RESUMEN
Mindfulness meditation training has been shown to be an effective stress reduction strategy, but less is known about its immunoregulatory impact. In a randomized controlled trial of stressed customer service workers, the present study tested whether a 30-day smartphone-based mindfulness meditation training program (compared to a problem-solving control program) would affect pro-inflammatory gene expression. Both interventions led to reductions in stress levels, but there was no difference in stress reduction between conditions. Consistent with predictions, mindfulness training reduced activity of the pro-inflammatory NF-κB transcription control pathway compared to the active control. These results suggest that mindfulness training may be a particularly effective method for improving immune cell gene expression in stressful work environments.
Asunto(s)
Meditación , Atención Plena , Adulto , Expresión Génica , Humanos , Meditación/métodos , Atención Plena/métodos , Teléfono Inteligente , Estrés Psicológico/genética , Estrés Psicológico/terapiaRESUMEN
Treatment of sleep disorders promotes the long-term use of commercially available sleep inducers that have several adverse effects, including addiction, systemic fatigue, weakness, loss of concentration, headache, and digestive problems. Therefore, we aimed to limit these adverse effects by investigating a natural product, the extract of the Hibiscus syriacus Linnaeus flower (HSF), as an alternative treatment. In the electric footshock model, we measured anxiety and assessed the degree of sleep improvement after administering HSF extract. In the restraint model, we studied the sleep rate using PiezoSleep, a noninvasive assessment system. In the pentobarbital model, we measured sleep improvement and changes in sleep-related factors. Our first model confirmed the desirable effects of HSF extract and its active constituent, saponarin, on anxiolysis and Wake times. HSF extract also increased REM sleep time. Furthermore, HSF extract and saponarin increased the expression of cortical GABAA receptor α1 (GABAAR α1) and c-Fos in the ventrolateral preoptic nucleus (VLPO). In the second model, HSF extract and saponarin restored the sleep rate and the sleep bout duration. In the third model, HSF extract and saponarin increased sleep maintenance time. Moreover, HSF extract and saponarin increased cortical cholecystokinin (CCK) mRNA levels and the expression of VLPO c-Fos. HSF extract also increased GABAAR α1 mRNA level. Our results suggest that HSF extract and saponarin are effective in maintaining sleep and may be used as a novel treatment for sleep disorder. Eventually, we hope to introduce HSF and saponarin as a clinical treatment for sleep disorders in humans.
Asunto(s)
Apigenina/uso terapéutico , Glucósidos/uso terapéutico , Hibiscus , Extractos Vegetales/uso terapéutico , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Sueño/efectos de los fármacos , Animales , Apigenina/farmacología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiología , Corticosterona/sangre , Modelos Animales de Enfermedad , Electroencefalografía , Glucósidos/farmacología , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Pentobarbital , Extractos Vegetales/farmacología , Área Preóptica/efectos de los fármacos , Área Preóptica/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas Sprague-Dawley , Receptores de GABA-A/genética , Fármacos Inductores del Sueño , Trastornos del Sueño-Vigilia/sangre , Trastornos del Sueño-Vigilia/genética , Trastornos del Sueño-Vigilia/fisiopatología , Estrés Psicológico/sangre , Estrés Psicológico/complicaciones , Estrés Psicológico/genética , Estrés Psicológico/fisiopatologíaRESUMEN
Depression is deemed a mood disorder characterized by a high rate of relapse. Therefore, overcoming of the recurrent depression is globally expecting. Kososan, a traditional Japanese herbal medicine, has been clinically used for mild depressive mood, and our previous studies have shown some evidence for its antidepressive-like efficacy in experimental animal models of depression. However, it remains unclear whether kososan has beneficial effects on recurrent depression. Here, we examined its effect using a mouse model of modified repeated social defeat stress (SDS) paradigm. Male BALB/c mice were exposed to a 5-min SDS from unfamiliar aggressive CD-1 mice for 5 days. Kososan extract (1.0 kg/kg/day) or an antidepressant milnacipran (60 mg/kg/day) was administered orally for 26 days (days 7-32) to depression-like mice with social avoidant behaviors on day 6. Single 5 min of SDS was subjected to mice recovered from the social avoidance on day 31, and then the recurrence of depression-like behaviors was evaluated on day 32. Hippocampal gene expression patterns were also assayed by DNA microarray analysis. Water- or milnacipran-administered mice resulted in a recurrence of depression-like behaviors by re-exposure of single SDS, whereas kososan-administered mice did not recur depression-like behaviors. Distinct gene expression patterns were also found for treating kososan and milnacipran. Collectively, this finding suggests that kososan exerts a preventive effect on recurrent depression-like behaviors in mice. Pretreatment of kososan is more useful for recurrent depression than that of milnacipran.
