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1.
Gene ; 806: 145920, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34455026

RESUMO

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.


Assuntos
Antidepressivos/farmacologia , Depressão/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Proteínas do Tecido Nervoso/genética , Derrota Social , Estresse Psicológico/tratamento farmacológico , Administração Oral , Animais , Depressão/genética , Depressão/fisiopatologia , Depressão/psicologia , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Japão , Masculino , Medicina Kampo/métodos , Camundongos , Camundongos Endogâmicos BALB C , Milnaciprano/farmacologia , Anotação de Sequência Molecular , Proteínas do Tecido Nervoso/classificação , Proteínas do Tecido Nervoso/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Recidiva , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia
2.
Behav Neurosci ; 135(5): 654-667, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34383514

RESUMO

The impact of stress on health and well-being is determined by the ability of an individual to cope with challenges imposed by the stressor. Animals exposed to social defeat stress show different patterns of response during confrontations, leading to distinct stress-induced consequences. Using an established resident-intruder paradigm, we explored the outcomes of adopting active or passive coping strategies during a social defeat protocol over peripheral and central nervous system (CNS) levels of inflammatory cytokines, growth factors, glucocorticoid, and oxidative stress markers in male Wistar rats. Animals that presented short latency to assume a defeated posture during confrontation-considered as susceptible to stress-exhibited increased levels of brain-derived neurotrophic factor (BDNF) in the amygdala (AMY) and in the bed nucleus of the stria terminalis (BNST), and decreased lipid peroxidation in the CNS, suggesting changes in antioxidative defenses as well as stress-induced neuroadaptations. On the other hand, animals with longer latencies to assume a submissive posture-considered to be resilient to stress-presented lower levels of CNS BDNF compared to short-latency animals and decreased enzymatic antioxidant defenses in the CNS in comparison to controls, which might indicate an increased risk of central oxidative damage. From the results, behavioral reactivity cannot be considered a predictor of success in responding to stress; however, the findings of this study reinforce the idea that exposure to stress has no predetermined negative effects. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Derrota Social , Estresse Psicológico , Adaptação Psicológica , Animais , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Ratos Wistar
3.
Life Sci ; 282: 119821, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34271059

RESUMO

AIMS: C57BL/6J mice are well-known to exhibit resilience to chronic social defeat stress (CSDS) for induction of depressive-like behavior. Establishment of protocols for reproducible induction of depressive-like behavior in C57BL/6J mice would be useful to elucidate the underlying molecular mechanisms using target gene-knock-in and -out mice whose background is generally C57BL/6J. Here, we developed a modified CSDS protocol for reproducible induction of depressive-like behavior in C57BL/6J mice, and compared the profile of their gut microbiota with that with the standard CSDS protocol. MAIN METHODS: To prevent acclimation of defeated C57BL/6J mice to aggressive ICR mice, the sensory contact following a daily 10 min-defeat episode was performed by housing an individual defeated mouse in a cage set next to a cage for the aggressor one. KEY FINDINGS: The number of attacks by ICR mice on C57BL/6J ones was significantly increased with the modified CSDS protocol, and the susceptible mice exhibited greater hippocampal inflammation and an increased immobility time in the forced swim test, compared in the case of the standard CSDS protocol, and the reproducibility was confirmed in another set of experiments. Both the standard and modified CSDS protocols changed the diversity and relative composition of gut microbiota in the susceptible mice, but there was no apparent difference in them between the standard and modified CSDS-susceptible mice. SIGNIFICANCE: We established a CSDS protocol for reproducible induction of depressive-like behavior in C57BL/6J mice, and the features of the gut microbiota were similar in the susceptible mice with and without the depressive-like behavior.


