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OBJECTIVES: We performed a systematic review and meta-analysis to examine the prevalence and antecedents/consequences of chronic loneliness and social isolation (i.e. enduring or persistent experience that extends over a certain period of time) among older adults. Moreover, we conducted a meta-regression to explore sources of heterogeneity. METHOD: A search was conducted in four electronic databases. We included observational studies that reported prevalence and, where available, antecedents/consequences of chronic loneliness or chronic social isolation amongst older adults. Key characteristics of the studies were extracted. RESULTS: Across 17 studies included in the meta-analysis, the estimated prevalence of chronic loneliness was 20.8% (95% CI: 16.1-25.5%), including 21.7% among women (95% CI: 16.1-27.4%) and 16.3% among men (95% CI: 10.6-21.9%). One study reported chronic social isolation (13.4%) and found that chronic social isolation predicted higher depression scores. Meta-regressions indicated that loneliness was less prevalent when assessed with single-item measures. Regarding antecedents/consequences, spousal loss can contribute to chronic loneliness which in turn may contribute to adverse health-related outcomes. CONCLUSION: About one in five older adults experiences chronic loneliness reflecting the need to address chronic loneliness. More longitudinal research is needed on chronic loneliness and social isolation, particularly from low and middle-income countries.
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Chronic social isolation (CSIS) generates two stress-related phenotypes: resilience and susceptibility. However, the molecular mechanisms underlying CSIS resilience remain unclear. We identified altered proteome components and biochemical pathways and processes in the prefrontal cortex cytosolic fraction in CSIS-resilient rats compared to CSIS-susceptible and control rats using liquid chromatography coupled with tandem mass spectrometry followed by label-free quantification and STRING bioinformatics. A sucrose preference test was performed to distinguish rat phenotypes. Potential predictive proteins discriminating between the CSIS-resilient and CSIS-susceptible groups were identified using machine learning (ML) algorithms: support vector machine-based sequential feature selection and random forest-based feature importance scores. Predominantly, decreased levels of some glycolytic enzymes, G protein-coupled receptor proteins, the Ras subfamily of GTPases proteins, and antioxidant proteins were found in the CSIS-resilient vs. CSIS-susceptible groups. Altered levels of Gapdh, microtubular, cytoskeletal, and calcium-binding proteins were identified between the two phenotypes. Increased levels of proteins involved in GABA synthesis, the proteasome system, nitrogen metabolism, and chaperone-mediated protein folding were identified. Predictive proteins make CSIS-resilient vs. CSIS-susceptible groups linearly separable, whereby a 100% validation accuracy was achieved by ML models. The overall ratio of significantly up- and downregulated cytosolic proteins suggests adaptive cellular alterations as part of the stress-coping process specific for the CSIS-resilient phenotype.
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Proteoma , Resiliencia Psicológica , Ratas , Animales , Proteoma/metabolismo , Corteza Prefrontal/metabolismo , Aislamiento Social , Fenotipo , Susceptibilidad a Enfermedades/metabolismo , Estrés Psicológico/metabolismoRESUMEN
Chronic social isolation (CSIS) of rats serves as an animal model of depression and generates CSIS-resilient and CSIS-susceptible phenotypes. We aimed to investigate the prefrontal cortical synaptoproteome profile of CSIS-resilient, CSIS-susceptible, and control rats to delineate biochemical pathways and predictive biomarker proteins characteristic for the resilient phenotype. A sucrose preference test was performed to distinguish rat phenotypes. Class separation and machine learning (ML) algorithms support vector machine with greedy forward search and random forest were then used for discriminating CSIS-resilient from CSIS-susceptible and control rats. CSIS-resilient compared to CSIS-susceptible rat proteome analysis revealed, among other proteins, downregulated glycolysis intermediate fructose-bisphosphate aldolase C (Aldoc), and upregulated clathrin heavy chain 1 (Cltc), calcium/calmodulin-dependent protein kinase type II (Cam2a), synaptophysin (Syp) and fatty acid synthase (Fasn) that are involved in neuronal transmission, synaptic vesicular trafficking, and fatty acid synthesis. Comparison of CSIS-resilient and control rats identified downregulated mitochondrial proteins ATP synthase subunit beta (Atp5f1b) and citrate synthase (Cs), and upregulated protein kinase C gamma type (Prkcg), vesicular glutamate transporter 1 (Slc17a7), and synaptic vesicle glycoprotein 2 A (Sv2a) involved in signal transduction and synaptic trafficking. The combined protein differences make the rat groups linearly separable, and 100% validation accuracy is achieved by standard ML models. ML algorithms resulted in four panels of discriminative proteins. Proteomics-data-driven class separation and ML algorithms can provide a platform for accessing predictive features and insight into the molecular mechanisms underlying synaptic neurotransmission involved in stress resilience.
