RESUMO
The menopause transition is a vulnerable period for developing both psychiatric and metabolic disorders, and both can be enhanced by stressful events worsening their effects. The present study aimed to evaluate whether a cafeteria diet (CAF) combined with chronic variable stress (CVS) exacerbates anxious- or depressive-like behavior and neuronal activation, cell proliferation and survival, and microglia activation in middle-aged ovariectomized (OVX) rats. In addition, body weight, lipid profile, insulin resistance, and corticosterone as an index of metabolic changes or hypothalamus-pituitary-adrenal (HPA) axis activation, and the serum pro-inflammatory cytokines IL-6, IL-ß, and TNFα were measured. A CAF diet increased body weight, lipid profile, and insulin resistance. CVS increased corticosterone and reduced HDL. A CAF produced anxiety-like behaviors, whereas CVS induced depressive-like behaviors. CVS increased serum TNFα independently of diet. A CAF and CVS separately enhanced the percentage of Iba-positive cells in the hippocampus; the combination of factors further increased Iba-positive cells in the ventral hippocampus. A CAF and CVS increased the c-fos-positive cells in the hippocampus; the combination of factors increased the number of positive cells expressing c-fos in the ventral hippocampus even more. The combination of a CAF and CVS generates a slight neuroinflammation process and neuronal activation in a hippocampal region-specific manner and differentially affects the behavior.
Assuntos
Corticosterona , Resistência à Insulina , Menopausa , Microglia , Proteínas Proto-Oncogênicas c-fos , Animais , Feminino , Ratos , Ansiedade/etiologia , Ansiedade/psicologia , Peso Corporal , Depressão/etiologia , Dieta/efeitos adversos , Lipídeos , Menopausa/metabolismo , Microglia/metabolismo , Estresse Psicológico/metabolismo , Fator de Necrose Tumoral alfa , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
Introduction: Natural products such as phytoestrogens-enriched foods or supplements have been considered as an alternative therapy to reduce depressive symptoms associated with menopause. It is known that the aqueous extract of Punica granatum (AE-PG) exerts antidepressant-like effects by activating ß-estrogen receptors and facilitates the antidepressant response of the clinical drug citalopram (CIT). However, the effects on neuroplasticity are unknown. Objectvie investigated the antidepressant-like response of combining AE-PG and CIT at sub-optimal doses, analyzing their effects on the formation and maturation of dendrite spines in granule cells as well as on the dendrite complexity. Methods: Ovariectomized Wistar rats (3-month-old) were randomly assigned to one of the following groups: A) control (saline solution as vehicle of CIT and AE-PG, B) AE-PG at a sub-threshold dose (vehicle of CIT plus AE-PG at 0.125 mg/kg), C) CIT at a sub-threshold dose (0.77 mg/kg plus vehicle of AE-PG), and D) a combination of CIT plus AE-PG (0.125 mg/kg and 0.77 mg/kg, respectively). All rats were treated intraperitoneally for 14 days. Antidepressant-like effects were evaluated using the force swimming test test (FST). The complexity of dendrites and the number and morphology of dendrite spines of neurons were assessed in the dentate gyrus after Golgi-Cox impregnation. The expressions of the mature brain-derived neurotrophic factor (mBDNF) in plasma and of mBDNF and synaptophysin in the hippocampus, as markers of synaptogenesis, were also determined. Results: Administration of CIT combined with AE-PG, but not alone, induced a significant antidepressant-like effect in the FST with an increase in the dendritic complexity and the number of dendritic spines in the dentate gyrus (DG) of the hippocampus, revealed by the thin and stubby categories of neurons at the granular cell layer. At the same time, an increase of mBDNF and synaptophysin expression was observed in the hippocampus of rats that received the combination of AE-PG and CIT.