Assuntos
Comportamento Animal , Depressão/microbiologia , Microbioma Gastrointestinal , Derrota Social , Estresse Psicológico/microbiologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos ICR
4.
Phytother Res ; 35(9): 5133-5142, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34327733

RESUMO

Gastrodia elata Blume has multiple bioactive functions, such as antioxidant and antidepressant activities, immune modulation, neuroplasticity, and neuroprotection. We previously found that the water extract of G. elata exerts antidepressant-like effects in unpredictable chronic mild stress models and animals exposed to the forced swimming test. We aimed to investigate the mechanisms by which the water extract of G. elata protects against subchronic- and mild-social defeat-stress-induced dysbiosis. After a 10-day subchronic and mild-social-defeat-stress program, oral treatment with the water extract of G. elata (500 mg/kg bw) resulted in reversal of depression-like behavior. In addition, monoamine analyses showed that the water extract of G. elata normalized the 5-hydroxyindoleacetic acid:5-HT ratio in the prefrontal cortex and colon and reduced the defeat-stress-induced kynurenine:tryptophan ratio in the colon. After the 10-day subchronic and mild social-defeat-stress program, the water extract of G. elata altered the intestinal microbiome by increasing Actinobacteria levels, modulating intestinal inflammation, and shifting the relative abundances of multiple bacterial groups in the gut. Our results suggest that the water extract of G. elata exhibits a potent antidepressant-like effect via the regulation of monoaminergic neurotransmission and alteration of gut microbiota composition and function, and that it may be an effective prevention for depression.


Assuntos
Depressão , Gastrodia , Microbioma Gastrointestinal , Neurotransmissores , Extratos Vegetais , Animais , Depressão/tratamento farmacológico , Gastrodia/química , Camundongos , Neurotransmissores/metabolismo , Extratos Vegetais/farmacologia , Derrota Social
5.
Neuropsychopharmacology ; 46(9): 1594-1605, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34099867

RESUMO

The global number of patients with depression increases in correlation to exposure to social stress. Chronic stress does not trigger depression in all individuals, as some remain resilient. The underlying molecular mechanisms that contribute to stress sensitivity have been poorly understood, although revealing the regulation of stress sensitivity could help develop treatments for depression. We previously found that striatal Shati/Nat8l, an N-acetyltransferase, was increased in a depression mouse model. We investigated the roles of Shati/Nat8l in stress sensitivity in mice and found that Shati/Nat8l and brain-derived neurotrophic factor (BDNF) levels in the dorsal striatum were increased in stress-susceptible mice but not in resilient mice exposed to repeated social defeat stress (RSDS). Knockdown of Shati/Nat8l in the dorsal striatum induced resilience to RSDS. In addition, blockade of BDNF signaling in the dorsal striatum by ANA-12, a BDNF-specific receptor tropomyosin-receptor-kinase B (TrkB) inhibitor, also induced resilience to stress. Shati/Nat8l is correlated with BDNF expression after RSDS, and BDNF is downstream of Shati/Nat8l pathways in the dorsal striatum; Shati/Nat8l is epigenetically regulated by BDNF via histone acetylation. Our results demonstrate that striatal Shati/Nat8l-BDNF pathways determine stress sensitivity through epigenetic regulation. The striatal Shati/Nat8l-BDNF pathway could be a novel target for treatments of depression and could establish a novel therapeutic strategy for depression patients.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Derrota Social , Acetiltransferases/genética , Animais , Corpo Estriado/metabolismo , Epigênese Genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL
6.
Brain Behav Immun ; 96: 200-211, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34062230

RESUMO

Major depressive disorder (MDD) is a common and serious psychiatric disease that involves brain inflammation. Bifidobacterium breve is commonly used as a probiotic and was shown to improve colitis and allergic diseases by suppressing the inflammatory response. Heat-sterilized B. breve has beneficial effects on inflammation. We hypothesize, therefore, that this probiotic might reduce depression symptoms. We tested this is a mouse model of social defeat stress. C57BL/6J mice exposed to chronic social defeat stress (CSDS) for five consecutive days developed a mild depression-like behavior characterized by a social interaction impairment. CSDS also altered the gut microbiota composition, such as increased abundance of Bacilli, Bacteroidia, Mollicutes, and Verrucomicrobiae classes and decreased Erysipelotrichi class. The prophylactic effect of heat-sterilized B. breve as a functional food ingredient was evaluated on the depression-like behavior in mice. The supplementation started two weeks before and lasted two weeks after the last exposure to CSDS. Two weeks after CSDS, the mice showed deficits in social interaction and increased levels of inflammatory cytokines, including interleukin-1ß (IL-1ß) in the prefrontal cortex (PFC) and hippocampus (HIP). Heat-sterilized B. breve supplementation significantly prevented social interaction impairment, suppressed IL-1ß increase in the PFC and HIP, and modulated the alteration of the gut microbiota composition induced by CSDS. These findings suggest that heat-sterilized B. breve prevents depression-like behavior and IL-1ß expression induced by CSDS through modulation of the gut microbiota composition in mice. Therefore, heat-sterilized B. breve used as an ingredient of functional food might prevent MDD.


