RESUMO
Stressors can initiate a cascade of central and peripheral changes that modulate mesocorticolimbic dopaminergic circuits and, ultimately, behavioral response to rewards. Driven by the absence of conclusive evidence on this topic and the Research Domain Criteria framework, random-effects meta-analyses were adopted to quantify the effects of acute stressors on reward responsiveness, valuation, and learning in rodent and human subjects. In rodents, acute stress reduced reward responsiveness (g = -1.43) and valuation (g = -0.32), while amplifying reward learning (g = 1.17). In humans, acute stress had marginal effects on valuation (g = 0.25), without affecting responsiveness and learning. Moderation analyses suggest that acute stress neither has unitary effects on reward processing in rodents nor in humans and that the duration of the stressor and specificity of reward experience (i.e., food vs drugs) may produce qualitatively and quantitatively different behavioral endpoints. Subgroup analyses failed to reduce heterogeneity, which, together with the presence of publication bias, pose caution on the conclusions that can be drawn and point to the need of guidelines for the conduction of future studies in the field.
RESUMO
The link between neuroticism and the various indicators of daily cortisol fluctuations is frequently noted to be inconsistent or lacking in strength. The current study aimed to investigate the predictive capacity of both self-assessment and external evaluations of neuroticism, along with their interaction, on multiple indices of diurnal cortisol variations. This research involved the assessment of neuroticism using self-report and external evaluations among 166 working individuals, coupled with the collection of saliva samples over two consecutive workdays. Employing multilevel response surface analysis, our findings indicated that self-reported neuroticism exhibited a stronger association with cortisol indices compared to external evaluations. Additionally, the level of alignment between self-assessment and external ratings of neuroticism specifically impacted the prediction of estimates of daily cortisol production. We discuss the theoretical and practical implications of these results.
Assuntos
Ritmo Circadiano , Hidrocortisona , Neuroticismo , Saliva , Humanos , Hidrocortisona/metabolismo , Neuroticismo/fisiologia , Masculino , Feminino , Adulto , Saliva/química , Saliva/metabolismo , Ritmo Circadiano/fisiologia , Adulto Jovem , Transtornos de Ansiedade/metabolismo , Autorrelato , Pessoa de Meia-Idade , Autoavaliação (Psicologia)RESUMO
Pharmacological inhibition of fatty acid amide hydrolase (FAAH) activity has antidepressant-like effects in preclinical models of stress. In this study, we investigated whether the antidepressant-like effects of FAAH inhibition are associated with corresponding changes in gut microbial and lipidomic profiles, which are emerging as critical components in the pathophysiology of depression. Adult male Wistar rats experienced five weeks of repeated social defeat or control procedure and were treated with the FAAH inhibitor URB694 (0.3 mg/kg/day, i.p.) or vehicle starting from the third week. Repeated social defeat induced the emergence of depressive-like behavioral (sucrose preference reduction and passive coping behaviors in the forced swim test) and neuroendocrine (increased corticosterone levels) changes, which were prevented by URB694 treatment. Repeated social defeat also provoked a significant variation in gut microbiota (changes in the relative abundance of 14 bacterial taxa) and lipidic (e.g., glycerophospholipids) composition. These stress-induced changes were prevented by URB694 treatment. These findings indicate that inhibition of FAAH activity with URB694 blocks the co-occurrence of depressive-like behavioral and neuroendocrine changes and alterations in gut microbial and lipid composition in rats exposed to repeated social defeat. In conclusion, these results suggest that the gut microbiota-lipid crosstalk may represent a novel biological target for FAAH inhibitors to enhance stress resilience.