RESUMO
Melatonin is a hormone synthesized by the pineal gland with neuroprotective and neurodevelopmental effects. Also, melatonin acts as an antidepressant by modulating the generation of new neurons in the dentate gyrus of the hippocampus. The positive effects of melatonin on behavior and neural development may suggest it is used for reverting stress but also for the alterations produced by chemotherapeutic drugs influencing behavior and brain plasticity. In this sense, temozolomide, an alkylating/anti-proliferating agent used in treating brain cancer, is associated with decreased cognitive functions and depression. We hypothesized that melatonin might prevent the effects of temozolomide on depression- and anxiety-like behavior by modulating some aspects of the neurogenic process in adult Balb/C mice. Mice were treated with temozolomide (25 mg/kg) for three days of two weeks, followed by melatonin (8 mg/kg) for fourteen days. Temozolomide produced short- and long-term decrements in cell proliferation (Ki67-positive cells: 54.89% and 53.38%, respectively) and intermediate stages of the neurogenic process (doublecortin-positive cells: 68.23% and 50.08%, respectively). However, melatonin prevented the long-term effects of temozolomide with the increased number of doublecortin-positive cells (47.21%) and the immunoreactivity of 2' 3'-Cyclic-nucleotide-3 phosphodiesterase (CNPase: 82.66%), an enzyme expressed by mature oligodendrocytes, in the hilar portion of the dentate gyrus. The effects of melatonin in the temozolomide group occurred with decreased immobility in the forced swim test (45.55%) but not anxiety-like behavior. Thus, our results suggest that melatonin prevents the harmful effects of temozolomide by modulating doublecortin cells, hilar oligodendrocytes, and depression-like behavior tested in the forced swim test. Our study could point out melatonin's beneficial effects for counteracting temozolomide's side effects.
Assuntos
Depressão , Melatonina , Animais , Camundongos , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Proteínas do Domínio Duplacortina , Melatonina/farmacologia , Camundongos Endogâmicos BALB C , Neurônios , Temozolomida/efeitos adversos , Temozolomida/farmacologiaRESUMO
Depression is a neuropsychiatric disorder with a high impact on the worldwide population. To overcome depression, antidepressant drugs are the first line of treatment. However, pre-clinical studies have pointed out that antidepressants are not entirely efficacious and that the quality of the living environment after stress cessation may play a relevant role in increasing their efficacy. As it is unknown whether a short daily exposure to environmental enrichment during chronic stress and antidepressant treatment will be more effective than just the pharmacological treatment, this study analyzed the effects of fluoxetine, environmental enrichment, and their combination on depressive-associated behavior. Additionally, we investigated hippocampal neurogenesis in mice exposed to chronic mild stress. Our results indicate that fluoxetine reversed anhedonia. Besides, fluoxetine reversed the decrement of some events of the hippocampal neurogenic process caused by chronic mild stress. Conversely, short daily exposure to environmental enrichment changed the deterioration of the coat and anhedonia. Although, this environmental intervention did not produce significant changes in the neurogenic process affected by chronic mild stress, fluoxetine plus environmental enrichment showed similar effects to those caused by environmental enrichment to reverse depressive-like behaviors. Like fluoxetine, the combination reversed the declining number of Ki67, doublecortin, calretinin cells and mature newborn neurons. Finally, this study suggests that short daily exposure to environmental enrichment improves the effects of fluoxetine to reverse the deterioration of the coat and anhedonia in chronically stressed mice. In addition, the combination of fluoxetine with environmental enrichment produces more significant effects than those caused by fluoxetine alone on some events of the neurogenic process. Thus, environmental enrichment improves the benefits of pharmacological treatment by mechanisms that need to be clarified.
Assuntos
Anedonia/efeitos dos fármacos , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estresse Psicológico/fisiopatologia , Anedonia/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Calbindina 2/metabolismo , Proliferação de Células , Proteína Duplacortina/metabolismo , Meio Ambiente , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Antígeno Ki-67/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Estresse FisiológicoRESUMO
Menopause, natural or surgical, might facilitate the onset of psychiatric pathologies. Some reports suggest that their severity could increase if the decline of ovarian hormones occurs abruptly and before natural endocrine senescence. Therefore, we compared the effects of ovariectomy on microglia's morphological alterations, the complexity of newborn neurons, and the animal's ability to cope with stress. Young adult (3 months) and middle-aged (15 months) female Wistar rats were subjected to an ovariectomy (OVX) or were sham-operated. After 3 weeks, animals were assigned to one of the following independent groups: (1) young adult OVX + no stress; (2) young adult sham + no stress; (3) young adult OVX + stress; (4) young adult sham + stress; (5) middle-aged OVX + no stress; (6) middle-aged sham + no stress; (7) middle-aged OVX + stress; (8) middle-aged sham + stress. Acute stress was induced by forced swimming test (FST) exposure. Immobility behavior was scored during FST and 30 min after; animals were euthanized, their brains collected and prepared for immunohistochemical detection of Iba-1 to analyze morphological alterations in microglia, and doublecortin (DCX) detection to evaluate the dendrite complexity of newborn neurons. OVX increased immobility behavior, induced microglia morphological alterations, and reduced dendrite complexity of newborn neurons in young adult rats. FST further increased this effect. In middle-aged rats, the main effects were related to the aging process without OVX or stress exposure. In conclusion, surgical menopause favors in young adult rats, but not in middle-aged, the vulnerability to develop immobility behavior, retracted morphology of microglial cells, and decreased dendrite complexity of newborn neurons.
