encéfalo/imunologia , Gravidez , Citocinas/metabolismo , Masculino , Regulação para Cima , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fatores Reguladores de Interferon/metabolismo , Fatores Reguladores de Interferon/genética , Lipopolissacarídeos , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ansiedade/imunologia , Ansiedade/metabolismo , Camundongos Endogâmicos C57BL , Transdução de SinaisRESUMO
The role of the gut microbiota in the gut-brain axis has attracted attention in recent years. Some gut microbiota produces γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter in mammals, in vitro, but the correlation between gut microbiota composition and intestinal GABA concentration, as well as the action of intestinal GABA in vivo, are poorly understood. Herein, we found that the intestinal GABA concentration was increased in mice by the intervention of the gut microbiota with neomycin or Bifidobacterium bifidum TMC3115 (TMC3115). Administration of TMC3115 reduced anxiety without affecting serum levels of serotonin, corticosterone, or GABA. We further found that intestinal epithelial cells expressed GABA receptor subunits and mediated mitogen-activated protein kinase signaling upon GABA stimulation. In addition, administration of TMC3115 induced mitogen-activated protein kinase signaling in colonic epithelial cells but not in small intestinal epithelial cells in mice. These results indicate that GABA produced by the gut microbiota, mainly in the colon, may affect host behavioral characteristics via GABA receptors expressed in intestinal epithelial cells without being transferred to the blood. This study suggests a novel mechanism by which intestinal GABA exerts physiological effects, even in the presence of the blood-brain barrier.
Assuntos
Ansiedade , Células Epiteliais , Microbioma Gastrointestinal , Ácido gama-Aminobutírico , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Ácido gama-Aminobutírico/metabolismo , Ansiedade/metabolismo , Células Epiteliais/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Neomicina/farmacologia , Camundongos Endogâmicos C57BL , Receptores de GABA/metabolismo , Bifidobacterium/metabolismo , Probióticos/farmacologia , HumanosRESUMO
Early social isolation (SI) leads to various abnormalities in emotion and behavior during adulthood. However, the negative impact of SI on offspring remains unclear. This study has discovered that paternal early SI causes social memory deficits and anxiety-like behavior in F1 young adult mice, with alterations of myelin and synapses in the medial prefrontal cortex (mPFC). The 2-week SI in the F1 progeny exacerbates social memory impairment and hypomyelination in the mPFC. Furthermore, the down-regulation of miR-124, a key inhibitor of myelinogenesis, or over-expression of its target gene Nr4a1 in the mPFC of the F1 mice improves social interaction ability and enhances oligodendrocyte maturation and myelin formation. Mechanistically, elevated levels of miR-124 in the sperm of paternal SI mice are transmitted epigenetically to offspring, altering the expression levels of miR-124/Nr4a1/glucocorticoid receptors in mPFC oligodendrocytes. This, in turn, impedes the establishment of myelinogenesis-dependent social behavior. This study unveils a novel mechanism through which miR-124 mediates the intergenerational effects of early isolation stress, ultimately impairing the establishment of social behavior and neurodevelopment.
Assuntos
MicroRNAs , Córtex Pré-Frontal , Comportamento Social , Isolamento Social , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Camundongos , Masculino , Córtex Pré-Frontal/metabolismo , Oligodendroglia/metabolismo , Camundongos Endogâmicos C57BL , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Comportamento Animal/fisiologia , Bainha de Mielina/metabolismo , Bainha de Mielina/genética , Ansiedade/genética , Ansiedade/metabolismo , FemininoRESUMO
Interpersonal closeness has important health benefits; however, recent work suggests that in certain contexts, closeness can come at a cost. In the current study, curvilinear relations between mother-child closeness and health (e.g., depressive and anxiety symptoms and hair cortisol concentrations [HCC]) were tested. Our sample consisted of 117 mother (Mage = 36.86) and child (Mage = 73.07 months, 50.86% male) dyads. A quadratic relationship between maternal perceived closeness with their child and self-reported depressive and anxiety symptoms, along with overall hair cortisol output, was hypothesized. Path analysis suggested that the quadratic term was predictive of maternal cortisol (ß = 0.28, p = 0.001) and depression (ß = 0.23, p = 0.014), such that both high and low perceived closeness predict greater maternal depressive symptoms and HCCs as compared to moderate levels of closeness. Results are discussed in terms of parenting support and burnout.