Asunto(s)
Antidepresivos/farmacología , Depresión/prevención & control , Medicamentos Herbarios Chinos/farmacología , Proteínas del Tejido Nervioso/genética , Derrota Social , Estrés Psicológico/tratamiento farmacológico , Administración Oral , Animales , Depresión/genética , Depresión/fisiopatología , Depresión/psicología , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ontología de Genes , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatología , Japón , Masculino , Medicina Kampo/métodos , Ratones , Ratones Endogámicos BALB C , Milnaciprán/farmacología , Anotación de Secuencia Molecular , Proteínas del Tejido Nervioso/clasificación , Proteínas del Tejido Nervioso/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Recurrencia , Estrés Psicológico/genética , Estrés Psicológico/fisiopatologíaRESUMEN
Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is considered one of the mechanisms underlying the development of major depressive disorder (MDD), but the exact nature of this dysfunction is unknown. We investigated the relationship between hypothalamus volume (HV) and blood-derived DNA methylation in MDD. We obtained brain MRI, clinical and molecular data from 181 unmedicated MDD and 90 healthy control (HC) participants. MDD participants received a 16-week standardized antidepressant treatment protocol, as part of the first Canadian Biomarker Integration Network in Depression (CAN-BIND) study. We collected bilateral HV measures via manual segmentation by two independent raters. DNA methylation and RNA sequencing were performed for three key HPA axis-regulating genes coding for the corticotropin-binding protein (CRHBP), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5). We used elastic net regression to perform variable selection and assess predictive ability of methylation variables on HV. Left HV was negatively associated with duration of current episode (ρ = -0.17, p = 0.035). We did not observe significant differences in HV between MDD and HC or any associations between HV and treatment response at weeks 8 or 16, overall depression severity, illness duration or childhood maltreatment. We also did not observe any differentially methylated CpG sites between MDD and HC groups. After assessing functionality by correlating methylation levels with RNA expression of the respective genes, we observed that the number of functionally relevant CpG sites differed between MDD and HC groups in FKBP5 (χ2 = 77.25, p < 0.0001) and NR3C1 (χ2 = 7.29, p = 0.007). Cross-referencing functionally relevant CpG sites to those that were highly ranked in predicting HV in elastic net modeling identified one site from FKBP5 (cg03591753) and one from NR3C1 (cg20728768) within the MDD group. Stronger associations between DNA methylation, gene expression and HV in MDD suggest a novel putative molecular pathway of stress-related sensitivity in depression. Future studies should consider utilizing the epigenome and ultra-high field MR data which would allow the investigation of HV sub-fields.
Asunto(s)
Metilación de ADN , Trastorno Depresivo Mayor , Hipotálamo , Estrés Psicológico , Biomarcadores/metabolismo , Canadá , Metilación de ADN/genética , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/patología , Humanos , Sistema Hipotálamo-Hipofisario/fisiología , Hipotálamo/patología , Tamaño de los Órganos , Sistema Hipófiso-Suprarrenal/fisiología , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Estrés Psicológico/genética , Estrés Psicológico/fisiopatologíaRESUMEN
Both inflammatory proteins and microRNAs (miRNA) have been reported to be associated with various psychiatric disorders. However, the association between inflammatory proteins and miRNAs remains largely unknown, especially for patients with depression, anxiety, or stress- and adjustment disorders. In this study, we analyzed plasma levels of 92 inflammatory proteins from 178 patients with depression, anxiety, or stress- and adjustment disorders at baseline and after 8-week psychological treatments which resulted in a significant decrease in the Montgomery Åsberg Depression Rating Scale (MADRS-S) score. We investigated the response of the proteins after treatment and the correlation with miR-144-5p. After Benjamini-Hochberg correction for multiple testing, a total of 36 inflammatory proteins changed significantly after 8-week psychological treatments. Among the 36 significantly changed proteins, 21 proteins showed a decrease, and 17/21 proteins were inversely associated with plasma miR-144-5p levels at baseline. In addition, decreases in these proteins were associated with increases in miR-144-5p after treatment. The findings were similar after stratification by use of medications. The associations between the proteins and depression at baseline, measured by MADRS-S, as well as the change in protein levels and treatment response were, however, less clear. These findings need to be examined in future studies.
Asunto(s)
Trastornos de Adaptación/genética , Trastornos de Ansiedad/genética , Depresión/genética , Inflamación/metabolismo , MicroARNs/metabolismo , Proteínas/metabolismo , Estrés Psicológico/genética , Trastornos de Adaptación/psicología , Trastornos de Adaptación/terapia , Adulto , Trastornos de Ansiedad/psicología , Trastornos de Ansiedad/terapia , Depresión/psicología , Depresión/terapia , Femenino , Estudios de Seguimiento , Humanos , Inflamación/sangre , Masculino , MicroARNs/genética , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Estrés Psicológico/terapia , Resultado del Tratamiento , Adulto JovenRESUMEN
Studies have evidenced that epigenetic marks associated with type 2 diabetes (T2D) can be inherited from parents or acquired through fetal and early-life events, as well as through lifelong environments or lifestyles, which can increase the risk of diabetes in adulthood. However, epigenetic modifications are reversible, and can be altered through proper intervention, thus mitigating the risk factors of T2D. Mind-body intervention (MBI) refers to interventions like meditation, yoga, and qigong, which deal with both physical and mental well-being. MBI not only induces psychological changes, such as alleviation of depression, anxiety, and stress, but also physiological changes like parasympathetic activation, lower cortisol secretion, reduced inflammation, and aging rate delay, which are all risk factors for T2D. Notably, MBI has been reported to reduce blood glucose in patients with T2D. Herein, based on recent findings, we review the effects of MBI on diabetes and the mechanisms involved, including epigenetic modifications.