Assuntos
Microglia , Estresse Psicológico , Animais , Dendritos , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Feminino , Humanos , Proteínas Associadas aos Microtúbulos , Neurônios , Neuropeptídeos , Ovariectomia , Ratos , Ratos WistarRESUMO
Depression may be precipitated by the negative impact of chronic stress, which is considered to play a key role in this neuropsychiatric disorder. Interestingly, depressed patients show decreased levels of melatonin. This hormone acts pro-neurogenic and exhibits anti-depressant effects in rodent models of predictive antidepressant-like effects. However, the benefits of melatonin in reversing the deleterious effects of chronic mild stress on the alterations in behaviour and in the neurogenic niche of the hippocampus in male BALB/c mice are unknown. In this study, we compared the effects of melatonin (2.5â¯mg/kg) and citalopram (5â¯mg/kg), an antidepressant drug belonging to the selective serotonin reuptake inhibitors, in male BALB/c mice exposed to chronic mild stress (CMS). We also investigated the potential effects of melatonin and citalopram on microglial cells, hippocampal neurogenesis and peripheral cytokine profiles. Melatonin and citalopram induced similar antidepressant-like activities that occurred with some of the the following findings: (1) reversal of the morphological alterations in microglia; (2) reversal of the decreased immunoreactivity to CX3CL1 and CX3CR1 in the dentate gyrus; (3) positive regulation of cell proliferation, survival and complexity of the dendritic trees of doublecortin-cells; and (4) modifications of peripheral CX3CL1 expression. This outcome is consistent with the hypothesis about the antidepressant-like effect of melatonin and supports its relevance as a modulator of the niche in the dentate gyrus.
Assuntos
Quimiocina CX3CL1 , Melatonina , Animais , Depressão/tratamento farmacológico , Hipocampo , Masculino , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Microglia , NeurogêneseRESUMO
Adult neurogenesis occurs in the dentate gyrus (DG) of the hippocampus. New neurons help to counteract the effects of stress and several interventions including antidepressant drugs, environmental modifications and internal factors act pro-neurogenic with consequences in the dorsal and ventral DG. Melatonin, the main product synthesized by the pineal gland, induces antidepressant-like effects and modulates several events of the neurogenic process. However, the information related to the capability of melatonin to modulate dendrite maturation and complexity in the dorsal and ventral regions of the DG and their correlation with its antidepressant-like effect is absent. Thus, in this study, we analyzed the impact of melatonin (0, 0.5, 1, 2.5, 5 or 10 mg/kg) administered daily for fourteen days on the number, dendrite complexity and distribution of doublecortin (DCX)-cells in the dorsal-ventral regions of the DG in male Balb/C mice. Doublecortin is a microtubule-associated protein that is expressed during the course of dendritic maturation of newborn neurons. Also, we analyzed the impact of melatonin on despair-like behavior in the forced swim test. We first found a significant increase in the number and higher dendrite complexity, mainly with the doses of 2.5, 5 and 10 mg/kg of melatonin (81%, 122%, 78%). These cells showed more complex dendritic trees in the ventral- and the dorsal- DG. Concomitantly, the doses of 5 and 10 mg/kg of melatonin decreased depressant-like behavior (76%, 82%). Finally, the data corroborate the antidepressant-like effect of melatonin and the increasing number of doublecortin-associated cells. Besides, the data indicate that melatonin favors the number and dendrite complexity of DCX-cells in the dorsal- and ventral- region of the DG, which may explain part of the antidepressant-like effect of melatonin.
Assuntos
Antidepressivos/uso terapêutico , Dendritos/efeitos dos fármacos , Dendritos/metabolismo , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Melatonina/uso terapêutico , Animais , Depressão/tratamento farmacológico , Depressão/metabolismo , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Associadas aos Microtúbulos/metabolismo , Neurogênese/efeitos dos fármacos , Neuropeptídeos/metabolismoRESUMO
Several interventions have been shown to counteract the effects of stress that may be related to improved neuroplasticity and neuronal activation. In this sense, environmental enrichment (ENR) protects against acute stress and increases neuroplasticity. It has been suggested that the use of patterned auditory stimuli (PAS) may be beneficial in increasing the effectiveness of ENR on disorders related to stress, such as depression and anxiety. Examples of PAS are classical music compositions that have interesting effects at both clinical and preclinical levels. Thus, we analyzed the effects of the exposure to PAS, represented in this study by Mozart's compositions, during ENR housing for 35 days in adult male Balb/C mice to evaluate depression-associated behavior using the forced-swim test (FST) paradigm with an additional short exposure to PAS. We found that the ENR mice that were exposed to PAS during both housing and behavioral task (ENR + PAS/FST + PAS) show decreased immobility and the number of despair episodes within a higher latency to show the first bout of immobility. Additionally, we found increased neuronal activation evaluated by the identification of activity-regulated cytoskeleton-associated protein- (Arc-) labeled cells in the prefrontal cortex (PFC) in mice exposed to PAS during housing and in the absence or presence of PAS during FST. Moreover, we found increased neuronal activation in the auditory cortex (AuCx) of mice exposed to PAS during FST. Our study suggests that the exposure to PAS during an emotional challenge decreases despair-like behavior in rodents that were previously housed in an enriched environment in combination with auditory stimuli. Thus, our data indicate that the role of the exposure to PAS as an intervention or in combination with positive environment to aid in treating neuropsychiatric disorders is worth pursuing.