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Resiliencia Psicológica , Ratas , Animales , Corteza Prefrontal/metabolismo , Aislamiento Social , Biomarcadores/metabolismo , Fenotipo , Susceptibilidad a EnfermedadesRESUMEN
Depression is linked to changes in GABAergic inhibitory neurons, especially parvalbumin (PV) interneurons, which are susceptible to redox dysregulation. Olanzapine (Olz) is an atypical antipsychotic whose mode of action remains unclear. We determined the effect of Olz on PV-positive (+) and glutamate decarboxylase 67 (GAD67) + cell numbers in the layers of dorsal hippocampus (dHIPP) cornu ammonis (CA1-CA3) and dentate gyrus (DG) subregions in rats exposed to chronic social isolation (CSIS), which is an animal model of depression. Antioxidative enzymes and proinflammatory cytokine levels were also examined. CSIS decreased the PV+ cell numbers in the Stratum Oriens (SO) and Stratum Pyramidale (SP) of dCA1 and dDG. It increased interleukin-6 (IL-6), suppressor of cytokine signaling 3 (SOCS3), and copper-zinc superoxide dismutase (CuZnSOD) levels, and it decreased catalase (CAT) protein levels. Olz in CSIS increased the number of GAD67+ cells in the SO and SP layers of dCA1 with no effect on PV+ cells. It reduced the PV+ and GAD67+ cell numbers in the Stratum Radiatum of dCA3 in CSIS. Olz antagonizes the CSIS-induced increase in CuZnSOD, CAT and SOCS3 protein levels with no effect on IL-6. Data suggest that the protective Olz effects in CSIS may be mediated by altering the number of PV+ and GAD67+ cells in dHIPP subregional layers.
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Interleucina-6 , Parvalbúminas , Ratas , Animales , Parvalbúminas/metabolismo , Olanzapina/farmacología , Interleucina-6/metabolismo , Recuento de Células , Hipocampo/metabolismoRESUMEN
Fluoxetine (Flx) is the most commonly used antidepressant to treat major depressive disorder. However, its molecular mechanisms of action are not defined as yet. A comparative proteomic approach was used to identify proteome changes in the prefrontal cortex (PFC) cytosolic and non-synaptic mitochondria (NSM)-enriched fractions of adult male Wistar rats following chronic social isolation (CSIS), a rat model of depression, and Flx treatment in CSIS and control rats, using liquid chromatography online tandem mass spectrometry. Flx reversed CSIS-induced depressive - like behavior according to preference for sucrose and immobility in the forced swim test, indicating its antidepressant effect. Flx treatment in controls led to an increase of the expression of cytosolic proteins involved in the microtubule cytoskeleton and intracellular calcium homeostasis and of enzymes involved in bioenergetic and transmembrane transport in NSM. CSIS downregulated the cytosolic proteins involved in proteasome pathway, and glutathione antioxidative system, and upregulated the expression of enzymes participating in mitochondrial-energy metabolism and transport. The presence of cytochrome c in the cytosol may suggest compromised mitochondrial membrane integrity. Flx treatment in CSIS rats downregulated protein involved in oxidative phosphorylation, such as complex III and manganese superoxide dismutase, and upregulated vesicle-mediated transport and synaptic signaling proteins in the cytosol, and neuronal calcium-binding protein 1 in NSM. Our study identified PFC modulated proteins and affected biochemical pathways that may represent potential markers/targets underlying CSIS-induced depression and effective Flx treatment, and highlights the role of protein systems involved in NSM and various metabolic pathways potentially involved in neuronal plasticity.
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Trastorno Depresivo Mayor , Fluoxetina , Animales , Antidepresivos/uso terapéutico , Calcio/metabolismo , Proteínas de Unión al Calcio/metabolismo , Citocromos c/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Trastorno Depresivo Mayor/metabolismo , Complejo III de Transporte de Electrones/metabolismo , Complejo III de Transporte de Electrones/farmacología , Fluoxetina/farmacología , Glutatión/metabolismo , Hipocampo/metabolismo , Masculino , Corteza Prefrontal/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteoma , Proteómica , Ratas , Ratas Wistar , Sacarosa/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
Social contacts play an important role in the development and survival of social animals. Social isolation (SI) at adolescence often induces abnormalities in many kinds of behaviors. This study assessed whether five weeks of continuous SI at adulthood could alter social behaviors and whether dorsal raphe nucleus (DR) to medial prefrontal cortex (mPFC) 5-HT neural projections were involved in this alteration in C57BL/6J adult male mice. The present study found that five weeks chronic social isolation (CSI) at adulthood increased mounting and sniffing behaviors in resident-intruder test, and lengthened duration staying in interaction zone of stranger cage in the three-chamber social preference test. CSI also reduced the release of 5-HT in the mPFC detected by 5-HT 1.0 sensor and measured by in vivo fiber photometry test. Meanwhile, the c-Fos expression indicated that CSI reduced the activity of serotonergic neurons. Chemogenetic activation of DR-mPFC 5-HTergic projection reduced sniffing of CSI mice in the resident-intruder test, but didn't significantly affect mounting behavior. It also decreased the interaction time during the three-chamber social preference test. Thus, 5-HT neural projections from the DR to the mPFC are involved in changes of social exploration behaviors induced by CSI at adulthood.