Asunto(s)
Diabetes Mellitus Tipo 2/prevención & control , Terapias Mente-Cuerpo/métodos , Estrés Psicológico/terapia , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/genética , Epigénesis Genética , Humanos , Hidrocortisona/metabolismo , Sistema Nervioso Parasimpático/metabolismo , Estrés Psicológico/complicaciones , Estrés Psicológico/genéticaRESUMEN
BACKGROUND: Progestational stress has been proven to be a risk for the neural development of offspring, especially in the hippocampus. However, whether Chaihu Shugan San (CSS) can ameliorate hippocampal neural development via the regulation of brain-derived neurotrophic factor (BDNF), and N-methyl-D-aspartate receptors (NMDAR) 2A (NR2A) and 2B (NR2B), and the mechanism of such action remains unclear. METHODS: Thirty-six female rats were randomly allocated into control, chronic immobilization stress (CIS) and CSS groups according to the random number table, respectively. The male offspring were fed for 21 days after birth then randomly divided into the same three groups (6 rats/group) as the female rats. Female rats, except for the control group, underwent 21-day CIS to established a progestational stress anxiety-like model which was evaluated by body weight, the elevated plus-maze (EPM) test and serum dopamine (DA) measured using an enzyme-linked immunosorbent assay (ELISA). The expression levels of estrogen receptors (ERα/ERß) and progesterone receptor (PR) in female rat ovaries were quantified by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. The hippocampal tissue in the 21-day offspring was observed by hematoxylin-eosin (HE) staining. The concentration of BDNF, NR2A, and NR2B were measured by RT-qPCR and immunohistochemistry in the CA3 and dentate gyrus (DG) regions of offsprings' hippocampus. RESULTS: Compared with the female control group, significant differences in body weight, EPM test and DA concentration were observed in the CIS group, meanwhile, the concentration of ERα (P < 0.05), PR (P < 0.05) and ERß in the ovaries were decreased. In the offsprings' hippocampus of the CIS group, the chromatin of the nucleus was edge set and with condensed and irregular morphology nucleus, and the cytoplasm was unevenly stained with spaces around the cells, moreover, the expression levels of BDNF, NR2A, and NR2B were also declined (P < 0.05). However, Chaihu Shugan San reversed these changes, especially the BDNF in the DG region (P < 0.05), and NR2A and NR2B in the CA3 and DG region (P < 0.05). CONCLUSIONS: CSS could ameliorate the neural development of the hippocampus in offspring damaged by anxiety-like progestational stress in female rats via regulating the expression levels of ERα, ERß, and PR in female rat ovaries and BDNF, NR2A, and NR2B in the hippocampus of their offspring.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Extractos Vegetales/farmacología , Efectos Tardíos de la Exposición Prenatal , Receptores de N-Metil-D-Aspartato/metabolismo , Estrés Psicológico/tratamiento farmacológico , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Modelos Animales de Enfermedad , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Femenino , Edad Gestacional , Hipocampo/metabolismo , Hipocampo/patología , Masculino , Ovario/efectos de los fármacos , Ovario/metabolismo , Embarazo , Ratas Wistar , Receptores de N-Metil-D-Aspartato/genética , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Restricción Física , Transducción de Señal , Estrés Psicológico/genética , Estrés Psicológico/metabolismo , Estrés Psicológico/patologíaRESUMEN
BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a polygenic disorder characterized principally by dysregulated inflammation impacting the gastrointestinal tract. However, there also is increasing evidence for a clinical association with stress and depression. Given the role of the hypothalamus in stress responses and in the pathogenesis of depression, useful insights could be gleaned from understanding its genetic role in IBD. METHODS: We conducted genetic correlation analyses on publicly available genome-wide association study summary statistics for depression and IBD traits to identify genetic commonalities. We used partitioned linkage disequilibrium score regression, leveraging our ATAC sequencing and promoter-focused Capture C data, to measure enrichment of IBD single-nucleotide polymorphisms within promoter-interacting open chromatin regions of human embryonic stem cell-derived hypothalamic-like neurons (HNs). Using the same data sets, we performed variant-to-gene mapping to implicate putative IBD effector genes in HNs. To contrast these results, we similarly analyzed 3-dimensional genomic data generated in epithelium-derived colonoids from rectal biopsy specimens from donors without pathologic disease noted at the time of colonoscopy. Finally, we conducted enrichment pathway analyses on the implicated genes to identify putative IBD dysfunctional pathways. RESULTS: We found significant genetic correlations (rg) of 0.122 with an adjusted P (Padj) = 1.4 × 10-4 for IBD: rg = 0.122; Padj = 2.5 × 10-3 for ulcerative colitis and genetic correlation (rg) = 0.094; Padj = 2.5 × 10-3 for Crohn's disease, and significant approximately 4-fold (P = .005) and approximately 7-fold (P = .03) enrichment of IBD single-nucleotide polymorphisms in HNs and colonoids, respectively. We implicated 25 associated genes in HNs, among which CREM, CNTF, and RHOA encode key regulators of stress. Seven genes also additionally were implicated in the colonoids. We observed an overall enrichment for immune and hormonal signaling pathways, and a colonoid-specific enrichment for microbiota-relevant terms. CONCLUSIONS: Our results suggest that the hypothalamus warrants further study in the context of IBD pathogenesis.