Assuntos
Compostos de Bifenilo , Carbamatos , Depressão , Microbioma Gastrointestinal , Animais , Masculino , Ratos , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Depressão/etiologia , Modelos Animais de Doenças , Lipidômica , Lipídeos , Ratos Wistar , Estresse Psicológico/tratamento farmacológicoRESUMO
Bifidobacteria are commensal microorganisms that typically inhabit the mammalian gut, including that of humans. As they may be vertically transmitted, they commonly colonize the human intestine from the very first day following birth and may persist until adulthood and old age, although generally at a reduced relative abundance and prevalence compared to infancy. The ability of bifidobacteria to persist in the human intestinal environment has been attributed to genes involved in adhesion to epithelial cells and the encoding of complex carbohydrate-degrading enzymes. Recently, a putative mucin-degrading glycosyl hydrolase belonging to the GH136 family and encoded by the perB gene has been implicated in gut persistence of certain bifidobacterial strains. In the current study, to better characterize the function of this gene, a comparative genomic analysis was performed, revealing the presence of perB homologues in just eight bifidobacterial species known to colonize the human gut, including Bifidobacterium bifidum and Bifidobacterium longum subsp. longum strains, or in non-human primates. Mucin-mediated growth and adhesion to human intestinal cells, in addition to a rodent model colonization assay, were performed using B. bifidum PRL2010 as a perB prototype and its isogenic perB-insertion mutant. These results demonstrate that perB inactivation reduces the ability of B. bifidum PRL2010 to grow on and adhere to mucin, as well as to persist in the rodent gut niche. These results corroborate the notion that the perB gene is one of the genetic determinants involved in the persistence of B. bifidum PRL2010 in the human gut.
Assuntos
Bifidobacterium bifidum , Animais , Bifidobacterium bifidum/genética , Bifidobacterium/genética , Células Epiteliais/microbiologia , Mucinas , MamíferosRESUMO
RATIONALE: Exposure to traumatic events can lead to alterations in social and anxiety-related behaviors. Emerging evidence suggests that peripheral host-defense processes are implicated in the expression of stress-induced behavioral responses and may be targeted to mitigate the negative sequalae of stress exposure. OBJECTIVES: In this study, we used the peripherally restricted FAAH inhibitor URB937 to investigate the effects of the fatty acyl ethanolamide (FAE) family of lipid mediators - which include the endocannabinoid anandamide and the endogenous PPAR-α agonists, oleoylethanolamide and palmitoylethanolamide - on behavioral and peripheral biochemical responses to two ethologically distinct rat models of stress. METHODS: Male adult rats were exposed to acute social defeat, a model of psychological stress (Experiment 1), or to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a test of innate predator-evoked fear (Experiment 2), and subsequently treated with URB937 (1 or 3 mg/kg, intraperitoneal) or vehicle. Behavioral analyses were conducted 24 h (Experiment 1) or 7 days (Experiment 2) after exposure. RESULTS: URB937 administration prevented the emergence of both social avoidance behavior after social defeat stress and anxiety-related behaviors after TMT exposure. Further, URB937 administration blocked social defeat-induced transient increase in plasma concentrations of pro-inflammatory cytokines and the elevation in plasma corticosterone levels observed 24 h after social defeat CONCLUSIONS: Enhancement of peripheral FAAH-regulated lipid signaling prevents the emergence of stress-induced social avoidance and anxiety-like behaviors in male rats through mechanisms that may involve an attenuation of peripheral cytokine release induced by stress exposure.
RESUMO
This study examines the predictive value of conflict and conflict-related variations in negative emotion dynamics, with respect to three cortisol indicators (cortisol awakening responses; overall cortisol output; diurnal cortisol slopes). A total of 166 workers provided momentary reports on conflict(s) with colleagues and negative emotions 10 times a day for 2 workdays and salivary cortisol samples 5 times a day. The results of latent growth curve piecewise multilevel models revealed that the occurrence of a conflict and the number of conflicts introduced significant variations in specific cortisol parameters indicating greater cortisol levels throughout the day. Moreover, the conflict-elicited negative emotion boost predicted a lower reduction of cortisol levels from morning to evening. Last, the postconflict decline in negative emotions was negatively associated with overall cortisol production. This study contributes to establishing a potential association between naturally occurring episodic conflicts at work and daily cortisol patterns, identifying within-person fluctuations in negative emotions as psychological mechanisms through which this occurs. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
Assuntos
Emoções , Hidrocortisona , Humanos , Bases de Dados Factuais , Análise MultinívelRESUMO
In the present ecological study, we analyzed the relations of a set of self-efficacy beliefs at work to parameters of diurnal cortisol variation. Specifically, using data collected during two consecutive working days from 166 workers, we tested a mediation model positing social and work-related self-efficacy beliefs as mediators of the relations between self-regulatory emotional self-efficacy beliefs in managing negative emotions and cortisol indicators. Results from the multilevel mediation analyses supported the proposed model for work-related self-efficacy, which resulted as a significant mediator of the relation between self-regulatory emotional self-efficacy beliefs in managing negative emotions and the overall cortisol daily production indexed by computing the area under the curve with respect to the ground. Findings suggest the importance of self-efficacy beliefs for workers' physiological adjustment. Theoretical and practical contributions of the findings are discussed.
