Age-related increases in cardiac excitability, refractoriness and impulse conduction favor arrhythmogenesis in male rats.

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.

Exploring the Ecological Effects of Naturally Antibiotic-Insensitive Bifidobacteria in the Recovery of the Resilience of the Gut Microbiota during and after Antibiotic Treatment.

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.

Safe in my heart: resting heart rate variability longitudinally predicts emotion regulation, worry, and sense of safeness during COVID-19 lockdown.

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.

Elevated miR-34a expression and altered transcriptional profile are associated with adverse electromechanical remodeling in the heart of male rats exposed to social stress.

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.

Osteopathic Manipulative Treatment and Cardiovascular Autonomic Parameters in Rugby Players: A Randomized, Sham-Controlled Trial.

OBJECTIVE: The purpose of this study was to investigate the effects of osteopathic manipulative treatment (OMT) on cardiovascular autonomic parameters after a rugby match. METHODS: Resting and reactivity (ie, response to orthostasis) measures of mean arterial pressure, heart rate, and heart rate variability were assessed in 23 male players after a single session of OMT, both 18 to 20 hours after a rugby match and in a corresponding no-match condition, in a randomized, sham-controlled, crossover design. RESULTS: Signs of reduced heart rate variability and elevated mean arterial pressure and heart rate were found 18 to 20 hours after a rugby match compared with the no-match condition. A significant increase in heart rate variability and a significant reduction in mean arterial pressure were observed after OMT in both the after-match and no-match conditions. Heart rate and heart rate variability responses to orthostasis were not affected by previous match competition, but were significantly larger after OMT compared with sham treatment. CONCLUSION: This study suggests the presence of cardiovascular autonomic alterations in rugby players after a competitive match, which may be indicative of prolonged fatigue and incomplete recovery. In these players, favorable changes in cardiovascular autonomic parameters were observed following a single session of OMT.

Effects of prefrontal transcranial direct current stimulation on autonomic and neuroendocrine responses to psychosocial stress in healthy humans.

Prolonged or repeated activation of the stress response can have negative psychological and physical consequences. The prefrontal cortex (PFC) is thought to exert an inhibitory influence on the activity of autonomic and neuroendocrine stress response systems. In this study, we further investigated this hypothesis by increasing PFC excitability using transcranial direct current stimulation (tDCS). Healthy male participants were randomized to receive either anodal (excitatory) tDCS (n = 15) or sham stimulation (n = 15) over the left dorsolateral prefrontal cortex (DLPFC) immediately before and during the exposure to a psychosocial stress test. Autonomic (heart rate (HR) and its variability) and neuroendocrine (salivary cortisol) parameters were assessed. One single session of excitatory tDCS over the left DLPFC (i) reduced HR and favored a larger vagal prevalence prior to stress exposure, (ii) moderated stress-induced HR acceleration and sympathetic activation/vagal withdrawal, but (iii) had no effect on stress-induced cortisol release. However, anodal tDCS over the left DLPFC prevented stress-induced changes in the cortisol awakening response. Finally, participants receiving excitatory tDCS reported a reduction in their levels of state anxiety upon completion of the psychosocial stress test. In conclusion, this study provides first insights into the efficacy of one single session of excitatory tDCS over the left DLPFC in attenuating autonomic and neuroendocrine effects of psychosocial stress exposure. These findings might be indicative of the important role of the left DLPFC, which is a cortical target for noninvasive brain stimulation treatment of depression, for successful coping with stressful stimuli.

Febrile and sleep responses to an immune challenge are affected by trait aggressiveness in rats.