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Corteza Prefrontal , Serotonina , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Corteza Prefrontal/metabolismo , Serotonina/metabolismo , Conducta Social , Aislamiento SocialRESUMEN
Chronic Social Isolation (CSI) is a model of prolonged stress employed in a variety of studies to induce depression and anxious behavior in rats. The present study aims to evaluate the effect of CSI on male Wistar rats in terms of "anhedonic-type" behavior in the Sucrose Preference Test (SPT) and anxiogenic profile in the elevated-plus-maze (EPM) test, as well as evaluating the effect of resocialization upon sucrose consumption. A total of 24 adolescent male Wistar rats were evaluated. The animals were housed either together (communally) or socially isolated for 21 days, and then exposed for four consecutive days to the SPT test [water vs. a 32% sucrose solution (SS)]. Four days later, they were again subjected to the SPT test (32% vs. 0.7% SS), and then tested on the EPM apparatus 3 days later. Following the completion of the anxiogenic profile of the model, the animals were resocialized for 72 h and then re-tested once again using the SPT (32% vs. 0.7% SS). Twenty-four hours after this final consumption, the animals were euthanized to record the weight of their adrenal glands (AG). It was found that exposure to CSI produces anhedonic-type behavior and an anxiogenic profile in adolescent male rats, as evidenced in both the SPT and EPM tests, as well as in the animals' physiological stress response. It was also demonstrated that resocialization does not reverse the anhedonic-type behavior, nor the physiological response to stress.
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The molecular background of depression is intensively studied in terms of alterations of inhibitory circuits, mediated by gamma aminobutyric acid (GABA) signalization. We investigated the effects of chronic social isolation (CSIS) and chronic fluoxetine (Flx) treatment (15 mg/kg/day) (3 weeks), on Parvalbumin (PV) and GAD67 expression in a layer-specific manner in rat dorsal hippocampal subregions. CSIS-induced depressive- and anxiety-like behaviours were confirmed with decrease in sucrose preference and increase in marble burying during behavioural testing, while Flx antagonized these effects. CSIS altered PV expression in stratum pyramidale (SP) of dorsal cornu ammonis 1 (dCA1) and stratum radiatum (SR) of dCA3. Flx antagonized this effect, and boosted PV expression in SP of the entire dCA and the dorsal dentate gyrus (dDG), as well as in the SR of dCA1/CA3. CSIS showed no significant effects on GAD67 expression, while Flx boosted its expression within the SR of the entire CA and SO of the dCA3. A correlation between SP of dCA1 and SR of dCA3 with regard to PV changes, implicates their possible role in the inhibitory circuit alterations. Flx-induced increase in GAD67 expression, specifically in SR of the entire dHIPP, may impose its involvement in the cell metabolic processes. Strong negative correlation between GAD67 and sucrose preference following Flx-treatment of CSIS rats was revealed. PV + cells of the SP layer of dCA1 and CA2 could be a potential target for the antidepressant action of Flx, while strong effect of Flx on GAD67 expression in the SR should be more extensively studied.
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Depresión/metabolismo , Fluoxetina/farmacología , Hipocampo/efectos de los fármacos , Neuronas/efectos de los fármacos , Parvalbúminas/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Aislamiento Social , Animales , Conducta Animal/efectos de los fármacos , Glutamato Descarboxilasa/metabolismo , Hipocampo/metabolismo , Masculino , Neuronas/metabolismo , Ratas , Ratas Wistar , Conducta SocialRESUMEN
In the early stage of life, experiencing social isolation can generate long-lasting deleterious effects on behaviors and brain development. However, the effects of chronic social isolation during adolescence on social behaviors and its underlying neurobiological mechanisms remain unclear. The present study found that four weeks of social isolation during adolescence impaired social recognition ability in the three-chamber test and five-trial social recognition test, and increased aggressive-like behaviors, but reduced environmental exploration, as showed in the social interaction test. Chronic social isolation decreased levels of dopamine D2 receptor in the shell of the nucleus accumbens (NAcc) and medial prefrontal cortex. It also reduced TH in the NAcc. Using in vivo fiber photometry, it was also found that isolated mice displayed a reduction in NAcc shell activity upon exploring unfamiliar social stimuli. An injection of a 100 ng dose of the D2R agonist quinpirole into the shell of the NAcc reversed behavioral abnormalities induced by chronic social isolation. These data suggest that the dopamine system is involved in alterations in social behaviors induced by chronic social isolation. This finding sheds light on the mechanism underlying abnormalities in social behavior induced by adolescent chronic social isolation and provides a promising target to treat mental diseases relevant to social isolation.