Assuntos
Hidrocortisona , Autoeficácia , Humanos , Emoções , NegociaçãoRESUMO
The impact of psychosocial stressors on cardiovascular health in women is of growing interest in both the popular and scientific literature. Rodent models are useful for providing direct experimental evidence of the adverse cardiovascular consequences of psychosocial stressors, yet studies in females are scarce. Here, we investigated the effects of repeated exposure to witness social defeat stress (WS) on cardiomyocyte contractile function and intracellular Ca2+ homeostasis in young adult wild-type Groningen female rats. Female rats bore witness to an aggressive social defeat episode between two males for nine consecutive days or were exposed to a control procedure. Stress-related behaviors were assessed during the first and last WS/control exposure. Twenty-four hours after the last exposure, plasma corticosterone levels were measured, and cardiomyocytes were isolated for analyses of contractile properties and Ca2+ transients, and expression levels of proteins involved in intracellular Ca2+dynamics. The results show an impairment of the intrinsic cardiac mechanical properties and prolonged intracellular Ca2+decay in WS female rats showing social stress-related behavioral (larger amounts of burying behavior) and neuroendocrine (elevated plasma corticosterone levels) phenotypes. Further, the results implicate alterations in the sarcoplasmic reticulum Ca2+-ATPase/phospholamban complex in the contractile defects described in cardiomyocytes of WS female rats. In conclusion, this study highlights the utility of the WS model as an ethologically relevant social stressor for investigating pathophysiological processes that occur in the heart of female subjects and may increase vulnerability to social stress-related cardiovascular risk.
Assuntos
Corticosterona , Miócitos Cardíacos , Masculino , Ratos , Feminino , Humanos , Animais , Miócitos Cardíacos/metabolismo , Corticosterona/metabolismo , Contração Muscular , Cálcio/metabolismoRESUMO
AIMS: Nfix is a transcription factor belonging to the Nuclear Factor I (NFI) family comprising four members (Nfia, b, c, x). Nfix plays important roles in the development and function of several organs. In muscle development, Nfix controls the switch from embryonic to fetal myogenesis by promoting fast twitching fibres. In the adult muscle, following injury, lack of Nfix impairs regeneration, inducing higher content of slow-twitching fibres. Nfix is expressed also in the heart, but its function has been never investigated before. We studied Nfix role in this organ. METHODS: Using Nfix-null and wild type (WT) mice we analyzed: (1) the expression pattern of Nfix during development by qPCR and (2) the functional alterations caused by its absence, by in vivo telemetry and in vitro patch clamp analysis. RESULTS AND CONCLUSIONS: Nfix expression start in the heart from E12.5. Adult hearts of Nfix-null mice show a hearts morphology and sarcomeric proteins expression similar to WT. However, Nfix-null animals show tachycardia that derives form an intrinsic higher beating rate of the sinus node (SAN). Molecular and functional analysis revealed that sinoatrial cells of Nfix-null mice express a significantly larger L-type calcium current (Cacna1d + Cacna1c). Interestingly, downregulation of Nfix by sh-RNA in primary cultures of neonatal rat ventricular cardiomyocytes induced a similar increase in their spontaneous beating rate and in ICaL current. In conclusion, our data provide the first demonstration of a role of Nfix that, increasing the L-type calcium current, modulates heart rate.