Assuntos
Bifidobacterium breve , Transtorno Depressivo Maior , Animais , Depressão/prevenção & controle , Temperatura Alta , Interleucina-1beta , Camundongos , Camundongos Endogâmicos C57BL , Comportamento Social , Derrota Social , Estresse Psicológico
7.
Neuropsychopharmacology ; 46(9): 1584-1593, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33941861

RESUMO

Territorial reactive aggression in mice is used to study the biology of aggression-related behavior and is also a critical component of procedures used to study mood disorders, such as chronic social defeat stress. However, quantifying mouse aggression in a systematic, representative, and easily adoptable way that allows direct comparison between cohorts within or between studies remains a challenge. Here, we propose a structural equation modeling approach to quantify aggression observed during the resident-intruder procedure. Using data for 658 sexually experienced CD-1 male mice generated by three research groups across three institutions over a 10-year period, we developed a higher-order confirmatory factor model wherein the combined contributions of latency to the first attack, number of attack bouts, and average attack duration on each trial day (easily observable metrics that require no specialized equipment) are used to quantify individual differences in aggression. We call our final model the Mouse Aggression Detector (MAD) model. Correlation analyses between MAD model factors estimated from multiple large datasets demonstrate generalizability of this measurement approach, and we further establish the stability of aggression scores across time within cohorts and demonstrate the utility of MAD for selecting aggressors which will generate a susceptible phenotype in social defeat experiments. Thus, this novel aggression scoring technique offers a systematic, high-throughput approach for aggressor selection in chronic social defeat stress studies and a more consistent and accurate study of mouse aggression itself.


Assuntos
Agressão , Derrota Social , Animais , Comportamento Animal , Individualidade , Masculino , Camundongos , Padrões de Referência , Comportamento Social , Estresse Psicológico
8.
Biochem Pharmacol ; 188: 114561, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33857491

RESUMO

Major depressive disorder (MDD) is a common, chronic, recurrent disease. The existing drugs are ineffective for approximately half of patients, so the development of antidepressant drugs with novel mechanisms is urgent. Cumulative evidence has shown neuro-inflammation plays a key role in the etiology of major depressive disorder. Clinical studies implicated that bile acids, an important component of gut-brain axis, inhibit neuro-inflammation and mediate the pathophysiology of the MDD. Here, we found that ganoderic acid A (GAA) modulated bile acid receptor FXR (farnesoid X receptor), inhibited brain inflammatory activity, and showed antidepressant effects in the chronic social defeat stress depression model, tail suspension, forced swimming, and sucrose preference tests. GAA directly inhibited the activity of the NLRP3 inflammasome, and activated the phosphorylation and expression of the AMPA receptor by modulating FXR in the prefrontal cortex of mice. If we knocked out FXR or injected the FXR-specific inhibitor z-gugglesterone (GS), the antidepressant effects induced by GAA were completely abolished. These results suggest that GAA modulates the bile acid receptor FXR and subsequently regulates neuroimmune and antidepressant behaviors. GAA and its receptor FXR have potential as targets for the treatment of MDD.


Assuntos
Antidepressivos/uso terapêutico , Depressão/metabolismo , Ácidos Heptanoicos/uso terapêutico , Lanosterol/análogos & derivados , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores Citoplasmáticos e Nucleares/deficiência , Sinapses/metabolismo , Animais , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Depressão/psicologia , Ácidos Heptanoicos/farmacologia , Lanosterol/farmacologia , Lanosterol/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Receptores Citoplasmáticos e Nucleares/genética , Derrota Social , Sinapses/efeitos dos fármacos , Sinapses/genética
10.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803578