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Dopamina/metabolismo , Conducta Social , Aislamiento Social/psicología , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Dopamina/farmacología , Agonistas de Dopamina/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Núcleo Accumbens/metabolismo , Corteza Prefrontal/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismoRESUMEN
The susceptibility of an individual to chronic social isolation (CSIS) stress may cause major depression (MD) whereby some individuals are resistant to the stress. Recent studies relate MD with altered expression of synaptic proteins in specific brain regions. To explore the neurobiological underpinnings and identify candidate biomarkers of susceptibility or resilience to CSIS, a comparative proteomic approach was used to map hippocampal synaptic protein alterations of rats exposed to 6 weeks of CSIS, an animal model of depression. This model generates two stress-response phenotypes: CSIS-sensitive (depressive-like behaviour) and CSIS-resilience assessed by means of sucrose preference and forced swim tests. Our aim was to characterize the synaptoproteome changes representative of potential long-term changes in protein expression underlying susceptibility or resilience to stress. Proteomic data showed increased expression of glycolytic enzymes, the energy-related mitochondrial proteins, actin cytoskeleton, signalling transduction and synaptic transmission proteins in CSIS-sensitive rats. Protein levels of glutamate-related enzymes such as glutamate dehydrogenase and glutamine synthetase were also increased. CSIS-resilient rats showed similar proteome changes, however with a weaker increase compared to CSIS-sensitive rats. The main difference was observed in the level of protein expression of vesicle-mediated transport proteins. Nonetheless, only few proteins were uniquely up-regulated in the CSIS-resilient rats, whereby Cytochrome b-c1 complex subunit 2, mitochondrial (Uqcrc2) and Voltage-dependent anion-selective channel protein 1 (Vdac1) were uniquely down-regulated. Identified altered activated pathways and potential protein biomarkers may help us better understand the molecular mechanisms underlying synaptic neurotransmission in MD or resilience, crucial for development of new therapeutics.
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Hipocampo/metabolismo , Resiliencia Psicológica/fisiología , Aislamiento Social , Estrés Psicológico/metabolismo , Sinapsis/metabolismo , Animales , Masculino , Proteómica , Ratas , Ratas WistarRESUMEN
Antidepressant fluoxetine (Flx) is the first therapeutic choice for the treatment of major depression (MD), however neuroanatomical spots of its action remain unclear. Immunohistochemical detection of c-Fos protein expression has been used for mapping activated neuronal circuits upon various stressors and drugs. We investigated the effect of 3 weeks of Flx treatment (15 mg/kg/day) on changes in neuronal activity, by mapping the number of c-Fos+ cells, in several brain subregions in adult male rats of control and following 3 weeks of chronic social isolation (CSIS), an animal model of depression. The aim was to identify brain subregions activated by vehicle or Flx treatment in both controls or simultaneously applied with CSIS. Flx prevented depressive- and anxiety-like behaviors in CSIS rats. In controls, Flx increased the number of c-Fos+ cells in the anterior/posterior piriform cortex (aPirCx, pPirCx), retrosplenial cortex dysgranular (RSD) and granular, c region (RSGc), dorsal hippocampal subregions (CA1d, CA2, CA3d, DGd), lateral habenula (LHB), paraventricular thalamic nucleus, posterior part (PVP) and lateral/basolateral complex of amygdala (LA/BL). CSIS-induced neuronal activation was observed in brain subregions implicated in mood and other mental disorders such as aPirCx, pPirCx, caudate putamen (CPu), acumbens nucleus shell (AcbSh), RSD, RSGc, DGd, PVP and LA/BL. Flx increased neuronal activation in both controls and CSIS rats in the CA1d, CA2, CA3d, PVP, LA/BL, while in striatum increased neuronal activation was observed only in CSIS. Our data identify activated CSIS-related brain subregions and/or Flx treatment, in which Flx increased c-Fos protein expression in CSIS rats.