RESUMO
The present study aimed to investigate sex differences in measures of cardiac chronotropy and heart rate variability (HRV) in 132 young adult wild-type Groningen rats (n = 45 females). Electrocardiographic signals were recorded for 48 h in freely moving rats to quantify heart rate (HR) and inter-beat interval (IBI) as measures of cardiac chronotropy, and time- and frequency-domain HRV parameters as physiological readouts of cardiac vagal modulation. Females showed greater vagally-mediated HRV despite having higher HR and shorter IBI than males during undisturbed conditions. Such differences were evident i) at any given level of HRV, and ii) both during the 12-h light/inactive and 12-h dark/active phase of the daily cycle. These findings replicate the paradoxical cardiac chronotropic control reported by human meta-analytic findings, since one would expect greater vagally-mediated HRV to be associated with lower HR and longer IBI. Lastly, the association between some HRV measures and HR was stronger in female than male rats. Overall, the current study in young adult rats provides data illustrating a sex-dependent association between vagally-mediated HRV and indexes of cardiac chronotropy. The current results i) are in line with human findings, ii) suggest to always consider biological sex in the analysis and interpretation of HRV data in rats, and iii) warrant the use of rats for investigating the neuro-hormonal basis and temporal evolution of the impact of sex on the association between vagally-mediated HRV and cardiac chronotropy, which could inform the human condition.
RESUMO
The effects of excitability, refractoriness, and impulse conduction have been independently related to enhanced arrhythmias in the aged myocardium in experimental and clinical studies. However, their combined arrhythmic effects in the elderly are not yet completely understood. Hence, the aim of the present work is to relate relevant cardiac electrophysiological parameters to enhanced arrhythmia vulnerability in the in vivo senescent heart. We used multiple-lead epicardial potential mapping in control (9-month-old) and aged (24-month-old) rat hearts. Cardiac excitability and refractoriness were evaluated at numerous epicardial test sites by means of the strength-duration curve and effective refractory period, respectively. During sinus rhythm, durations of electrogram intervals and waves were prolonged in the senescent heart, compared with control, demonstrating a latency in tissue activation and recovery. During ventricular pacing, cardiac excitability, effective refractory period, and dispersion of refractoriness increased in the aged animal. This scenario was accompanied by impairment of impulse propagation. Moreover, both spontaneous and induced arrhythmias were increased in senescent cardiac tissue. Histopathological evaluation of aged heart specimens revealed connective tissue deposition and perinuclear myocytolysis in the atria, while scattered microfoci of interstitial fibrosis were mostly present in the ventricular subendocardium. This work suggests that enhanced arrhythmogenesis in the elderly is a multifactorial process due to the joint increase in excitability and dispersion of refractoriness in association with enhanced conduction inhomogeneity. The knowledge of these electrophysiological changes will possibly contribute to improved prevention of the age-associated increase in cardiac arrhythmias.
Assuntos
Arritmias Cardíacas , Sistema de Condução Cardíaco , Masculino , Ratos , Animais , Miocárdio , Ventrículos do Coração , Átrios do CoraçãoRESUMO
BACKGROUND: Surgeons are exposed to high levels of intraoperative stress, which could compromise their psychological well-being in the long term. This study aimed at exploring the effects of real operations on the activity of stress response systems (i.e., cardiac autonomic function and hypothalamic-pituitary-adrenal axis) during and in the aftermath of surgery, and the moderating role of individual psychobiological characteristics and different levels of experience (senior vs expert surgeons). METHODS: Heart rate, heart rate variability, and salivary cortisol measures (as indexes of cardiac autonomic and hypothalamic-pituitary-adrenal axis activity, respectively) were assessed during real operations and in the perioperative period in a sample of surgeons (n = 16). Surgeons' psychometric characteristics were collected using questionnaires. RESULTS: Real operations triggered both cardiac autonomic and cortisol stress responses which were independent from surgeons' level of experience. Intraoperative stress responses did not affect cardiac autonomic activity during the following night but were associated with a blunted cortisol awakening response. Moreover, senior surgeons reported higher levels of negative affectivity and depressive symptoms than expert surgeons prior to the surgery. Lastly, the magnitude of heart rate responses to surgery positively correlated with scores on negative affectivity, depression, perceived stress, and trait anxiety scales. CONCLUSION: This exploratory study allows to put forward the hypotheses that in surgeons cardiac autonomic and cortisol stress responses to real operations (i) may be associated with specific individual psychological characteristics regardless of the level of experience, (ii) and may have a longer lasting impact on hypothalamic-pituitary-adrenal axis function with potential implications for surgeons' physical and psychological well-being.