Assuntos
Ansiedade , Depressão , Cabelo , Hidrocortisona , Relações Mãe-Filho , Mães , Humanos , Cabelo/química , Feminino , Hidrocortisona/metabolismo , Masculino , Adulto , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Depressão/metabolismo , Criança , Pré-EscolarRESUMO
Prolactin (PRL) assumes a pivotal role during the postpartum phase, particularly within the hippocampus-a region densely populated with receptors for stress hormones, where stress significantly inhibits adult hippocampal neurogenesis (AHN). The reduction in neurogenesis is implicated in the pathogenesis of anxiety and depression. Mothers are at an increased risk of developing depression when exposed to chronic stress. Therefore, it is imperative to investigate the potential role of PRL in depression-like behaviors stemming from prolonged postpartum stress, and to explore any underlying mechanisms. Despite pup separation (PS) being a natural postpartum care practice, the impact of various PS methods on lactating dams remains uncertain. Lactating C57BL/6J mice, from postpartum day (PPD) 1 to PPD 21, underwent no PS (NPS), brief PS (15 min per day, PS15), or long PS (180 min per day, PS180), followed by 21 days of chronic restraint stress (CRS). Behavioral tests were conducted, and measurements included serum PRL concentration, PRL-R expression, and AHN in the hippocampus. Dams with CRS exhibited cognitive decline, depressive- and anxiety-like behaviors, and reduced PRL secretion, correlating with lower levels of AHN. PS15 dams displayed lower levels of depressive- and anxiety-like behaviors and cognitive decline compared to NPS and PS180 dams. Significantly, PS15 dams exhibited higher levels of AHN, PRL-R expression in the hippocampus, and serum PRL concentration. This study collectively reveals reduced serum PRL and AHN in dams with cognitive decline and depressive- and anxiety-like behaviors after CRS. Brief PS confers resistance to behavioral deficits after CRS, increasing serum PRL concentration and reversing AHN decrease in dams.
Assuntos
Hipocampo , Lactação , Camundongos Endogâmicos C57BL , Neurogênese , Prolactina , Estresse Psicológico , Animais , Prolactina/sangue , Prolactina/metabolismo , Feminino , Hipocampo/metabolismo , Neurogênese/fisiologia , Estresse Psicológico/metabolismo , Lactação/metabolismo , Camundongos , Período Pós-Parto , Ansiedade/metabolismo , Privação Materna , Depressão/metabolismo , Receptores da Prolactina/metabolismoRESUMO
Chronic stress is associated with anxiety and cognitive impairment. Repeated social defeat (RSD) in mice induces anxiety-like behavior driven by microglia and the recruitment of inflammatory monocytes to the brain. Nonetheless, it is unclear how microglia communicate with other cells to modulate the physiological and behavioral responses to stress. Using single-cell (sc)RNAseq, we identify novel, to the best of our knowledge, stress-associated microglia in the hippocampus defined by RNA profiles of cytokine/chemokine signaling, cellular stress, and phagocytosis. Microglia depletion with a CSF1R antagonist (PLX5622) attenuates the stress-associated profile of leukocytes, endothelia, and astrocytes. Furthermore, RSD-induced social withdrawal and cognitive impairment are microglia-dependent, but social avoidance is microglia-independent. Furthermore, single-nuclei (sn)RNAseq shows robust responses to RSD in hippocampal neurons that are both microglia-dependent and independent. Notably, stress-induced CREB, oxytocin, and glutamatergic signaling in neurons are microglia-dependent. Collectively, these stress-associated microglia influence transcriptional profiles in the hippocampus related to social and cognitive deficits.