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Antidepresivos de Segunda Generación/uso terapéutico , Fluoxetina/uso terapéutico , Sistema Límbico/efectos de los fármacos , Neuronas/efectos de los fármacos , Aislamiento Social , Estrés Psicológico/tratamiento farmacológico , Factores de Edad , Animales , Antidepresivos de Segunda Generación/farmacología , Enfermedad Crónica , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Depresión/tratamiento farmacológico , Depresión/metabolismo , Depresión/patología , Fluoxetina/farmacología , Giro del Cíngulo/efectos de los fármacos , Giro del Cíngulo/metabolismo , Giro del Cíngulo/patología , Sistema Límbico/metabolismo , Sistema Límbico/patología , Masculino , Neuronas/metabolismo , Neuronas/patología , Ratas , Ratas Wistar , Estrés Psicológico/metabolismo , Estrés Psicológico/patologíaRESUMEN
AIMS: To examine the differences in the hippocampal proteome profiles of resilience or susceptibility to chronic social isolation (CSIS), animal model of depression, and to identify biomarkers that can distinguish the two. MAIN METHODS: Comparative subproteomic approach was used to identify changes in hippocampal cytosol and nonsynaptic mitochondria (NSM) of CSIS-resilient compared to CSIS-sensitive or control rats. The resilient and sensitive phenotypes of CSIS rats were distinguished based on their sucrose preference values. Selected proteins were validated by Western blot or immunofluorescence. KEY FINDINGS: Predominantly down-regulated processes such as cytosolic cytoskeleton organization, the calcium signaling pathway, ubiquitin proteasome degradation, redox system, malate/aspartate shuttling and glutamate metabolism in CSIS-resilient compared to CSIS-sensitive rats were found. Decreased protein expression of glycolytic enzymes with simultaneous increased expression of Aco2 involved in tricarboxylic acid cycle and expression of several subunits composing oxidative phosphorylation involved enzymes (Uqcrc2, Atp5f1a, Atp5f1b) were found, indicating shift in energy production from glycolysis to oxidative phosphorylation in NSM. The four-fold higher level of mitochondrial glyceraldehyde-3-phosphate dehydrogenase of resilient rats indicated its transfer from the cytosol to the NSM. An increased level of transketolase along with the reduced pyruvate kinase level suggested an activated pentose phosphate pathway in CSIS-resilient relative to control rats. Cytosolic up-regulated CSIS proteins were implicated in antioxidative and proteasomal systems, while down-regulated NSM protein was involved in oxidative phosphorylation. SIGNIFICANCE: The identified altered activated pathways and potential biomarkers enhance understanding of molecular mechanisms underlying resilience or susceptibility to CSIS, crucial in developing new therapeutic strategies.
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Glucólisis , Hipocampo/metabolismo , Mitocondrias/metabolismo , Fosforilación Oxidativa , Proteómica , Resiliencia Psicológica , Estrés Psicológico/metabolismo , Animales , Biomarcadores/metabolismo , Masculino , Fenotipo , Ratas , Aislamiento SocialRESUMEN
Chronic social stress and/or pharmacological treatments differentially modulate the expression of c-Fos, a marker of neuronal activity, in subregions of the rat brain. Here, we examined the effect of the atypical antipsychotic Clozapine (Clz) (20â¯mg/kg/day for 3 weeks) on the neuronal activation pattern of c-Fos protein expression in stress-relevant brain subregions of adult male Wistar rats exposed to chronic social isolation (CSIS: 3 weeks), an animal model of depression and schizophrenia, and controls. The protein expression of c-Fos was also used to map neuronal populations in brain subregions activated by CSIS alone. Subregions which showed significantly increased c-Fos protein expression following CSIS included the retrosplenial cortex (RSC), (subregions:RSC granular cortex, c region (RSGc) and dysgranular (RSD)), dentate gyrus, dorsal (DGd), paraventricular thalamic nucleus, posterior part (PVP), lateral (LA)/basolateral (BL) complex of amygdala, caudate putamen (CPu) and accumbens nucleus, shell (AcbSh). Increases in c-Fos protein expression in the RSGc, RSD, DGd, PVP, LA/BL complex of amygdala and striatum (CPu, Acb Core (AcbC) and AcbSh) following Clz treatment in controls were found. Clz applied simultaneously with CSIS modulated neuronal activity in CPu, AcbC and AcbSh subregions compared to CSIS alone, increasing c-Fos protein expression. Furthermore, Clz revealed synergistic effects with CSIS in the CA1d and PVP. These identified neural circuits reflect brain subregions activated following CSIS and/or Clz administration. These data further contribute to the understanding of the effectiveness of Clz in the modulation of brain subregion activation in response to CSIS.