RESUMO
This study explored the relationships between self-esteem level and self-esteem variability at work with parameters of diurnal cortisol rhythm, using intensive longitudinal data collected during two consecutive working days from N = 166 workers. Participants self-reported measures of sex, height, weight, self-esteem, neuroticism, and negative events at T0. Then, they answered a single item of self-esteem 4 times per day. Self-esteem variability was assessed by means of the relative variability index approach proposed by Mestdagh et al. (2018). Further, participants collected salivary samples at specific time points for analysis of diurnal cortisol patterns. Self-esteem average levels and a specific form of self-esteem variability were associated with diurnal cortisol parameters. In particular, results showed a relationship between low self-esteem and blunted cortisol awakening response, specifically when low self-esteem levels were stable over time. Moreover, self-esteem variability predicted a lower diurnal cortisol decline and a smaller magnitude of overall cortisol production. Present findings highlight the neuroendocrine correlates of self-esteem level and variation at work, suggesting potential pathways by which short-term variability in self-esteem states may impact hypothalamic-pituitary-adrenal axis functioning and long-term workers' health and well-being.
Assuntos
Hidrocortisona , Sistema Hipotálamo-Hipofisário , Humanos , Adulto , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Saliva/química , Ritmo Circadiano/fisiologiaRESUMO
Chronic social stress has been epidemiologically linked to increased risk for cardiovascular disease, yet the underlying pathophysiological mechanisms are still largely elusive. Mitochondrial (dys)function represents a potential intersection point between social stress exposure and (mal)adaptive cardiac responses. In this study, we used a rodent model of social stress to study the extent to which alterations in the cellular mechanical properties of the heart were associated with changes in indexes of mitochondrial function. Male adult rats were exposed to repeated episodes of social defeat stress or left undisturbed (controls). ECG signals were recorded during and after social defeat stress. Twenty-four hours after the last social defeat, cardiomyocytes were isolated for analyses of mechanical properties and intracellular Ca2+ dynamics, mitochondrial respiration, and ATP content. Results indicated that social defeat stress induced potent cardiac sympathetic activation that lasted well beyond stress exposure. Moreover, cardiomyocytes of stressed rats showed poor contractile performance (e.g., slower contraction and relaxation rates) and intracellular Ca2+ derangement (e.g., slower Ca2+ clearing), which were associated with indexes of reduced reserve respiratory capacity and decreased ATP production. In conclusion, this study suggests that repeated social stress provokes impaired cardiomyocyte contractile performance and signs of altered mitochondrial bioenergetics in the rat heart. Future studies are needed to clarify the causal link between cardiac and mitochondrial functional remodeling under conditions of chronic social stress.
RESUMO
Amoxicillin-clavulanic acid (AMC) is the most widely used antibiotic, being frequently prescribed to infants. Particular members of the genus Bifidobacterium are among the first microbial colonizers of the infant gut, and it has been demonstrated that they exhibit various activities beneficial for their human host, including promotion/maintenance of the human gut microbiota homeostasis. It has been shown that natural resistance of bifidobacteria to AMC is limited to a small number of strains. In the current study, we investigated the mitigation effects of AMC-resistant bifidobacteria in diversity preservation of the gut microbiota during AMC treatment. To this end, an in vitro coculture experiment based on infant fecal samples and an in vivo study employing a rodent model were performed. The results confirmed the ability of AMC-resistant bifidobacterial strains to bolster gut microbiota resilience, while specific covariance analysis revealed strain-specific and variable impacts on the microbiota composition by individual bifidobacterial taxa. IMPORTANCE The first microbial colonizers of the infant gut are members of the genus Bifidobacterium, which exhibit different activities beneficial to their host. Amoxicillin-clavulanic acid (AMC) is the most frequently prescribed antibiotic during infancy, and few strains of bifidobacteria are known to show a natural resistance to this antibiotic. In the present work, we evaluated the possible positive effects of AMC-resistant bifidobacterial strains in maintaining gut microbiota diversity during AMC exposure, performing an in vitro and in vivo experiment based on an infant gut model and a rodent model, respectively. Our results suggested the ability of AMC-resistant bifidobacterial strains to support gut microbiota restoration.