RESUMO

Relapse in the seeking and intake of cocaine is one of the main challenges when treating its addiction. Among the triggering factors for the recurrence of cocaine use are the re-exposure to the drug and stressful events. Cocaine relapse engages the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and the hippocampal dentate gyrus (DG), which are responsible for emotional and episodic memories. Moreover, D3 receptor (D3R) antagonists have recently arisen as a potential treatment for preventing drug relapse. Thus, we have assessed the impact of D3R blockade in the expression of some dopaminergic markers and the activity of the mTOR pathway, which is modulated by D3R, in the BLA and DG during the reinstatement of cocaine-induced conditioned place preference (CPP) evoked by drug priming and social stress. Reinstatement of cocaine CPP paralleled an increasing trend in D3R and dopamine transporter (DAT) levels in the BLA. Social stress, but not drug-induced reactivation of cocaine memories, was prevented by systemic administration of SB-277011-A (a selective D3R antagonist), which was able, however, to impede D3R and DAT up-regulation in the BLA during CPP reinstatement evoked by both stress and cocaine. Concomitant with cocaine CPP reactivation, a diminution in mTOR phosphorylation (activation) in the BLA and DG occurred, which was inhibited by D3R blockade in both nuclei before the social stress episode and only in the BLA when CPP reinstatement was provoked by a cocaine prime. Our data, while supporting a main role for D3R signalling in the BLA in the reactivation of cocaine memories evoked by social stress, indicate that different neural circuits and signalling mechanisms might mediate in the reinstatement of cocaine-seeking behaviours depending upon the triggering stimuli.


Assuntos
Complexo Nuclear Basolateral da Amígdala/metabolismo , Cocaína/farmacologia , Condicionamento Clássico , Giro Denteado/metabolismo , Receptores de Dopamina D3/metabolismo , Estresse Psicológico/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nitrilas/administração & dosagem , Nitrilas/farmacologia , Fosforilação/efeitos dos fármacos , Receptores de Dopamina D3/antagonistas & inibidores , Derrota Social , Serina-Treonina Quinases TOR/metabolismo , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/farmacologia
11.
PLoS Biol ; 19(3): e3000709, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33690628

RESUMO

Daily rhythms are disrupted in patients with mood disorders. The lateral habenula (LHb) and dorsal raphe nucleus (DRN) contribute to circadian timekeeping and regulate mood. Thus, pathophysiology in these nuclei may be responsible for aberrations in daily rhythms during mood disorders. Using the 15-day chronic social defeat stress (CSDS) paradigm and in vitro slice electrophysiology, we measured the effects of stress on diurnal rhythms in firing of LHb cells projecting to the DRN (cellsLHb→DRN) and unlabeled DRN cells. We also performed optogenetic experiments to investigate if increased firing in cellsLHb→DRN during exposure to a weak 7-day social defeat stress (SDS) paradigm induces stress-susceptibility. Last, we investigated whether exposure to CSDS affected the ability of mice to photoentrain to a new light-dark (LD) cycle. The cellsLHb→DRN and unlabeled DRN cells of stress-susceptible mice express greater blunted diurnal firing compared to stress-näive (control) and stress-resilient mice. Daytime optogenetic activation of cellsLHb→DRN during SDS induces stress-susceptibility which shows the direct correlation between increased activity in this circuit and putative mood disorders. Finally, we found that stress-susceptible mice are slower, while stress-resilient mice are faster, at photoentraining to a new LD cycle. Our findings suggest that exposure to strong stressors induces blunted daily rhythms in firing in cellsLHb→DRN, DRN cells and decreases the initial rate of photoentrainment in susceptible-mice. In contrast, resilient-mice may undergo homeostatic adaptations that maintain daily rhythms in firing in cellsLHb→DRN and also show rapid photoentrainment to a new LD cycle.


Assuntos
Ritmo Circadiano/fisiologia , Habenula/fisiologia , Estresse Psicológico/metabolismo , Animais , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Dorsal da Rafe/metabolismo , Habenula/citologia , Habenula/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/fisiologia , Neurônios/fisiologia , Optogenética/métodos , Serotonina/farmacologia , Derrota Social , Estresse Psicológico/fisiopatologia
12.
Biochem Biophys Res Commun ; 553: 107-113, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33765554