Asunto(s)
Depresión/genética , Predisposición Genética a la Enfermedad , Hipotálamo/fisiopatología , Enfermedades Inflamatorias del Intestino/genética , Estrés Psicológico/genética , Eje Cerebro-Intestino , Estudios de Casos y Controles , Mapeo Cromosómico , Conjuntos de Datos como Asunto , Depresión/fisiopatología , Estudio de Asociación del Genoma Completo , Humanos , Sistema Hipotálamo-Hipofisario/fisiopatología , Hipotálamo/citología , Enfermedades Inflamatorias del Intestino/fisiopatología , Desequilibrio de Ligamiento , Neuronas , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Estrés Psicológico/fisiopatologíaRESUMEN
Alzheimer's disease (AD), considered the most common type of dementia, is characterized by a progressive loss of memory, visuospatial, language and complex cognitive abilities. In addition, patients often show comorbid depression and aggressiveness. Aging is the major factor contributing to AD; however, the initial cause that triggers the disease is yet unknown. Scientific evidence demonstrates that AD, especially the late onset of AD, is not the result of a single event, but rather it appears because of a combination of risk elements with the lack of protective ones. A major risk factor underlying the disease is neuroinflammation, which can be activated by different situations, including chronic pathogenic infections, prolonged stress and metabolic syndrome. Consequently, many therapeutic strategies against AD have been designed to reduce neuro-inflammation, with very promising results improving cognitive function in preclinical models of the disease. The literature is massive; thus, in this review we will revise the translational evidence of these early strategies focusing in anti-diabetic and anti-inflammatory molecules and discuss their therapeutic application in humans. Furthermore, we review the preclinical and clinical data of nutraceutical application against AD symptoms. Finally, we introduce new players underlying neuroinflammation in AD: the activity of the endocannabinoid system and the intestinal microbiota as neuroprotectors. This review highlights the importance of a broad multimodal approach to treat successfully the neuroinflammation underlying AD.
Asunto(s)
Envejecimiento/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Antiinflamatorios/uso terapéutico , Cannabinoides/uso terapéutico , Hipoglucemiantes/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Envejecimiento/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/fisiopatología , Ensayos Clínicos como Asunto , Disfunción Cognitiva/genética , Disfunción Cognitiva/inmunología , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/prevención & control , Depresión/genética , Depresión/inmunología , Depresión/fisiopatología , Depresión/prevención & control , Suplementos Dietéticos , Microbioma Gastrointestinal/inmunología , Humanos , Inflamación , Resistencia a la Insulina , Síndrome Metabólico/genética , Síndrome Metabólico/inmunología , Síndrome Metabólico/fisiopatología , Síndrome Metabólico/prevención & control , Neuroinmunomodulación/efectos de los fármacos , Estrés Psicológico/genética , Estrés Psicológico/inmunología , Estrés Psicológico/fisiopatología , Estrés Psicológico/prevención & controlRESUMEN
Much research has demonstrated the beneficial effects of mindfulness-based stress reduction (MBSR) on psychological and physical health, but it is not known whether MBSR may impact cellular aging in healthy populations. Further, little research has evaluated MBSR against an active control condition, which precludes strong conclusions regarding the unique effects of mindfulness on psychological functioning. The present study examined the effects of MBSR versus music therapy-based stress reduction (MTSR) on trait mindfulness, self-compassion, and several psychological health outcomes, as well as leukocyte telomere length (LTL). One hundred and fifty eight Singaporean Chinese adults were recruited and randomly assigned to an eight-week MBSR or MTSR course. Participants provided blood samples and completed a battery of self-report measures pre- and post-intervention. Analyses showed that participants in the MBSR condition demonstrated significantly greater improvements in depressive symptoms, trait mindfulness, and self-compassion compared to the control condition. Treatment condition did not predict changes in LTL, anxiety, stress, or happiness, though there was a trend for duration of home mindfulness practice to predict increases in LTL. Overall, the study demonstrated MBSR's unique effects in reducing depressive symptoms. Improvements in trait mindfulness and self-compassion correspond with theorized mechanisms of change underlying mindfulness training. The lack of intervention effect with regards to LTL suggests that a more intensive intervention may be required for mindfulness to exert noticeable impact on aging at the cellular level, or that the effect may only emerge over a longer term.