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Clozapina/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Estrés Psicológico/metabolismo , Animales , Antipsicóticos/farmacología , Encéfalo/metabolismo , Clozapina/farmacología , Cuerpo Estriado/efectos de los fármacos , Depresión/metabolismo , Modelos Animales de Enfermedad , Giro del Cíngulo/metabolismo , Masculino , Neostriado/metabolismo , Neuronas/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Ratas , Ratas Wistar , Esquizofrenia/tratamiento farmacológico , Aislamiento Social/psicología , Estrés Psicológico/tratamiento farmacológicoRESUMEN
Physical exercise and chronic social stress are both known to impact general health and hypothalamic-pituitary-adrenal (HPA) axis function, albeit typically in opposing directions. Therefore, the question we investigated in this study was how these two factors - physical exercise and chronic social isolation - would interact when presented simultaneously in a female rodent model. Adult female prairie voles were separated into four experimental groups: (1) isolated without wheel access, (2) isolated with wheel access, (3) paired without wheel access, and (4) paired with wheel access. Plasma, hair, and adrenal glands were sampled to investigate changes in stress physiology. Our results indicate that, when isolated, wheel access had a mitigating effect on HPA activity. However, in paired animals, wheel access had the opposite effect, as both adrenal mass and increase in hair corticosterone concentrations were greater in paired animals with wheel access. Strong correlations were detected between change in hair corticosterone and adrenal mass, while no correlations were found between plasma corticosterone and either of the other markers. These results imply that the HPA axis is highly sensitive to both the social environment and the physical demands placed on the individual, and that when investigating the effects of chronic isolation, both hair corticosterone and adrenal mass may be more reliable markers than a single plasma corticosterone sample.
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Sistema Hipotálamo-Hipofisario/fisiología , Condicionamiento Físico Animal/fisiología , Sistema Hipófiso-Suprarrenal/fisiología , Medio Social , Aislamiento Social , Estrés Fisiológico/fisiología , Estrés Psicológico/fisiopatología , Animales , Arvicolinae , Corticosterona/análisis , Femenino , MasculinoRESUMEN
Dysregulation of GABAergic system is becoming increasingly associated with depression, psychiatric disorder that imposes severe clinical, social and economic burden. Special attention is paid to the fast-spiking parvalbumin-positive (PV+) interneurons, GABAergic neurons which are highly susceptible to redox dysregulation and oxidative stress and implicated in a variety of psychiatric diseases. Here we analyzed the number of PV+ and cleaved caspase-3-positive (CC3+) cells in the rat medial prefrontal cortical (mPFC) subregions following chronic social isolation (CSIS), an animal model of depression and schizophrenia. Also, we examined potential protective effects of antidepressant fluoxetine (FLX) and atypical antipsychotic clozapine (CLZ) on the number of these cells in mPFC subregions, when applied parallel with CSIS in doses that correspond to therapeutically effective ones in patients. Immunofluorescence analysis revealed decreased number of PV+ cells in cingulate cortex area 1, prelimbic area (PrL), infralimbic area (IL) and dorsal peduncular cortex of the mPFC in isolated rats, which coincided with depressive- and anxiety-like behaviors. In addition, CSIS-induced increase in the number of CC3+ cells was detected in aforementioned subregions of mPFC. Treatments with either FLX or CLZ prevented behavioral changes, decrease in PV+ and increase in CC3+ cell numbers in PrL and IL subregions in isolated rats. These results indicate the importance of intact GABAergic signaling in these areas for resistance against CSIS-induced behavioral changes, as well as subregion-specific protective effects of FLX and CLZ in mPFC of CSIS rats.
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Clozapina/farmacología , Fluoxetina/farmacología , Fármacos Neuroprotectores/farmacología , Parvalbúminas/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Aislamiento Social , Animales , Caspasa 3/metabolismo , Recuento de Células/estadística & datos numéricos , Depresión/metabolismo , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , RatasRESUMEN
The dysfunction of parvalbumin-positive (PV+) interneurons, the most abundant type of hippocampal GABAergic inhibitory interneuron, has been implicated in mood disorders. We recently reported that adult male Wistar rats exposed to three weeks of social isolation show depressive- and anxiety-like behaviors and a reduced number of PV+ interneurons in all hippocampal subregions. As GABA neurotransmission has been proposed as a potential therapeutic target of antidepressant and antipsychotic medications, we examined whether treatment with the antidepressant fluoxetine (Flx) (15â¯mg/kg/day) or the antipsychotic clozapine (Clz) (20â¯mg/kg/day) during three weeks of social isolation in rats offered protection from the isolation stress-induced reduction in the number of PV+ interneurons in hippocampal subregions. Using immunofluorescence analysis, we revealed that both chronic Flx and Clz partially prevented the isolation-induced changes. Flx prevented the reduction in the number of PV+ interneurons in the CA2, CA3, without affecting the CA1 and dentate gyrus DG areas, whereas Clz prevented this decrement in the CA2, CA3 and DG regions but not in CA1 areas. Moreover, Flx increased the number of PV+ interneurons in CA1 in control animals. These findings suggest that chronic administration of Flx or Clz may offer partial protection from social isolation stress via modulation of the hippocampal GABAergic system.