RESUMO

Chronic social defeat stress (CSDS) is widely applied to study of depression in rodents. 10-day CSDS was a most commonly employed paradigm but with high resilience ratio (∼30%), producing potential variation in depression-like behavioral symptoms. Whether prolonged period (21 days) of CSDS would promote less resilience and reduce behavioral variability remains unknown. We applied 10-day and 21-day CSDS paradigms to induce mouse model of depression and compared their resilience ratio and behavioral phenotypes. Mice under 21-day CSDS had significantly lower resilience ratio and greater changes in behavioral indicators relative to mice under 10-day CSDS. Behavioral indicators from 21-day CSDS paradigm had higher correlations and better prediction for susceptibility which indicating higher uniformity in behavioral phenotypes. Furthermore, a subset of behavioral indicators in 21-day CSDS had high prediction efficacy and should be first applied to screen susceptibility of CSDS. Thus, our study demonstrates that 21-day CSDS is a more robust paradigm inducing reliable depression-like behaviors relative to 10-day CSDS, and should be preferentially used in rodent studies of depression.


Assuntos
Depressão/psicologia , Resiliência Psicológica , Derrota Social , Estresse Psicológico/psicologia , Animais , Doença Crônica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo
13.
Neuropsychopharmacology ; 46(9): 1606-1616, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33692477

RESUMO

Chronic stress is a risk factor for a variety of psychiatric disorders, including depression. Although impairments to motivated behavior are a major symptom of clinical depression, little is known about the circuit mechanisms through which stress impairs motivation. Furthermore, research in animal models for depression has focused on impairments to hedonic aspects of motivation, whereas patient studies suggest that impairments to appetitive, goal-directed motivation contribute significantly to motivational impairments in depression. Here, we characterized goal-directed motivation in repeated social defeat stress (R-SDS), a well-established mouse model for depression in male mice. R-SDS impaired the ability to sustain and complete goal-directed behavior in a food-seeking operant lever-press task. Furthermore, stress-exposed mice segregated into susceptible and resilient subpopulations. Interestingly, susceptibility to stress-induced motivational impairments was unrelated to stress-induced social withdrawal, another prominent effect of R-SDS in mouse models. Based on evidence that ventral hippocampus (vHP) modulates sustainment of goal-directed behavior, we monitored vHP activity during the task using fiber photometry. Successful task completion was associated with suppression of ventral hippocampal neural activity. This suppression was diminished after R-SDS in stress-susceptible but not stress-resilient mice. The serotonin selective reuptake inhibitor (SSRI) escitalopram and ketamine both normalized vHP activity during the task and restored motivated behavior. Furthermore, optogenetic vHP inhibition was sufficient to restore motivated behavior after stress. These results identify vHP hyperactivity as a circuit mechanism of stress-induced impairments to goal-directed behavior and a putative biomarker that is sensitive to antidepressant treatments and that differentiates susceptible and resilient individuals.


Assuntos
Objetivos , Derrota Social , Animais , Comportamento Animal , Hipocampo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Motivação , Comportamento Social , Estresse Psicológico
14.
Int J Mol Sci ; 22(5)2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673448

RESUMO

There is huge scientific interest in the neuropeptide oxytocin (OXT) due to its putative capacity to modulate a wide spectrum of physiological and cognitive processes including motivation, learning, emotion, and the stress response. The present review seeks to increase the understanding of the role of OXT in an individual's vulnerability or resilience with regard to developing a substance use disorder. It places specific attention on the role of social stress as a risk factor of addiction, and explores the hypothesis that OXT constitutes a homeostatic response to stress that buffers against its negative impact. For this purpose, the review summarizes preclinical and clinical literature regarding the effects of OXT in different stages of the addiction cycle. The current literature affirms that a well-functioning oxytocinergic system has protective effects such as the modulation of the initial response to drugs of abuse, the attenuation of the development of dependence, the blunting of drug reinstatement and a general anti-stress effect. However, this system is dysregulated if there is continuous drug use or chronic exposure to stress. In this context, OXT is emerging as a promising pharmacotherapy to restore its natural beneficial effects in the organism and to help rebalance the functions of the addicted brain.