Assuntos
Disfunção Cognitiva , Hipocampo , Camundongos Endogâmicos C57BL , Microglia , Derrota Social , Animais , Microglia/metabolismo , Camundongos , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/etiologia , Masculino , Hipocampo/metabolismo , Estresse Psicológico/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Transcriptoma , Comportamento Social , Ansiedade/metabolismo , Compostos OrgânicosRESUMO
Early life stress alters gut microbiota and increases the risk of neuropsychiatric disorders, including social deficits and anxiety, in the host. However, the role of gut commensal bacteria in early life stress-induced neurobehavioral abnormalities remains unclear. Using the maternally separated (MS) mice, our research has unveiled a novel aspect of this complex relationship. We discovered that the reduced levels of amino acid transporters in the intestine of MS mice led to low glutamine (Gln) levels in the blood and synaptic dysfunction in the medial prefrontal cortex (mPFC). Abnormally low blood Gln levels limit the brain's availability of Gln, which is required for presynaptic glutamate (Glu) and γ-aminobutyric acid (GABA) replenishment. Furthermore, MS resulted in gut microbiota dysbiosis characterized by a reduction in the relative abundance of Lactobacillus reuteri (L. reuteri). Notably, supplementation with L. reuteri ameliorates neurobehavioral abnormalities in MS mice by increasing intestinal amino acid transport and restoring synaptic transmission in the mPFC. In conclusion, our findings on the role of L. reuteri in regulating intestinal amino acid transport and buffering early life stress-induced behavioral abnormalities provide a novel insight into the microbiota-gut-brain signaling basis for emotional behaviors.
Assuntos
Ansiedade , Microbioma Gastrointestinal , Estresse Psicológico , Animais , Microbioma Gastrointestinal/fisiologia , Camundongos , Ansiedade/microbiologia , Ansiedade/metabolismo , Estresse Psicológico/microbiologia , Estresse Psicológico/metabolismo , Aminoácidos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Sistemas de Transporte de Aminoácidos/metabolismo , Córtex Pré-Frontal/metabolismo , Comportamento Animal , Disbiose/microbiologia , Privação Materna , Glutamina/metabolismo , Eixo Encéfalo-Intestino/fisiologia , Transmissão Sináptica , Feminino , Ácido Glutâmico/metabolismoRESUMO
The triggers of status epilepticus (SE) in non-epileptic patients can vary widely, from idiopathic causes to exposure to chemoconvulsants. Regardless of its etiology, prolonged SE can cause significant brain damage, commonly resulting in the development of epilepsy, which is often accompanied by increased anxiety. GABAA receptor (GABAAR)-mediated inhibition has a central role among the mechanisms underlying brain damage and the ensuing epilepsy and anxiety. During SE, calcium influx primarily via ionotropic glutamate receptors activates signaling cascades which trigger a rapid internalization of synaptic GABAARs; this weakens inhibition, exacerbating seizures and excitotoxicity. GABAergic interneurons are more susceptible to excitotoxic death than principal neurons. During the latent period of epileptogenesis, the aberrant reorganization in synaptic interactions that follow interneuronal loss in injured brain regions, leads to the formation of hyperexcitable, seizurogenic neuronal circuits, along with disturbances in brain oscillatory rhythms. Reduction in the spontaneous, rhythmic "bursts" of IPSCs in basolateral amygdala neurons is likely to play a central role in anxiogenesis. Protecting interneurons during SE is key to preventing both epilepsy and anxiety. Antiglutamatergic treatments, including antagonism of calcium-permeable AMPA receptors, can be expected to control seizures and reduce excitotoxicity not only by directly suppressing hyperexcitation, but also by counteracting the internalization of synaptic GABAARs. Benzodiazepines, as delayed treatment of SE, have low efficacy due to the reduction and dispersion of their targets (the synaptic GABAARs), but also because themselves contribute to further reduction of available GABAARs at the synapse; furthermore, benzodiazepines may be completely ineffective in the immature brain.
Assuntos
Ansiedade , Receptores de GABA-A , Estado Epiléptico , Estado Epiléptico/metabolismo , Receptores de GABA-A/metabolismo , Animais , Humanos , Ansiedade/metabolismo , Inibição Neural/fisiologiaRESUMO
BACKGROUND: Social isolation not only increases the risk of mortality in later life but also causes depressive symptoms, cognitive and physical disabilities. Although RNA m6A modifications are suggested to play key roles in brain development, neuronal signaling and neurological disorders, both the roles of m6A and the enzymes that regulate RNA m6A modification in social isolation induced abnormal behavior is unknown. The present study aims to explore the possible epitranscriptomic role of RNA m6A modifications and its enzymes in social isolation induced impaired behavior. METHODS: 3-4 weeks mice experiencing 8 weeks social isolation stress (SI) were used in the present study. We quantified m6A levels in brain regions related to mood and cognitive behavior. And the expression of hippocampal m6A enzymes was also determined. The role of hippocampal m6A and its enzymes in SI induced abnormal behavior was further verified by the virus tool. RESULTS: SI led to not only depressive and anxiety-like behaviors but also cognitive impairment, with corresponding decreases in hippocampal m6A and METTL14. Hippocampal over-expression METTL14 with lentivirus not only rescued these behaviors but also enhanced the hippocampal m6A level. Hippocampal over-expression METTL14 resulted in increased synaptic related genes. CONCLUSIONS: We provide the first evidence that post-weaning social isolation reduces hippocampal m6A level and causes altered expression of m6A enzyme in mice. Importantly, hippocampal METTL14 over-expression alleviated the SI-induced depression/anxiety-like and impaired cognitive behaviors and enhanced m6A level and synaptic related genes expression.