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Antidepresivos de Segunda Generación/farmacología , Antipsicóticos/farmacología , Clozapina/farmacología , Fluoxetina/farmacología , Hipocampo/efectos de los fármacos , Aislamiento Social , Animales , Recuento de Células , Hipocampo/metabolismo , Hipocampo/patología , Interneuronas/efectos de los fármacos , Interneuronas/metabolismo , Interneuronas/patología , Masculino , Parvalbúminas/metabolismo , Distribución Aleatoria , Ratas Wistar , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Estrés Psicológico/patologíaRESUMEN
Brain oxidative stress and neuroinflammation are implicated in psychiatric disorders. Thus, it is important to investigate the effects of individual psychotropic agents on antioxidative defense and proinflammatory mediators in brain regions associated with these disorders. Psychosocial stress is recognized as a threat to mental health, and the hippocampus is a primary target of stress-related damage. Chronic social isolation (CSIS) is a mild psychosocial stress used to model the pathophysiology of depression. We examined the antioxidative and anti-inflammatory potential of the antidepressant fluoxetine (FLX) and atypical antipsychotic clozapine (CLZ) in the hippocampus in the CSIS model of depression. We measured the effects of FLX and CLZ on depressive- and anxiety-like behaviors in non-stressed rats and rats exposed to 21d of CSIS. We further evaluated the content of reduced glutathione (GSH), the protein expression and activity of the GSH-related enzymes, the subcellular localization of nuclear factor-kappa B (NF-κB) and protein levels of proinflammatory mediators cyclooxygenase-2 (COX-2), interleukin-1beta (IL-1ß), and tumor necrosis factor-alpha (TNF-α) in these groups of rats. CSIS resulted in an increase in depressive- and anxiety-like behaviors that corresponded with compromised glutathione peroxidase (GPx)-mediated antioxidative defense and increased TNF-α, but not with changes in NF-κB, IL-1ß and COX-2 levels. FLX and CLZ, applied during CSIS, prevented the behavioral changes associated with CSIS, and inhibited the increase in TNF-α, but did not affect GPx-mediated antioxidative defense. Furthermore, both drugs decreased hippocampal GPx activity when applied to non-stressed rats. These results emphasize the significance of hippocampal TNF-α-mediated proinflammmatory signaling in the pathophysiology of depressive symptoms and the importance of the anti-inflammatory action of both FLX and CLZ in the prevention of these symptoms.
Asunto(s)
Ansiolíticos/farmacología , Antidepresivos de Segunda Generación/farmacología , Clozapina/farmacología , Fluoxetina/farmacología , Hipocampo/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Ansiolíticos/uso terapéutico , Antidepresivos de Segunda Generación/uso terapéutico , Ansiedad/tratamiento farmacológico , Clozapina/uso terapéutico , Fluoxetina/uso terapéutico , Hipocampo/metabolismo , Masculino , FN-kappa B/metabolismo , Ratas , Ratas WistarRESUMEN
Chronic psychosocial stress modulates brain antioxidant systems and causes neuroinflammation that plays a role in the pathophysiology of depression. Although the antidepressant fluoxetine (FLX) represents the first-line treatment for depression and the atypical antipsychotic clozapine (CLZ) is considered as a second-line treatment for psychotic disorders, the downstream mechanisms of action of these treatments, beyond serotonergic or dopaminergic signaling, remain elusive. We examined behavioral changes, glutathione (GSH)-dependent defense and levels of proinflammatory mediators in the prefrontal cortex (PFC) of adult male Wistar rats exposed to 21days of chronic social isolation (CSIS). We also tested the ability of FLX (15mg/kg/day) or CLZ (20mg/kg/day), applied during CSIS, to prevent stress-induced changes. CSIS caused depressive- and anxiety-like behaviors, compromised GSH-dependent defense, and induced nuclear factor-kappa B (NF-κB) activation with a concomitant increase in cytosolic levels of proinflammatory mediators cyclooxigenase-2, interleukin-1beta and tumor necrosis factor-alpha in the PFC. NF-κB activation and proinflammatory response in the PFC were not found in CSIS rats treated with FLX or CLZ. In contrast, only FLX preserved GSH content in CSIS rats. CLZ not only failed to protect against CSIS-induced GSH depletion, but it diminished its levels when applied to non-stressed rats. In conclusion, prefrontal cortical GSH depletion and the proinflammatory response underlying depressive- and anxiety-like states induced by CSIS were prevented by FLX. The protective effect of CLZ, which was equally effective as FLX on the behavioral level, was limited to proinflammatory components. Hence, different mechanisms underlie the protective effects of these two drugs in CSIS rats.