Sleep is altered in response to an immune challenge: non-rapid eye movement (NREM) sleep is increased and fragmented, REM sleep is inhibited. Sleep and immune response are affected by stress: several stressors inhibit sleep and increase waking time; stress-induced cortisol secretion affects the immune response, with immunosuppressive effects. Different levels of trait aggressiveness are associated with specific patterns of neuroendocrine and autonomic stress responsiveness. Aim of this study was to test the hypothesis that trait aggressiveness, by affecting response to stressors, modifies sleep alterations induced by the activation of the immune response. To this aim, rats were selected on the basis of their latency time to attack a male intruder in the resident-intruder test. Animals were instrumented for chronic recordings of sleep-wake activity and injected, intraperitoneally, with an immune challenge (250 µg/kg lipopolysaccharide - LPS, a component of gram-negative bacterial cell wall). Here we report that high aggressive (HA) rats responded to an immune challenge with a 24-h long increase in cortical brain temperature. During the first 12 post-injection hours, HA rats also responded with a prolonged increase in NREM sleep amount, and a 5-h long and continuous inhibition of REM sleep. In HA rats, the LPS-induced increase in the amount of time spent in NREM sleep was due to an increase in the number of episodes of this sleep phase, without any change in the bout duration. The LPS-induced REM sleep inhibition observed in HA rats was due to a decrease in both the number and duration of REM sleep bouts. In HA rats, during REM sleep, LPS administration significantly reduced the power of the EEG theta band. In non-aggressive (NA) rats, in response to LPS administration, cortical brain temperature was increased only for two hours, NREM sleep was unaffected, and REM sleep inhibition was scattered along the first 8 post-injection hours. The LPS-induced changes in the number of NREM sleep bouts of NA rats were limited to few and scattered hours, with a change in bout duration only in a single hour. A combination of decreases, in few hours, in both REM sleep bouts and their duration contributed to the REM sleep inhibition observed in NA rats. In NA rats, the power of EEG theta band was not modified, during REM sleep, by LPS administration. Gross motor activity was inhibited in both HA and NA rats. Results of this study show that trait aggressiveness affects febrile and sleep responses to an immune challenge.

Heart rate variability and inflammation: A meta-analysis of human studies.

The inflammatory reflex is known as the body's primary defense against infection and has been implicated in a number of diseases. The magnitude of the inflammatory response is important, as an extreme or insufficient response can be differentially harmful to the individual. Converging evidence suggests that the autonomic nervous system (ANS) regulates the inflammatory reflex. Heart rate variability (HRV) can be separated into components that primarily reflect parasympathetic (PNS) or vagal activity (i.e., indices of vagally mediated HRV) and a combination of both sympathetic (SNS) and PNS influences. Given the physiological relation between the vagus and inflammatory processes, one would expect to find higher HRV, especially indices of vagally-mediated HRV, to be associated with decreased levels of inflammation via the cholinergic anti-inflammatory pathway. However, existing findings here are mixed, such that studies have also shown a positive association between indices of HRV and markers of inflammation. Therefore, the present meta-analysis aimed to synthesize existing studies, estimating the general direction and strength of the relationship between different indices of HRV and inflammatory markers. A systematic search of the literature yielded 2283 studies that were screened for inclusion eligibility (159 studies eligible for inclusion); in sum, 51 studies reported/provided adequate information for inclusion in meta-analyses. Results generally showed negative associations between indices of HRV and markers of inflammation. In this regard, the standard deviation of R-R intervals (SDNN) and power in the high frequency band of HRV (HF-HRV) showed the strongest and most robust associations with inflammatory markers compared to other time- and frequency-domain measures of HRV. Overall, we propose that indices of HRV can be used to index activity of the neurophysiological pathway responsible for adaptively regulating inflammatory processes in humans.

The Utility of Rodent Models of Stress for Disentangling Individual Vulnerability to Depression and Cardiovascular Comorbidity.

PURPOSE OF REVIEW: This review offers a perspective of the utility of rodent models of stress for identifying sources of individual vulnerability to depression and cardiovascular disease comorbidity. RECENT FINDINGS: Differential stress susceptibility is found in rodents exposed to repeated social defeat as a function of their coping style. Specifically, passive coping rodents show an increase in inflammatory processes within the brain that favour the development of depressive-like symptoms and cardiovascular abnormalities. Similarly, only a sub-group of rats develops depressive-like symptoms following chronic mild stress exposure. Cardiovascular changes differ depending on individual stress susceptibility and may be related to an imbalance in the autonomic regulation of cardiac function in stress vulnerable subjects. Rodent models of stress that take into account individual phenotypic variations are useful for a better understanding of the role of neuroinflammatory and autonomic processes in the development of comorbid depression and cardiovascular disease under stressful conditions.

Autonomic dysfunction and heart rate variability in depression.

Depression occurs in people of all ages across all world regions; it is the second leading cause of disability and its global burden increased by 37.5% between 1990 and 2010. Autonomic changes are often found in altered mood states and appear to be a central biological substrate linking depression to a number of physical dysfunctions. Alterations of autonomic nervous system functioning that promotes vagal withdrawal are reflected in reductions of heart rate variability (HRV) indexes. Reduced HRV characterizes emotional dysregulation, decreased psychological flexibility and defective social engagement, which in turn are linked to prefrontal cortex hypoactivity. Altogether, these pieces of evidence support the idea that HRV might represent a useful endophenotype for psychological/physical comorbidities, and its routine application should be advised to assess the efficacy of prevention/intervention therapies in a number of psychosomatic and psychiatric dysfunctions. Further research, also making use of appropriate animal models, could provide a significant support to this point of view and possibly help to identify appropriate antidepressant therapies that do not interefere with physical health.