Assuntos
Hipocampo , Metiltransferases , Isolamento Social , Animais , Hipocampo/metabolismo , Masculino , Camundongos , Metiltransferases/genética , Metiltransferases/metabolismo , Depressão/genética , Depressão/metabolismo , Comportamento Animal/fisiologia , Ansiedade/genética , Ansiedade/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/genética , Camundongos Endogâmicos C57BL , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Epigênese Genética , Metilação de RNARESUMO
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.
Assuntos
Ansiedade , Medo , Lipopolissacarídeos , Microglia , Doenças Neuroinflamatórias , Transtornos de Estresse Pós-Traumáticos , Animais , Masculino , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/imunologia , Camundongos , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , Microglia/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/fisiologia , Ansiedade/imunologia , Ansiedade/metabolismo , Doenças Neuroinflamatórias/imunologia , Imunização/métodos , Modelos Animais de Doenças , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Comportamento Animal/efeitos dos fármacos , Estresse Psicológico/imunologia , Estresse Psicológico/metabolismo , Camundongos Endogâmicos C57BL , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/imunologiaRESUMO
Background: Cancer and psychiatric symptoms are associated. Fear of cancer recurrence (FCR) is the most common psychological problem for cancer survivors. Pharmacological interventions can help, but also have major drawbacks. Music therapy and music interventions have been shown to be a safe and practical complementary treatment. Objective: This randomized, controlled trial aimed to investigate the effects of music therapy and music intervention in attenuating non-small cell lung cancer (NSCLC) patients' anxiety related to FCR. Methods: NSCLC patients with FCR were randomly allocated to a music therapy and intervention group (G1) and Control group (G2). Patients' anxiety was measured using the State-Trait Anxiety Inventory scores and heart rates. Primary outcome measure were PET scans. Secondary measures were salivary cortisol, salivary α-amylase levels and heart rate. Findings: Patients in G1 showed higher glucose metabolism of 18F-FDG in the superior frontal gyrus, anterior cingulate, superior temporal gyrus, and parahippocampal gyrus, compared to those in G2 (all P < .001). Heart rates and salivary α-amylase area under the curve (AUC) and relative variation (VAR) in G1 were significantly lower than those in G2 (all P < .05). State-Trait Anxiety Inventory scores and cortisol AUC in G1 were significantly lower than those in G2 (all P < .05). Conclusions: Music therapy and interventions can reduce anxiety and endocrinological responses and change glucose metabolism of 18F-FDG in fear-related brain regions.Trial registration: Registered retrospectively, ISRCTN Registry, www.isrctn.com, ISRCTN23276302Clinical Implications: Cancer treatment centers and physical examination centers should consider providing music therapy and intervention to the appropriate patients as a routine component of a comprehensive clinical care during medical examinations.
Assuntos
Ansiedade , Carcinoma Pulmonar de Células não Pequenas , Medo , Neoplasias Pulmonares , Musicoterapia , Tomografia por Emissão de Pósitrons , Humanos , Masculino , Feminino , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/psicologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Pessoa de Meia-Idade , Musicoterapia/métodos , Neoplasias Pulmonares/psicologia , Neoplasias Pulmonares/terapia , Medo/psicologia , Medo/fisiologia , Tomografia por Emissão de Pósitrons/métodos , Ansiedade/terapia , Ansiedade/metabolismo , Recidiva Local de Neoplasia/psicologia , Recidiva Local de Neoplasia/metabolismo , Idoso , Hidrocortisona/metabolismo , Hidrocortisona/análise , Frequência Cardíaca/fisiologia , Fluordesoxiglucose F18RESUMO
BACKGROUND: During aging, both the brain and the immune system undergo a progressive impairment of physiological functions. Microglia, the immunocompetent cells of the central nervous system, shift towards a chronic mild inflammatory state that impacts brain homeostasis. Extracellular vesicles (EVs) released by microglia transport packages of molecular information that mirror the inflammatory status of donor cells and modulate the inflammatory phenotype of recipient microglia and other cell types. RESULTS: We demonstrated that intranasal administration of EVs derived from microglial-like BV2 cells to late adult mice (16-20 months of age) shifts microglia toward a "juvenile" morphology affecting their inflammatory profile. Mice treated with BV2-derived EVs have a reduction of anxiety-like behavior and an increased spatial learning, with sex-dependent differences. Further, BV2-derived EVs increased neuronal plasticity both in male and female mice. These findings suggest the involvement of microglial cells in vesicles-mediated anti-aging effect. CONCLUSIONS: Our data indicate that BV2-derived EVs could represent a resource to slow down age-dependent inflammation in the mouse brain.