Asunto(s)
Trastornos de Ansiedad , Atención Plena , Estrés Psicológico , Telómero , Adulto , Ansiedad , Trastornos de Ansiedad/genética , Trastornos de Ansiedad/terapia , Humanos , Estrés Psicológico/genética , Estrés Psicológico/terapia , Resultado del TratamientoRESUMEN
Homeostasis of bone metabolism is regulated by the central nervous system, and mood disorders such as anxiety are associated with bone metabolism abnormalities, yet our understanding of the central neural circuits regulating bone metabolism is limited. Here, we demonstrate that chronic stress in crewmembers resulted in decreased bone density and elevated anxiety in an isolated habitat mimicking a space station. We then used a mouse model to demonstrate that GABAergic neural circuitry in the ventromedial hypothalamus (VMH) mediates chronic stress-induced bone loss. We show that GABAergic inputs in the dorsomedial VMH arise from a specific group of somatostatin neurons in the posterior region of the bed nucleus of the stria terminalis, which is indispensable for stress-induced bone loss and is able to trigger bone loss in the absence of stressors. In addition, the sympathetic system and glutamatergic neurons in the nucleus tractus solitarius were employed to regulate stress-induced bone loss. Our study has therefore identified the central neural mechanism by which chronic stress-induced mood disorders, such as anxiety, influence bone metabolism.
Asunto(s)
Trastornos de Ansiedad/metabolismo , Resorción Ósea/metabolismo , Hipotálamo/metabolismo , Red Nerviosa/metabolismo , Neuronas/metabolismo , Estrés Psicológico/metabolismo , Adulto , Animales , Trastornos de Ansiedad/complicaciones , Trastornos de Ansiedad/genética , Trastornos de Ansiedad/patología , Resorción Ósea/etiología , Resorción Ósea/genética , Resorción Ósea/patología , Enfermedad Crónica , Femenino , Humanos , Hipotálamo/patología , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Red Nerviosa/patología , Neuronas/patología , Somatostatina/genética , Somatostatina/metabolismo , Estrés Psicológico/complicaciones , Estrés Psicológico/genética , Estrés Psicológico/patologíaRESUMEN
In traditional Chinese medicine, the role of the liver in depression is highly valued, and liver-relieving drugs, such as Sinisan, are often used to treat depression; however, the mechanism whereby these drugs work remains unclear. The present study aimed to reveal possible antidepressant mechanisms of Sinisan (SNS) by analyzing hepatic proteomics in chronic unpredictable mild stress (CUMS) mice. Using the CUMS mouse model of depression, the antidepressant effects of SNS were assessed by the sucrose preference test (SPT) and forced swimming test (FST). Hepatic differentially expressed proteins (DEPs) after SNS treatment were investigated by tandem mass tag (TMT) based quantitative proteomics analysis. Then, a bioinformatics analysis of DEPs was conducted through hierarchical clustering, Venn analysis, Gene Ontology (GO) annotation enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. DEP genes were further validated by quantitative real-time polymerase chain reaction (qRT-PCR) analysis and western blotting. Behavioral results demonstrated that SNS significantly increased sucrose intake in SPT and shortened the immobility time in FST in model mice. Eighty-two DEPs were identified, including 37 upregulated and 45 downregulated proteins, between model and SNS groups. Enrichment analysis of GO annotations indicated that SNS primarily maintained cellular iron ion homeostasis by iron ion transportation and regulated expression of some extracellular structural proteins for oxidation-reduction processes. KEGG and Venn analysis showed that mineral absorption, steroid hormone biosynthesis and metabolism might be the principal pathways through which SNS acts on depression. Furthermore, several proteins involved in the biosynthesis and metabolism of steroid hormone pathways were significantly up/downregulated by SNS, including CYP2B19, CYP7B1 (validated by qRT-PCR) and HSD3b5 (validated by qRT-PCR and western blotting). Our results indicate that SNS plays important roles in antidepressant actions by restoring DEPs, resulting in the biosynthesis and metabolism of steroid hormones. The current results provide novel perspectives for revealing potential protein targets of SNS in depression.
Asunto(s)
Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Hígado/efectos de los fármacos , Estrés Psicológico/tratamiento farmacológico , Animales , Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Depresión/genética , Depresión/metabolismo , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Proteómica , Estrés Psicológico/genética , Estrés Psicológico/metabolismoRESUMEN
The brain has evolved in an environment where food sources are scarce, and foraging for food is one of the major challenges for survival of the individual and species. Basic and clinical studies show that obesity or overnutrition leads to overwhelming changes in the brain in animals and humans. However, the exact mechanisms underlying the consequences of excessive energy intake are not well understood. Neurons expressing the neuropeptide hypocretin/orexin (Hcrt) in the lateral/perifonical hypothalamus (LH) are critical for homeostatic regulation, reward seeking, stress response, and cognitive functions. In this study, we examined adaptations in Hcrt cells regulating behavioral responses to salient stimuli in diet-induced obese mice. Our results demonstrated changes in primary cilia, synaptic transmission and plasticity, cellular responses to neurotransmitters necessary for reward seeking, and stress responses in Hcrt neurons from obese mice. Activities of neuronal networks in the LH and hippocampus were impaired as a result of decreased hypocretinergic function. The weakened Hcrt system decreased reward seeking while altering responses to acute stress (stress-coping strategy), which were reversed by selectively activating Hcrt cells with chemogenetics. Taken together, our data suggest that a deficiency in Hcrt signaling may be a common cause of behavioral changes (such as lowered arousal, weakened reward seeking, and altered stress response) in obese animals.