Social stress-induced depressive-like symptoms and changes in gut microbial and lipidomic profiles are prevented by pharmacological inhibition of FAAH activity in male rats.

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.

GH136-encoding gene (perB) is involved in gut colonization and persistence by Bifidobacterium bifidum PRL2010.

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.

Structural and electrical myocardial remodeling in a rodent model of depression.

OBJECTIVE: Despite a well-documented association between stress and depression with cardiac morbidity and mortality, there is no satisfactory explanation for the mechanisms linking affective and cardiac disorders. This study investigated cardiac electrophysiological properties in an animal model of depression. METHODS: Depression-relevant physiological and behavioral parameters were measured in adult male wild-type rats during and after a period of intermittent social defeat stress (n = 12) or empty cage exposure (control, n = 11). Nine days after the last defeat/empty cage exposure, high-definition epicardial mapping was performed under anesthesia. RESULTS: Stressed animals versus controls displayed a larger reduction in the circadian amplitude of heart rate (-32% [3%] versus -13 [2%]; p = .001) and body temperature (-33% [4%] versus -5% [2%]; p = .001) rhythms, had smaller body weight gain (+11% [1%] versus +17% [1%]; p < .001), and showed a larger reduction in sucrose solution intake (-19% [6%] versus -7% [4%]; p = .006). Epicardial mapping analysis revealed a decrease in the transversal conduction velocity of the wavefront (0.23 [0.0] versus 0.27 [0.1] m/s; p = .02) and a shortening of the effective refractory period (86.8 [2.1] versus 95.9 [3.0] milliseconds; p = .01) in stressed animals. Upon killing, moderate left ventricular fibrosis was observed in the stressed group. CONCLUSIONS: Intermittent social stress procedure is associated with depression-like symptoms and altered myocardial electrical stability in a potentially proarrhythmic manner. In particular, reduced myocardial refractoriness and impaired conduction, which are considered major determinants of arrhythmogenesis, represent possible mechanisms underlying cardiac vulnerability.

Sex differences in heart rate and heart rate variability in rats: Implications for translational research.

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.

Enhancement of peripheral fatty acyl ethanolamide signaling prevents stress-induced social avoidance and anxiety-like behaviors in male rats.

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.

Repeated witness social stress causes cardiomyocyte contractile impairment and intracellular Ca2+ derangement in female rats.

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.

Cardiac autonomic and cortisol stress responses to real operations in surgeons: relationship with individual psychobiological characteristics and experience.

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.

The integration of depressive behaviors and cardiac dysfunction during an operational measure of depression: investigating the role of negative social experiences in an animal model.

OBJECTIVE: There is a bidirectional association between depression and cardiovascular disease. The neurobiological mechanisms underlying this association may involve an inability to cope with disrupted social bonds. This study investigated in an animal model the integration of depressive behaviors and cardiac dysfunction after a disrupted social bond and during an operational measure of depression, relative to the protective effects of intact social bonds. METHODS: Depressive behaviors in the forced swim test and continuous electrocardiographic parameters were measured in 14 adult, female socially monogamous prairie voles (rodents), after 4 weeks of social pairing or isolation. RESULTS: After social isolation, animals exhibited (all values are mean ± standard error of the mean; isolated versus paired, respectively) increased heart rate (416 ± 14 versus 370 ± 14 bpm, p < .05) and reduced heart rate variability (3.3 ± 0.2 versus 3.9 ± 0.2 ln(ms(2))). During the forced swim test, isolated animals exhibited greater helpless behavior (immobility = 106 ± 11 versus 63 ± 11 seconds, p < .05), increased heart rate (530 ± 22 versus 447 ± 15 bpm, p < .05), reduced heart rate variability (1.8 ± 0.4 versus 2.7 ± 0.2 ln(ms(2)), p < .05), and increased arrhythmias (arrhythmic burden score = 181 ± 46 versus 28 ± 12, p < .05). CONCLUSIONS: The display of depressive behaviors during an operational measure of depression is coupled with increased heart rate, reduced heart rate variability, and increased arrhythmias, indicative of dysfunctional behavioral and physiological stress coping abilities as a function of social isolation. In contrast, social pairing with a sibling is behaviorally protective and cardioprotective. The present results can provide insight into a possible social mechanism underlying the association between depression and cardiovascular disease in humans.

Interaction Between Diet and Microbiota in the Pathophysiology of Alzheimer's Disease: Focus on Polyphenols and Dietary Fibers.

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.

Decline of cardiomyocyte contractile performance and bioenergetic function in socially stressed male rats.

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.