Assuntos
Bifidobacterium , Microbioma Gastrointestinal , Combinação Amoxicilina e Clavulanato de Potássio/farmacologia , Antibacterianos/farmacologia , Fezes/microbiologia , Humanos , LactenteRESUMO
Animal studies increasingly indicate that the gut microbiota composition and function can be involved in the pathophysiology and progression of Alzheimer's disease (AD) at multiple levels. However, few studies have investigated this putative gut-brain axis in human beings, and none of them considered diet as a determinant of intestinal microbiota composition. Epidemiological studies highlight that a high intake of fruit and vegetables, such as that typical of the Mediterranean diet, can modulate AD progression. Thus, nutritional interventions are being increasingly studied as a possible non-pharmacological strategy to slow down the progression of AD. In particular, polyphenols and fibers represent the nutritional compounds with the higher potential of counterbalancing the pathophysiological mechanisms of dementia due to their antioxidant, anti-inflammatory, and anti-apoptotic properties. These actions are mediated by the gut microbiota, that can transform polyphenols and fibers into biologically active compounds including, among others, phenyl-γ-valerolactones, urolithins, butyrate, and other short-chain fatty acids. In this review, the complex mechanisms linking nutrition, gut microbiota composition, and pathophysiology of cognitive decline in AD are discussed, with a particular focus on the role of polyphenols and fibers. The gaps between pre-clinical and clinical studies are particularly emphasized, as well as the urgent need for studies comprehensively evaluating the link between nutrition, microbiome, and clinical aspects of AD.
Assuntos
Doença de Alzheimer , Dieta Mediterrânea , Microbiota , Animais , Dieta , Fibras na Dieta , Humanos , Polifenóis/farmacologiaRESUMO
Resting heart rate variability (HRV), a surrogate index of cardiac vagal modulation, is considered a putative biomarker of stress resilience as it reflects the ability to effectively regulate emotions in a changing environment. However, most studies are cross-sectional, precluding longitudinal inferences. The high degree of uncertainty and fear at a global level that characterizes the COVID-19 pandemic offers a unique opportunity to explore the utility of HRV measures as longitudinal predictors of stress resilience. This study examined whether resting measures of HRV prior to the COVID-19 outbreak (i.e. nearly 2 years before; Time 0) could predict emotion regulation strategies and daily affect in healthy adults during the May 2020 lockdown (Time 1). Moreover, we evaluated the association between HRV measures, emotion regulation strategies, subjective perception of COVID-19 risk, and self-reported depressive symptoms at Time 1. Higher resting HRV at Time 0 predicted a stronger engagement in more functional emotion regulation strategies, as well as of higher daily feelings of safeness and reduced daily worry at Time 1. Moreover, depressive symptoms negatively correlated with HRV and positively correlated with the subjective perception of COVID-19 risk at Time 1. Current data support the view that HRV might not only be a marker but also a precursor of resilience under stressful times.
Assuntos
COVID-19 , Regulação Emocional , Adulto , Controle de Doenças Transmissíveis , Estudos Transversais , Frequência Cardíaca/fisiologia , Humanos , Pandemias , SARS-CoV-2 , Estresse PsicológicoRESUMO
Many factors acting during the neonatal period can affect neurological development of the infant. Neonatal seizures (NS) that frequently occur in the immature brain may influence autonomic maturation and lead to detectable cardiovascular signs. These autonomic manifestations can also have significant diagnostic and prognostic value. The analysis of Heart Rate Variability (HRV) represents the most used and feasible method to evaluate cardiac autonomic regulation. This narrative review summarizes studies investigating HRV dynamics in newborns with seizures, with the aim of highlighting the potential utility of HRV measures for seizure detection and management. While HRV analysis in critically ill newborns is influenced by many potential confounders, we suggest that it can enhance the ability to better diagnose seizures in the clinical setting. We present potential applications of the analysis of HRV, which could have a useful future role, beyond the research setting.