Asunto(s)
Conducta Alimentaria , Hipotálamo , Red Nerviosa , Neuronas , Obesidad , Orexinas , Animales , Hipotálamo/metabolismo , Hipotálamo/patología , Hipotálamo/fisiopatología , Masculino , Ratones , Ratones Transgénicos , Red Nerviosa/metabolismo , Red Nerviosa/patología , Red Nerviosa/fisiopatología , Neuronas/metabolismo , Neuronas/patología , Obesidad/genética , Obesidad/metabolismo , Obesidad/patología , Obesidad/fisiopatología , Orexinas/genética , Orexinas/metabolismo , Estrés Psicológico/genética , Estrés Psicológico/metabolismo , Estrés Psicológico/patología , Estrés Psicológico/fisiopatologíaRESUMEN
OBJECTIVE: As a brain-specific microRNA, the mechanism of miR-124 in depression has not been clarified so far. The present study aimed to explore the role of miR-124 in depression and its potential targets. METHODS: The depression model was first replicated by the chronic unpredictable mild stress (CUMS) method. miR-124 antagomir was injected into the hippocampus of CUMS rats. Sucrose preference test (SPT), open-field test (OFT), elevated-plus maze (EPM), and forced swimming test (FST) were used to analyze the depression-like behavior. The content of norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) in the hypothalamus was analyzed by ELISA. qRT-PCR and western blot assay were used for functional analysis. RESULTS: miR-124 expression was up-regulated in the hippocampus of CUMS -induced depression model rats, while CREB1 and BDNF were down-regulated. Administration of miR-124 antagomir in the hippocampus inhibited miR-124 expression in the hippocampus of CUMS rats. Additionally, SPT, OFT, EPM, and FST also showed that miR-124 antagomir can reduce the depression-like behavior of CUMS rats. Furthermore, miR-124 antagomir injection increased the levels of NE, DA and 5-HT in the hypothalamus of CUMS rats. Moreover, miR-124 antagomir injection increased the expression of cyclic AMP-responsive element-binding protein1 (CREB1) and brain-derived neurotrophic factor (BDNF) in the hippocampus. Using the dual-luciferase reporter assay, it was confirmed that miR-124 directly targets 3'UTR of CREB1 and BDNF genes. CONCLUSION: Knockdown of miR-124 can improve depression-like behavior in CUMS-induced depressive rats, which may be related at least in part to the up-regulation of CREB1 and BDNF expression in the hippocampus.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Depresión/metabolismo , Hipocampo/metabolismo , MicroARNs/metabolismo , Animales , Ansiedad/genética , Ansiedad/metabolismo , Conducta Animal/fisiología , Factor Neurotrófico Derivado del Encéfalo/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Depresión/genética , Modelos Animales de Enfermedad , Técnicas de Silenciamiento del Gen , Hipotálamo/metabolismo , Masculino , MicroARNs/genética , Norepinefrina/metabolismo , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Estrés Psicológico/genética , Estrés Psicológico/metabolismoRESUMEN
BACKGROUND: Medium spiny neurons (MSNs) comprise the main body (95% in mouse) of the dorsal striatum neurons and represent dopaminoceptive GABAergic neurons. The cAMP (cyclic Adenosine MonoPhosphate)-mediated cascade of excitation and inhibition responses observed in MSN intracellular signal transduction is crucial for neuroscience research due to its involvement in the motor and behavioral functions. In particular, all types of addictions are related to MSNs. Shedding the light on the mechanics of the above-mentioned cascade is of primary importance for this research domain. RESULTS: A mouse model of chronic social conflicts in daily agonistic interactions was used to analyze dorsal striatum neurons genes implicated in cAMP-mediated phosphorylation activation pathways specific for MSNs. Based on expression correlation analysis, we succeeded in dissecting Drd1- and Drd2-dopaminoceptive neurons (D1 and D2, correspondingly) gene pathways. We also found that D1 neurons genes clustering are split into two oppositely correlated states, passive and active ones, the latter apparently corresponding to D1 firing stage upon protein kinase A (PKA) activation. We observed that under defeat stress in chronic social conflicts the loser mice manifest overall depression of dopamine-mediated MSNs activity resulting in previously reported reduced motor activity, while the aggressive mice with positive fighting experience (aggressive mice) feature an increase in both D1-active phase and D2 MSNs genes expression leading to hyperactive behavior pattern corresponded by us before. Based on the alternative transcript isoforms expression analysis, it was assumed that many genes (Drd1, Adora1, Pde10, Ppp1r1b, Gnal), specifically those in D1 neurons, apparently remain transcriptionally repressed via the reversible mechanism of promoter CpG island silencing, resulting in alternative promoter usage following profound reduction in their expression rate. CONCLUSION: Based on the animal stress model dorsal striatum pooled tissue RNA-Seq data restricted to cAMP related genes subset we elucidated MSNs steady states exhaustive projection for the first time. We correspond the existence of D1 active state not explicitly outlined before, and connected with dynamic dopamine neurotransmission cycles. Consequently, we were also able to indicate an oscillated postsynaptic dopamine vs glutamate action pattern in the course of the neurotransmission cycles.