Asunto(s)
Antidepresivos/uso terapéutico , Clozapina/uso terapéutico , Citocinas/metabolismo , Fluoxetina/uso terapéutico , Glutatión/metabolismo , Trastornos del Humor/tratamiento farmacológico , Corteza Prefrontal/metabolismo , Animales , Mecanismos de Defensa , Modelos Animales de Enfermedad , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Masculino , Trastornos del Humor/etiología , Trastornos del Humor/patología , NADP/metabolismo , FN-kappa B , Óxido Nítrico Sintasa de Tipo II/metabolismo , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Wistar , Aislamiento Social/psicologíaRESUMEN
OBJECTIVES: Xiaochaihutang (XCHT) has antidepressant effects in multiple animal models of depression in our previous studies. But the antidepressant effects and exact mechanisms of XCHT in a rat model of chronic social isolation stress (CSIS) have never been studied. We therefore aimed to investigate the effects of XCHT on depressive/anxiety-related behaviours of CSIS-exposed rats and understand the neurological mechanism involving neurogenesis. METHODS: We established the CSIS model and then investigated the effects of XCHT on behavioural change. HPLC-MS/MS was adopted to quantify neurotransmitter levels in the cerebrospinal fluid (CSF). Immunofluorescence technology was used to study the effects of XCHT on neurogenesis; while expressions of 5-HT1A receptor signalling pathway in the hippocampus were measured using Western blotting. KEY FINDINGS: Xiaochaihutang significantly alleviated depressive/anxiety-like behaviours of CSIS-exposed rats. XCHT significantly regulated levels of monoamine neurotransmitters in the CSF without affecting Glu, GABA and ACh. XCHT also significantly increased neurogenesis in CSIS-exposed rats. Additionally, XCHT reversed CSIS-induced decrease of 5-HT1A receptor expression and promoted the expression of BDNF in the hippocampus. CONCLUSION: Our results suggest that XCHT could significantly regulate the depressive/anxiety-like behaviours induced by CSIS, which are likely attributed to the promotion of hippocampal neurogenesis and neurotrophin expressions through the activation of serotonergic system.
Asunto(s)
Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Trastorno Depresivo/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Estrés Psicológico/tratamiento farmacológico , Animales , Depresión/metabolismo , Trastorno Depresivo/metabolismo , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Neurogénesis/efectos de los fármacos , Neurotransmisores/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/metabolismo , Serotonina/metabolismo , Estrés Psicológico/metabolismoRESUMEN
Olanzapine, an atypical antipsychotic, is efficient in stress associated psychiatric diseases, but its effect on the liver, a primary organ for drug activation and detoxification, still remains unclear. The effect of olanzapine administration (7.5mg/kg/day), on rat hepatic glutathione (GSH)-dependent defense and proinflammatory cytokines following 6weeks of chronic social isolation (CSIS), which causes depressive- and anxiety-like behavior in adult male Wistar rats, was investigated. The subcellular distribution of nuclear factor-κB (NF-κB), cytosolic inducible nitric oxide synthase (iNOS) protein levels and hepatic histological alterations were also determined. Decreased GSH content and glutathione reductase activity associated with increased catalase and glutathione S-transferase activity following CSIS indicated hepatic oxidative stress. Moreover, CSIS caused NF-κB nuclear translocation and the concomitant increase in iNOS together with increase in interleukin-1beta and tumor necrosis factor alpha protein levels, but no effect on interleukin-6. Olanzapine treatment suppressed NF-κB activation and iNOS expression and caused modulation of GSH-dependent defense systems but failed to reverse CSIS-induced increase in hepatic proinflammatory cytokines. Portal inflammation, focal hepatocyte necrosis and an increased number of Kupffer cells in CSIS rats (vehicle- or olanzapine-treated) were found. Olanzapine-treated socially reared rats showed portal inflammation and focal hepatocyte necrosis. Data suggest that CSIS compromised GSH-dependent defense, triggered a proinflammatory response and histological alterations in rat liver. Olanzapine treatment partially reversed the alterations in hepatic GSH-dependent defense, but showed no anti-inflammatory effect suggesting that it may provide protective effect against hepatic CSIS-induced oxidative stress, but not against inflammation.