Assuntos
Ocitocina/metabolismo , Recompensa , Derrota Social , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Animais , Humanos , Inflamação , Ocitocina/fisiologia , Estresse Psicológico , Transtornos Relacionados ao Uso de Substâncias/psicologia , Transtornos Relacionados ao Uso de Substâncias/terapia
15.
Transl Psychiatry ; 11(1): 164, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33723234

RESUMO

Psychosocial stress is one of the main environmental factors contributing to the development of psychiatric disorders. In humans and rodents, chronic stress is associated with elevated inflammatory responses, indicated by increased numbers of circulating myeloid cells and activation of microglia, the brain-resident immune cells. The endocannabinoid system (ECS) regulates neuronal and endocrine stress responses via the cannabinoid receptor 1 (CB1). CB1-deficient mice (Cnr1-/-) are highly sensitive to stress, but if this involves altered inflammatory responses is not known. To test this, we exposed Cnr1+/+ and Cnr1-/- mice to chronic social defeat stress (CSDS). Cnr1-/- mice were extremely sensitive to a standard protocol of CSDS, indicated by an increased mortality rate. Therefore, a mild CSDS protocol was established, which still induced a behavioural phenotype in susceptible Cnr1-/- mice. These mice also showed altered glucocorticoid levels after mild CSDS, suggesting dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Mild CSDS induced weak myelopoiesis in the periphery, but no recruitment of myeloid cells to the brain. In contrast, mild CSDS altered microglial activation marker expression and morphology in Cnr1-/- mice. These microglial changes correlated with the severity of the behavioural phenotype. Furthermore, microglia of Cnr1-/- mice showed increased expression of Fkbp5, an important regulator of glucocorticoid signalling. Overall, the results confirm that CB1 signalling protects the organism from the physical and emotional harm of social stress and implicate endocannabinoid-mediated modulation of microglia in the development of stress-related pathologies.


Assuntos
Microglia , Derrota Social , Animais , Camundongos , Camundongos Endogâmicos C57BL , Sistema Hipófise-Suprarrenal , Receptor CB1 de Canabinoide/genética , Receptores de Canabinoides , Estresse Psicológico
16.
Transl Psychiatry ; 11(1): 125, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33589585

RESUMO

Reward and motivation deficits are prominent symptoms in many mood disorders, including depression. Similar reward and effort-related choice behavioral tasks can be used to study aspects of motivation in both rodents and humans. Chronic stress can precipitate mood disorders in humans and maladaptive reward and motivation behaviors in male rodents. However, while depression is more prevalent in women, there is relatively little known about whether chronic stress elicits maladaptive behaviors in female rodents in effort-related motivated tasks and whether there are any behavioral sex differences. Chronic nondiscriminatory social defeat stress (CNSDS) is a variation of chronic social defeat stress that is effective in both male and female mice. We hypothesized that CNSDS would reduce effort-related motivated and reward behaviors, including reducing sensitivity to a devalued outcome, reducing breakpoint in progressive ratio, and shifting effort-related choice behavior. Separate cohorts of adult male and female C57BL/6 J mice were divided into Control or CNSDS groups, exposed to the 10-day CNSDS paradigm, and then trained and tested in instrumental reward or effort-related behaviors. CNSDS reduced motivation to lever press in progressive ratio and shifted effort-related choice behavior from a high reward to a more easily attainable low reward in both sexes. CNSDS caused more nuanced impairments in outcome devaluation. Taken together, CNSDS induces maladaptive shifts in effort-related choice and reduces motivated lever pressing in both sexes.


Assuntos
Comportamento de Escolha , Derrota Social , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Motivação , Recompensa
17.
J Endocrinol ; 249(1): 19-30, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33608492

RESUMO

Stress has a major impact on the modulation of metabolism, as previously evidenced by hyperglycemia following chronic social defeat (CSD) stress in mice. Although CSD-triggered metabolic dysregulation might predispose to pre-diabetic conditions, insulin sensitivity remained intact, and obesity did not develop, when animals were fed with a standard diet (SD). Here, we investigated whether a nutritional challenge, a high-fat diet (HFD), aggravates the metabolic phenotype and whether there are particularly sensitive time windows for the negative consequences of HFD exposure. Chronically stressed male mice and controls (CTRL) were kept under (i) SD-conditions, (ii) with HFD commencing post-CSD, or (iii) provided with HFD lasting throughout and after CSD. Under SD conditions, stress increased glucose levels early post-CSD. Both HFD regimens increased glucose levels in non-stressed mice but not in stressed mice. Nonetheless, when HFD was provided after CSD, stressed mice did not differ from controls in long-term body weight gain, fat tissue mass and plasma insulin, and leptin levels. In contrast, when HFD was continuously available, stressed mice displayed reduced body weight gain, lowered plasma levels of insulin and leptin, and reduced white adipose tissue weights as compared to their HFD-treated non-stressed controls. Interestingly, stress-induced adrenal hyperplasia and hypercortisolemia were observed in mice treated with SD and with HFD after CSD but not in stressed mice exposed to a continuous HFD treatment. The present work demonstrates that CSD can reduce HFD-induced metabolic dysregulation. Hence, HFD during stress may act beneficially, as comfort food, by decreasing stress-induced metabolic demands.