Asunto(s)
Cuerpo Estriado/metabolismo , AMP Cíclico/genética , Dopamina/genética , Neuronas GABAérgicas/metabolismo , Expresión Génica , Neuronas/metabolismo , Animales , AMP Cíclico/metabolismo , Dopamina/metabolismo , Redes Reguladoras de Genes , Hipocampo/metabolismo , Hipotálamo/metabolismo , Masculino , Ratones Endogámicos C57BL , Núcleos del Rafe/metabolismo , Transducción de Señal/genética , Estrés Psicológico/genética , Área Tegmental Ventral/metabolismoRESUMEN
According to traditional Chinese medicine, lily bulb and Rehmannia decoction (LBRD) is a specialized formula for the treatment of "lily disease", the symptoms of which resemble the clinical manifestations of major depression. However, the molecular basis of the antidepressant mechanism of LBRD and the quality marker ingredients of LBRD remain unclear. This study aimed to investigate the quality marker ingredients of LBRD and to show the molecular mechanism of its antidepressant activities. In this study, we adopted the chronic unpredicted mild stress paradigm to construct a depression model. High-performance liquid chromatography (HPLC) was used to determine the levels of the main markers in LBRD. The underlying mechanism of LBRD was explored by measuring neurotransmitter and cytokine levels using enzyme-linked immunosorbent assay, and by quantifying differentially expressed gene (DEG) of transcriptome in the medial prefrontal cortex (mPFC) tissue through RNA sequencing. HPLC results showed that the average levels of quality marker ingredients of LBRD (ferulic acid, dioscin, verbascoside and catalpol) were 0.00079%, 0.00039%, 0.7% and 1.6% (w/w), respectively. LBRD intervention significantly attenuated the depressive phenotype compared with that in the depressed group. LBRD treatment altered the enriched DEGs in the signaling pathways of γ-aminobutyric acid (GABA) and glutamate neurotransmitter, synaptic plasticity and axon guidance, circadian rhythm and neural-immunity. GABAergic and glutamatergic synapses as well as brain-derived neurotrophic factor (BDNF)/TrkB-dependent phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin-1 (mTOR1), might be the main signaling pathways underlying the multi-target therapeutic effects of LBRD against depression.
Asunto(s)
Antidepresivos/farmacología , Depresión/genética , Extractos Vegetales/farmacología , Corteza Prefrontal/efectos de los fármacos , Estrés Psicológico/genética , Transcriptoma , Animales , Antidepresivos/química , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Citocinas/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Lilium/química , Masculino , Medicina Tradicional China , Ratones , Ratones Endogámicos C57BL , Neurotransmisores/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Extractos Vegetales/química , Corteza Prefrontal/metabolismo , Rehmannia/química , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismoRESUMEN
We introduce a novel hypothesis which states that the therapeutic utilisation of psilocybin has beneficial effects on genetic aging. Ex hypothesi, we predict a priori that controlled psilocybin interventions exert quantifiable positive impact on leucocyte telomere length (telomeres are a robust predictor of mortality and multifarious aging-related diseases). Our hypothesising follows the Popperian logic of scientific discovery, viz., bold (and refutable) conjectures form the very foundation of scientific progress. The 'psilocybin-telomere hypothesis' is formalised as a logically valid deductive (syllogistic) argument and we provide substantial evidence to support the underlying premises. Impetus for our theorising derives from a plurality of converging empirical sources indicating that psilocybin has persistent beneficial effects on various aspects of mental health (e.g., in the context of depression, anxiety, PTSD, OCD, addiction, etc.). Additional support is based on a large corpus of studies that establish reliable correlations between mental health and telomere attrition (improved mental health is generally correlated with longer telomeres). Another pertinent component of our argument is based on recent studies which demonstrate that "meditative states of consciousness" provide beneficial effects on genetic aging. Similarly, psilocybin can induce states of consciousness that are neurophysiologically and phenomenologically significantly congruent with meditative states. Furthermore, prior research has demonstrated that a single dose of psilocybin can occasion life-changing transformative experiences (≈ 70% of healthy volunteers rate their experience with psilocybin amongst the five personally most meaningful lifetime events, viz., ranked next to giving birth to a child or losing a loved one). We postulate that these profound psychological events leave quantifiable marks at the molecular genetic/epigenetic level. Given the ubiquitous availability and cost effectiveness of telomere length assays, we suggest that quantitative telomere analysis should be regularly included in future psilocybin studies as an adjunctive biological marker (i.e., to facilitate scientific consilience via methodological triangulation). In order to substantiate the 'psilocybin-telomere hypothesis' potential neuropsychopharmacological, endocrinological, and genetic mechanisms of action are discussed (e.g., HPA-axis reactivity, hippocampal neurogenesis, neurotropic growth factors such as BDNF, 5-HT2A receptor agonism, neuroplasticity/synaptoplasticity, brain-wide alterations in neuronal functional connectivity density, involvement of the SLC6A4 serotonin transporter gene, inter alia). The proposed research agenda is thus intrinsically highly interdisciplinary, and it has deep ramifications from a philosophy of science perspective as it connects the epistemic level (qualitative experiential phenomenology) with the ontic level (quantitative molecular genetics) of analysis. In the long term, multidisciplinary and innovative investigations of the 'psilocybin-telomere hypothesis' could contribute to the improvement of senotherapeutic psychological interventions and the identification of novel geroprotective and neuroprotective/restorative pharmaceutical targets to decelerate genetic aging and improve well-being and quality of life during the aging process.