Assuntos
Envelhecimento , Encéfalo , Vesículas Extracelulares , Inflamação , Microglia , Plasticidade Neuronal , Animais , Vesículas Extracelulares/metabolismo , Microglia/metabolismo , Camundongos , Plasticidade Neuronal/fisiologia , Feminino , Masculino , Inflamação/metabolismo , Encéfalo/metabolismo , Envelhecimento/metabolismo , Comportamento Animal/fisiologia , Camundongos Endogâmicos C57BL , Ansiedade/metabolismo , Aprendizagem Espacial/fisiologia , Administração IntranasalRESUMO
Ageing is characterised by a progressive increase in systemic inflammation and especially neuroinflammation. Neuroinflammation is associated with altered brain states that affect behaviour, such as an increased level of anxiety with a concomitant decline in cognitive abilities. Although multiple factors play a role in the development of neuroinflammation, microglia have emerged as a crucial target. Microglia are the only macrophage population in the CNS parenchyma that plays a crucial role in maintaining homeostasis and in the immune response, which depends on the activation and subsequent deactivation of microglia. Therefore, microglial dysfunction has a major impact on neuroinflammation. The gut microbiota has been shown to significantly influence microglia from birth to adulthood in terms of development, proliferation, and function. Diet is a key modulating factor that influences the composition of the gut microbiota, along with prebiotics that support the growth of beneficial gut bacteria. Although the role of diet in neuroinflammation and behaviour has been well established, its relationship with microglia functionality is less explored. This article establishes a link between diet, animal behaviour and the functionality of microglia. The results of this research stem from experiments on mouse behaviour, i.e., memory, anxiety, and studies on microglia functionality, i.e., cytochemistry (phagocytosis, cellular senescence, and ROS assays), gene expression and protein quantification. In addition, shotgun sequencing was performed to identify specific bacterial families that may play a crucial role in the brain function. The results showed negative effects of long-term consumption of a high fat diet on ageing mice, epitomised by increased body weight, glucose intolerance, anxiety, cognitive impairment and microglia dysfunction compared to ageing mice on a control diet. These effects were a consequence of the changes in gut microbiota modulated by the diet. However, by adding the prebiotics fructo- and galacto-oligosaccharides, we were able to mitigate the deleterious effects of a long-term high-fat diet.
Assuntos
Envelhecimento , Ansiedade , Dieta Hiperlipídica , Microbioma Gastrointestinal , Memória , Microglia , Prebióticos , Animais , Microglia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Camundongos , Ansiedade/metabolismo , Microbioma Gastrointestinal/fisiologia , Prebióticos/administração & dosagem , Masculino , Memória/fisiologia , Encéfalo/metabolismo , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias/metabolismo , Inflamação/metabolismoRESUMO
Accumulating evidence suggests an involvement of sphingolipids, vital components of cell membranes and regulators of cellular processes, in the pathophysiology of both Parkinson's disease and major depressive disorder, indicating a potential common pathway in these neuropsychiatric conditions. Based on this interaction of sphingolipids and synuclein proteins, we explored the gene expression patterns of α-, ß-, and γ-synuclein in a knockout mouse model deficient for acid sphingomyelinase (ASM), an enzyme catalyzing the hydrolysis of sphingomyelin to ceramide, and studied associations with behavioral parameters. Normalized Snca, Sncb, and Sncg gene expression was determined by quantitative PCR in twelve brain regions of sex-mixed homozygous (ASM-/-, n = 7) and heterozygous (ASM+/-, n = 7) ASM-deficient mice, along with wild-type controls (ASM+/+, n = 5). The expression of all three synuclein genes was brain region-specific but independent of ASM genotype, with ß-synuclein showing overall higher levels and the least variation. Moreover, we discovered correlations of gene expression levels between brain regions and depression- and anxiety-like behavior and locomotor activity, such as a positive association between Snca mRNA levels and locomotion. Our results suggest that the analysis of synuclein genes could be valuable in identifying biomarkers and comprehending the common pathological mechanisms underlying various neuropsychiatric disorders.