Assuntos
Estimulação Acústica/métodos , Depressão , Abrigo para Animais , Estresse Fisiológico/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Corticosterona/sangue , Meio Ambiente , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/fisiologia , Estresse Psicológico/psicologia , NataçãoRESUMO
Neurogenesis constitutively occurs in the olfactory epithelium of mammals, including humans. The fact that new neurons in the adult olfactory epithelium derive from resident neural stem/progenitor cells suggests a potential use for these cells in studies of neural diseases, as well as in neuronal cell replacement therapies. In this regard, some studies have proposed that the human olfactory epithelium is a source of neural stem/progenitor cells for autologous transplantation. Although these potential applications are interesting, it is important to understand the cell biology and/or whether human neural stem/progenitor cells in the olfactory epithelium sense external signals, such as brain-derived neurotrophic factor (BDNF), that is also found in other pro-neurogenic microenvironments. BDNF plays a key role in several biological processes, including cell migration. Thus, we characterized human neural stem/progenitor cells derived from the olfactory epithelium (hNS/PCs-OE) and studied their in vitro migratory response to BDNF. In the present study, we determined that hNS/PCs-OE express the protein markers Nestin, Sox2, Ki67 and ßIII-tubulin. Moreover, the doubling time of hNS/PCs-OE was approximately 38h. Additionally, we found that hNS/PCs-OE express the BDNF receptor TrkB, and pharmacological approaches showed that the BDNF-induced (40ng/ml) migration of differentiated hNS/PCs-OE was affected by the compound K252a, which prevents TrkB activation. This observation was accompanied by changes in the number of vinculin adhesion contacts. Our results suggest that hNS/PCs-OE exhibit a migratory response to BDNF, accompanied by the turnover of adhesion contacts.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/farmacologia , Movimento Celular/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Mucosa Olfatória/citologia , Receptor trkB/metabolismo , Carbazóis/farmacologia , Adesão Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colchicina/farmacologia , Inibidores Enzimáticos/farmacologia , Histonas/metabolismo , Humanos , Alcaloides Indólicos/farmacologia , Antígeno Ki-67/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fatores de Tempo , Tubulina (Proteína)/metabolismo , Vinculina/metabolismoRESUMO
The generation of new neurons during adulthood involves local precursor cell migration and terminal differentiation in the dentate gyrus. These events are influenced by the hippocampal microenvironment. Brain-derived neurotrophic factor (BDNF) is relevant for hippocampal neuronal development and behavior. Interestingly, studies that have been performed in controlled in vitro systems that involve isolated precursor cells that were derived from the dentate gyrus (AHPCs) have shown that BDNF induces the activation of the TrkB receptor and, consequentially, might activate signaling pathways that favor survival and neuronal differentiation. Based on the fact that the cellular events of AHPCs that are induced by single factors can be studied in this controlled in vitro system, we investigated the ability of BDNF and the involvement of protein kinase C (PKC), as one of the TrkB-downstream activated signaling proteins, in the regulation of migration, here reflected by motility, of AHPCs. Precursor cells were cultured following a concentration-response curve (1-640 ng/ml) for 24 or 96 h. We found that BDNF favored cell survival without altering the viability under culture proliferative conditions of the AHPCs. Concomitantly, glial- and neuronal-differentiated precursor cells increased as a consequence of survival promoted by BDNF. Additionally, pharmacological approaches showed that BDNF (40 ng/ml)-induced migration of AHPCs was blocked with the compounds K252a and GF109203x, which prevent the activation of TrkB and PKC, respectively. The results indicate that in the in vitro migration of differentiated AHPCs it is involved the BDNF and TrkB cascade. Our results provide additional information about the mechanism by which BDNF impacts adult neurogenesis in the hippocampus.