Asunto(s)
Envejecimiento/efectos de los fármacos , Modelos Genéticos , Modelos Psicológicos , Psilocibina/uso terapéutico , Psicotrópicos/uso terapéutico , Acortamiento del Telómero/efectos de los fármacos , Envejecimiento/genética , Envejecimiento/psicología , Envejecimiento Prematuro/tratamiento farmacológico , Envejecimiento Prematuro/genética , Envejecimiento Prematuro/prevención & control , Animales , Ansiedad/tratamiento farmacológico , Ansiedad/genética , Factor Neurotrófico Derivado del Encéfalo/fisiología , Estado de Conciencia/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Depresión/tratamiento farmacológico , Depresión/genética , Modelos Animales de Enfermedad , Sistema Endocrino/fisiopatología , Humanos , Neurotransmisores/fisiología , Estrés Oxidativo/efectos de los fármacos , Personalidad/efectos de los fármacos , Psilocibina/farmacología , Psicotrópicos/farmacología , Proyectos de Investigación , Proteínas de Transporte de Serotonina en la Membrana Plasmática/fisiología , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/genética , Acortamiento del Telómero/fisiologíaRESUMEN
Postmenopausal depression is closely associated with depletion of estrogen which modulates transmission of 5-HT, a key neurotransmitter that regulates stress-managing circuits in the brain. In this study, antidepressive efficacy of white ginseng (Panax gingseng Meyer, WG) was evaluated in stressed ovariectomized rats. Female Sprague Dawley rats were ovariectomized and repeatedly restraint stressed for 2 weeks (2h/day). Thirty minutes before restraint stress, rats were administered saline (control), WG 200 mg/kg (p.o.), WG 400 mg/kg (p.o.), or fluoxetine (PC, 10 mg/kg, i.p.). Tail suspension test (TST) and forced swimming test (FST) were performed to assess antidepressant effect of WG. After behavioral tests, levels of serum corticosterone (CORT) and hippocampal 5-HT were measured. Significant decrease of immobility time in TST and FST was shown in rats administered with PC or WG 400 compared to the control. WG200-treated rats showed remarkable reduction in immobility time of TST. PC, WG 200, or WG 400-administred group exhibited significant reduction of CORT compared to the control. PC or WG-treated rats exhibited remarkable increase in hippocampal 5-HT concentration compared to the control. Hippocampal 5-HT levels in WG groups were higher than those in the PC group. The present study demonstrated that WG had antidepressant efficacy in an animal model of menopausal depression. Treatment with WG enhanced hippocampal 5-HT level while suppressing depressive symptom and serum CORT level. These results provide evidence that WG plays an important role in activating serotonergic neurons in stressful situation, suggesting that WG might be a reliable natural alternative of antidepressant drugs to treat menopausal depression.
Asunto(s)
Depresión/tratamiento farmacológico , Trastorno Depresivo/tratamiento farmacológico , Panax/química , Serotonina/metabolismo , Animales , Antidepresivos/química , Antidepresivos/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Depresión/genética , Depresión/fisiopatología , Trastorno Depresivo/genética , Trastorno Depresivo/fisiopatología , Modelos Animales de Enfermedad , Suspensión Trasera/métodos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Ratas , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/genética , Estrés Psicológico/fisiopatología , NataciónRESUMEN
Recent research in functional genomics shows that social stressors affect the expression of immune response genes. These effects are mediated in part via our adaptive capacity for intracellular molecules to respond to extracellular signals, a process called signal transduction. Under this framework, one-way stressors can be transduced into cellular changes is through central nervous system (CNS) modulation of peripheral neural, endocrine, and molecular activity. Mindfulness meditation is a consciousness discipline used to cultivate attention and self-regulation, and may thus be relevant to the signal transduction process outlined in the social genomics literature. In this opinion article, we briefly review results from existing controlled trials that test the effects of mindfulness meditation on gene expression. We then speculate on a mind-body conceptual model, grounded in existing social genomics theory. In the spirit of hypothesis generation, we argue that mindfulness meditation changes brain activity patterns related to attention, self-regulation, and threat evaluation and so may alter the signal transduction process that regulates the expression of immune response genes.