Assuntos
Antígenos de Grupos Sanguíneos/análise , Dieta Hiperlipídica , Estresse Psicológico/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Dieta Hiperlipídica/psicologia , Ingestão de Energia , Teste de Tolerância a Glucose , Insulina/sangue , Leptina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/psicologia , Derrota Social , Estresse Psicológico/sangue , Ganho de Peso
18.
J Neurosci ; 41(11): 2523-2539, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33500273

RESUMO

Stress-induced depression is common worldwide. NAc, a "reward" center, is recently reported to be critical to confer the susceptibility to chronic social defeat stress (CSDS) and the depression-related outcome. However, the underlying molecular mechanisms have not been well characterized. In this study, we induced depression-like behaviors with CSDS and chronic mild stress in male mice to mimic social and environmental factors, respectively, and observed animal behaviors with social interaction test, tail suspension test, and sucrose preference test. To determine the role of neuronal nitric oxide synthase (nNOS) and its product nitric oxide (NO), we used brain region-specifically nNOS overexpression and stereotaxic injection of NO inhibitor or donor. Moreover, the downstream molecular cyclin-dependent kinase 5 (CDK5) was explored by conditional KO and gene mutation. We demonstrate that nNOS-implicated mechanisms in NAc shell (NAcSh), including increased cell number, increased protein expression levels, and increased specific enzyme activity, contribute the susceptibility to social defeat and the following depression-like behaviors. NAcSh nNOS does not directly respond to chronic mild stress but facilitates the depression-like behaviors. The increased NAcSh nNOS expression after CSDS leads to the social avoidance and depression-like behaviors in defeated mice, which is dependent on the nNOS enzyme activity and NO production. Moreover, we identify the downstream signal in NAcSh. S-nitrosylation of CDK5 by NO contributes to enhanced CDK5 activity, leading to depression-related behaviors in susceptible mice. Therefore, NAcSh nNOS mediates susceptibility to social defeat stress and the depression-like behaviors through CDK5.SIGNIFICANCE STATEMENT Stress-induced depression is common worldwide, and chronic exposure to social and psychological stressors is important cause of human depression. Our study conducted with chronic social defeat stress mice models demonstrates that nNOS in NAcSh is crucial to regulate the susceptibility to social defeat stress and the following depression-like behaviors, indicating NAcSh nNOS as the responding molecule to social factors of depression. Moreover, we discover the downstream mechanism of NAcSh nNOS in mediating the susceptibility is NO and S-nitrosylation of CDK5. Thus, NAcSh nNOS mediates susceptibility to social defeat stress through CDK5 is a potential mechanism for depression, which may interpret how the brain transduces social stress exposure into depression.


Assuntos
Quinase 5 Dependente de Ciclina/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Núcleo Accumbens/metabolismo , Derrota Social , Estresse Psicológico/metabolismo , Animais , Masculino , Camundongos
19.
J Neuroinflammation ; 18(1): 1, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402173