Assuntos
Ansiedade , Encéfalo , Depressão , Modelos Animais de Doenças , Locomoção , Camundongos Knockout , Esfingomielina Fosfodiesterase , Animais , Esfingomielina Fosfodiesterase/genética , Esfingomielina Fosfodiesterase/metabolismo , Camundongos , Encéfalo/metabolismo , Depressão/genética , Depressão/metabolismo , Ansiedade/genética , Ansiedade/metabolismo , Locomoção/genética , Masculino , Sinucleínas/metabolismo , Sinucleínas/genética , Comportamento Animal , Feminino , Genótipo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Camundongos Endogâmicos C57BLRESUMO
The symptoms of post-traumatic stress disorder (PTSD) include re-experiencing trauma, avoidance behaviors, negative alterations in cognition and mood. However, the underlying molecular mechanisms are unclear. Dysfunction of hypothalamic-pituitary-adrenal axis (HPA-axis) and dysregulation of glutamatergic and GABAergic systems were shown during PTSD. Therefore, regulating hormonal change or glutamate energy metabolism are considered as a therapeutic approach to alleviate this condition. Herbal medicine may be effective in treating PTSD due to its ability to target multiple underlying mechanisms with various compounds. Hominis placenta (HP) is a traditional medicine widely used in East Asia for various conditions. However, the effect on PTSD has not been clarified. We aimed to investigate the effects of HP treatment in single-prolonged stress with shock (SPSS)-induced PTSD mice and explore its possible mechanisms. HP treatment at ST36 acupoints, combined with herbal medicine and acupuncture point stimulation, was applied three times/week for 2 weeks. HP treatment effectively alleviated anxiety and cognitive decline in SPSS-induced PTSD mice, as detected by Open field and the Y-maze test. Additionally, HP decreased the corticosterone levels and proinflammatory cytokines in the serum, modulated brain energy metabolism, and inhibited glutamate excitotoxicity, while regulating neuronal activity through modulating brain-derived neurotrophic factor (BDNF) levels, as demonstrated by western blot and immunohistochemistry, and flow cytometry analyses. These findings reveal that HP treatment effectively alleviates PTSD-like behaviors by regulating energy metabolism and neuronal activity though modulation of the HPA-axis and BDNF levels in PTSD mice, indicating that HP treatment is a promising therapeutic approach for PTSD.
Assuntos
Comportamento Animal , Metabolismo Energético , Neurônios , Transtornos de Estresse Pós-Traumáticos , Animais , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/psicologia , Metabolismo Energético/efeitos dos fármacos , Feminino , Camundongos , Gravidez , Masculino , Comportamento Animal/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Placenta/metabolismo , Modelos Animais de Doenças , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ansiedade/metabolismo , Ansiedade/tratamento farmacológico , Corticosterona/sangue , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Citocinas/metabolismoRESUMO
Depression and anxiety are prominent symptoms of withdrawal syndrome, often caused by the abuse of addictive drugs like morphine. N-palmitoylethanolamide (PEA), a biologically active lipid, is utilized as an anti-inflammatory and analgesic medication. Recent studies have highlighted PEA's role in mitigating cognitive decline and easing depression resulting from chronic pain. However, it remains unknown whether PEA can influence negative emotions triggered by morphine withdrawal. This study seeks to explore the impact of PEA on such emotions and investigate the underlying mechanisms. Mice subjected to morphine treatment underwent a 10-day withdrawal period, followed by assessments of the effect of PEA on anxiety- and depression-like behaviors using various tests. Enzyme-linked immunosorbent assay was conducted to measure levels of monoamine neurotransmitters in specific brain regions. The findings indicate that PEA mitigated anxiety and depression symptoms and reduced 5-hydroxytryptamine, noradrenaline, and dopamine levels in the hippocampus and prefrontal cortex. In summary, PEA demonstrates a significant positive effect on negative emotions associated with morphine withdrawal, accompanied with the reduction in levels of monoamine neurotransmitters in key brain regions. These insights could be valuable for managing negative emotions arising from morphine withdrawal.