Assuntos
Sistema Nervoso Autônomo , Epilepsia , Encéfalo , Frequência Cardíaca , Humanos , Recém-Nascido , Convulsões/diagnóstico , Convulsões/terapiaRESUMO
This study investigated epigenetic risk factors that may contribute to stress-related cardiac disease in a rodent model. Experiment 1 was designed to evaluate the expression of microRNA-34a (miR-34a), a known modulator of both stress responses and cardiac pathophysiology, in the heart of male adult rats exposed to a single or repeated episodes of social defeat stress. Moreover, RNA sequencing was conducted to identify transcriptomic profile changes in the heart of repeatedly stressed rats. Experiment 2 was designed to assess cardiac electromechanical changes induced by repeated social defeat stress that may predispose rats to cardiac dysfunction. Results indicated a larger cardiac miR-34a expression after repeated social defeat stress compared to a control condition. This molecular modification was associated with increased vulnerability to pharmacologically induced arrhythmias and signs of systolic left ventricular dysfunction. Gene expression analysis identified clusters of differentially expressed genes in the heart of repeatedly stressed rats that are mainly associated with morphological and functional properties of the mitochondria and may be directly regulated by miR-34a. These results suggest the presence of an association between miR-34a overexpression and signs of adverse electromechanical remodeling in the heart of rats exposed to repeated social defeat stress, and point to compromised mitochondria efficiency as a potential mediator of this link. This rat model may provide a useful tool for investigating the causal relationship between miR-34a expression, mitochondrial (dys)function, and cardiac alterations under stressful conditions, which could have important implications in the context of stress-related cardiac disease.
Assuntos
MicroRNAs , Animais , Coração , Masculino , MicroRNAs/genética , Ratos , Estresse Psicológico/genéticaRESUMO
OBJECTIVE: The aim of this study was to assess age-related changes in cardiac autonomic modulation and heart rate variability (HRV) and their association with spontaneous and pharmacologically induced vulnerability to cardiac arrhythmias, to verify the translational relevance of mouse models for further in-depth evaluation of the link between autonomic changes and increased arrhythmic risk with advancing age. METHODS: Heart rate (HR) and time- and frequency-domain indexes of HRV were calculated from Electrocardiogram (ECG) recordings in two groups of conscious mice of different ages (4 and 19 months old) (i) during daily undisturbed conditions, (ii) following peripheral ß-adrenergic (atenolol), muscarinic (methylscopolamine), and ß-adrenergic + muscarinic blockades, and (iii) following ß-adrenergic (isoprenaline) stimulation. Vulnerability to arrhythmias was evaluated during daily undisturbed conditions and following ß-adrenergic stimulation. RESULTS: HRV analysis and HR responses to autonomic blockades revealed that 19-month-old mice had a lower vagal modulation of cardiac function compared with 4-month-old mice. This age-related autonomic effect was not reflected in changes in HR, since intrinsic HR was lower in 19-month-old compared with 4-month-old mice. Both time- and frequency-domain HRV indexes were reduced following muscarinic, but not ß-adrenergic blockade in younger mice, and to a lesser extent in older mice, suggesting that HRV is largely modulated by vagal tone in mice. Finally, 19-month-old mice showed a larger vulnerability to both spontaneous and isoprenaline-induced arrhythmias. CONCLUSION: The present study combines HRV analysis and selective pharmacological autonomic blockades to document an age-related impairment in cardiac vagal modulation in mice which is consistent with the human condition. Given their short life span, mice could be further exploited as an aged model for studying the trajectory of vagal decline with advancing age using HRV measures, and the mechanisms underlying its association with proarrhythmic remodeling of the senescent heart.