RESUMO

BACKGROUND: The NLRP3-mediated pyroptosis, which could be regulated by miRNA-27a, is a key player in the development of depression. Isoliquiritin is a phenolic flavonoid compound that has been demonstrated to suppress NLRP3-mediated pyroptosis. However, it is still unknown whether isoliquiritin could confer antidepressant activity via decreasing NLRP3-mediated pyroptosis by stimulating miRNA-27a. Thus, in the current study, we explored the antidepressant activity of isoliquiritin and its underlying mechanism. METHODS: Expression of miRNA-27a in depressed patients or mice was measured using qRT-PCR. Luciferase reporter assay was performed to illustrate the link between miRNA-27a and SYK. Lipopolysaccharide (LPS) and chronic social defeat stress (CSDS) depression models were established to investigate the antidepressant actions of isoliquiritin. Changes in miRNA-27a/SYK/NF-κB axis and NLRP3-mediated pyroptosis were also examined. The role of miRNA-27a in isoliquiritin-related antidepressant effect was further investigated by using miRNA-27a inhibitors and mimics of miRNA-27a. RESULTS: Our results showed the miRNA-27a expression was downregulated in the serum of depressed patients, and decreased serum and hippocampus expression of miRNA-27a were observed in rodent models of depression. SYK gene expression was significantly reduced by miRNA-27a mimic incubation. Isoliquiritin profoundly attenuated LPS or CSDS-induced depressive symptoms, as well as CSDS-induced anxiety behavior. In the hippocampus, LPS and CSDS decreased miRNA-27a mRNA expression; increased the protein levels of SYK, p-NF-κB, and NLRP3: cleaved Caspase-1, IL-1ß, and GSDMD-N: and elevated the concentration of IL-1ß, IL-6, and TNF-α, which were all restored by isoliquiritin administration. Meanwhile, isoliquiritin upregulated the hippocampal NeuN protein level, improved the survival and morphology of neurons, and decreased pyroptosis-related neuronal cell death. Moreover, isoliquiritin protected primary microglia against LPS and adenosine triphosphate (ATP) elicited NLRP3 inflammasome activation in vitro, evidenced by declined protein levels of p-NF-κB, NLRP3; cleaved Caspase-1, IL-1ß, and GSDMD-N; upregulated miRNA-27a mRNA expression; and decreased the mRNA and protein levels of SYK. Nevertheless, miRNA-27a inhibitors significantly reversed isoliquiritin-generated therapeutic efficacy in CSDS mice and in vitro. Furthermore, the cytoprotective effect of isoliquiritin was similar to that of miRNA-27a mimics in LPS and ATP-treated primary microglia. Taken together, these findings suggest that isoliquiritin possesses potent antidepressant property, which requires miRNA-27a/SYK/NF-κB axis controlled decrease of pyroptosis via NLRP3 cascade.


Assuntos
Chalcona/análogos & derivados , Depressão/metabolismo , Glucosídeos/uso terapêutico , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/efeitos dos fármacos , Quinase Syk/metabolismo , Adolescente , Adulto , Animais , Animais Recém-Nascidos , Células Cultivadas , Chalcona/farmacologia , Chalcona/uso terapêutico , Depressão/tratamento farmacológico , Depressão/psicologia , Feminino , Glucosídeos/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Piroptose/fisiologia , Derrota Social , Quinase Syk/antagonistas & inibidores , Adulto Jovem
20.
Transl Psychiatry ; 11(1): 47, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441546

RESUMO

Alterations in dopamine signalling have been implied in autism spectrum disorder (ASD), and these could be associated with the risk of developing a psychotic disorder in ASD adults. Negative social experiences and feelings of social defeat might result in an increase in dopamine functioning. However, few studies examined dopamine functioning in vivo in ASD. Here we examine whether striatal dopamine synthesis capacity is increased in ASD and associated with social defeat. Forty-four unmedicated, non-psychotic adults diagnosed with ASD and 22 matched controls, aged 18-30 years, completed a dynamic 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine positron emission tomography/computed tomography ([18F]-FDOPA PET/CT) scan to measure presynaptic dopamine synthesis capacity in the striatum. We considered unwanted loneliness, ascertained using the UCLA Loneliness Scale, as primary measure of social defeat. We found no statistically significant difference in striatal dopamine synthesis capacity between ASD and controls (F1,60 = 0.026, p = 0.87). In ASD, striatal dopamine synthesis capacity was not significantly associated with loneliness (ß = 0.01, p = 0.96). Secondary analyses showed comparable results when examining the associative, limbic, and sensorimotor sub-regions of the striatum (all p-values > 0.05). Results were similar before and after adjusting for age, sex, smoking-status, and PET/CT-scanner-type. In conclusion, in unmedicated, non-psychotic adults with ASD, striatal dopamine synthesis capacity is not increased and not associated with social defeat.


Assuntos
Transtorno do Espectro Autista , Dopamina , Adulto , Transtorno do Espectro Autista/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Di-Hidroxifenilalanina , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Derrota Social
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