Assuntos
Amidas , Ansiedade , Depressão , Etanolaminas , Morfina , Ácidos Palmíticos , Síndrome de Abstinência a Substâncias , Animais , Síndrome de Abstinência a Substâncias/psicologia , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Etanolaminas/farmacologia , Ácidos Palmíticos/farmacologia , Camundongos , Masculino , Morfina/farmacologia , Depressão/metabolismo , Depressão/tratamento farmacológico , Depressão/psicologia , Depressão/etiologia , Amidas/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Ansiedade/metabolismo , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Emoções/efeitos dos fármacos , Serotonina/metabolismo , Dependência de Morfina/metabolismo , Dependência de Morfina/psicologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Norepinefrina/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacosRESUMO
Depression and anxiety disorders are prevalent stress-related neuropsychiatric disorders and involve multiple molecular changes and dysfunctions across various brain regions. However, the specific and shared pathophysiological mechanisms occurring in these regions remain unclear. Previous research used a rat model of chronic mild stress (CMS) to segregate and identify depression-susceptible, anxiety-susceptible, and insusceptible groups; then the proteomes of six distinct brain regions (the hippocampus, prefrontal cortex, hypothalamus, pituitary, olfactory bulb, and striatum) were separately and quantitatively analyzed. To gain a comprehensive and systematic understanding of the molecular abnormalities, this study aimed to investigate and compare differential proteomics data from the six regions. Differentially expressed proteins (DEPs) were identified in between specific regions and across all regions and subjected to a series of bioinformatics analyses. Regional comparisons showed that stress-induced proteomic changes and corresponding gene ontology and pathway enrichments were largely distinct, attributable to differences in cell populations, protein compositions, and brain functions of these areas. Additionally, a notable degree of overlap in the significantly enriched terms was identified, potentially suggesting strong connections in the enrichment across different regions. Furthermore, intra-regional and inter-regional protein-protein interaction networks and drug-target-DEP networks were constructed. Integrated analysis of the three association networks in the six regions, along with the DisGeNET database, identified ten DEPs as potential targets for anti-depression/anxiety drugs. Collectively, these findings revealed commonalities and differences across different brain regions at the protein level induced by CMS, and identified several novel protein targets for the development of new therapeutics for depression and anxiety.
Assuntos
Ansiolíticos , Encéfalo , Proteoma , Ratos Sprague-Dawley , Estresse Psicológico , Animais , Estresse Psicológico/metabolismo , Estresse Psicológico/tratamento farmacológico , Proteoma/metabolismo , Masculino , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Ansiedade/metabolismo , Ansiedade/tratamento farmacológico , Depressão/metabolismo , Depressão/tratamento farmacológico , Mapas de Interação de Proteínas , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ratos , ProteômicaRESUMO
Puberty is a sensitive developmental period during which stressors can cause lasting brain and behavioural deficits. While the acute effects of pubertal lipopolysaccharide (LPS) and antimicrobial (AMNS) treatments are known, their enduring impacts on neurodegeneration-related mechanisms and behaviours remain unclear. This study examined these effects in male and female mice. At five weeks old, mice received 200ul of either broad-spectrum antimicrobials or water through oral gavage twice daily for seven days. At six weeks of age, they received an intraperitoneal injection of either saline or LPS. Four weeks later, adult mice underwent neurodegeneration-related behavioural tests, including the rotarod, forepaw stride length, reversed grid hang, open field, and buried pellet tests. Two days after the final test, brain and ileal samples were collected. Results showed that female mice treated with both AMNS and LPS exhibited deficits in neuromuscular strength, while males treated with LPS alone showed increased anxiety-like behaviours. Males treated with AMNS alone had decreased sigma-1 receptor (S1R) expression in the cornu ammonis 1 (CA1) and dentate gyrus (DG), while females treated with both AMNS and LPS had decreased S1R expression. Additionally, males treated with either LPS or AMNS had lower glial-derived neurotrophic factor receptor alpha-1 (GFRA1) expression in the primary motor cortex (M1) than females. Mice treated with LPS alone had decreased GFRA1 expression in the DG and decreased S1R expression in the secondary motor cortex (M2). These findings suggest that pubertal AMNS and LPS treatments may lead to enduring changes in biomarkers and behaviours related to neurodegeneration.