Antidepressant-like effects of pharmacological inhibition of FAAH activity in socially isolated female rats

Pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which terminates signaling of the endocannabinoid N-arachidonoylethanolamine (or anandamide, AEA), exerts favourable effects in rodent models of stress-related depression. Yet although depression seems to be more common among women than men and in spite of some evidence of sex differences in treatment efficacy, preclinical development of FAAH inhibitors for the pharmacotherapy of stress-related depression has been predominantly conducted in male animals. Here, adult female rats were exposed to six weeks of social isolation and, starting from the second week, treated with the FAAH inhibitor URB694 (0.3 mg/kg/day, i.p.) or vehicle. Compared to pair-housed females, socially isolated female rats treated with vehicle developed behavioral (mild anhedonia, passive stress coping) and physiological (reduced body weight gain, elevated plasma corticosterone levels) alterations. Moreover, prolonged social isolation provoked a reduction in brain-derived neurotrophic factor (BDNF) and AEA levels within the hippocampus. Together, these changes are indicative of an increased risk of developing a depressive-like state. Conversely, pharmacological inhibition of FAAH activity with URB694 restored both AEA and BDNF levels within the hippocampus of socially isolated rats and prevented the development of behavioral and physiological alterations. These results suggest a potential interplay between AEA-mediated signaling and hippocampal BDNF in the pathogenesis of depression-relevant behaviors and physiological alterations and antidepressant action of FAAH inhibition in socially isolated female rats

Bionic for training: Smart framework design for multisensor mechatronic platform validation

Home monitoring supports the continuous improvement of the therapy by sharing data with healthcare professionals. It is required when life-threatening events can still occur after hospital discharge such as neonatal apnea. However, multiple sources of external noise could affect data quality and/or increase the misdetection rate. In this study, we developed a mechatronic platform for sensor characterizations and a framework to manage data in the context of neonatal apnea. The platform can simulate the movement of the abdomen in different plausible newborn positions by merging data acquired simultaneously from three-axis accelerometers and infrared sensors. We simulated nine apnea conditions combining three different linear displacements and body postures in the presence of self-generated external noise, showing how it is possible to reduce errors near to zero in phenomena detection. Finally, the development of a smart 8Ws-based software and a customizable mobile application were proposed to facilitate data management and interpretation, classifying the alerts to guarantee the correct information sharing without specialized skills

RNA delivery by extracellular vesicles in mammalian cells and its applications.

The term 'extracellular vesicles' refers to a heterogeneous population of vesicular bodies of cellular origin that derive either from the endosomal compartment (exosomes) or as a result of shedding from the plasma membrane (microvesicles, oncosomes and apoptotic bodies). Extracellular vesicles carry a variety of cargo, including RNAs, proteins, lipids and DNA, which can be taken up by other cells, both in the direct vicinity of the source cell and at distant sites in the body via biofluids, and elicit a variety of phenotypic responses. Owing to their unique biology and roles in cell-cell communication, extracellular vesicles have attracted strong interest, which is further enhanced by their potential clinical utility. Because extracellular vesicles derive their cargo from the contents of the cells that produce them, they are attractive sources of biomarkers for a variety of diseases. Furthermore, studies demonstrating phenotypic effects of specific extracellular vesicle-associated cargo on target cells have stoked interest in extracellular vesicles as therapeutic vehicles. There is particularly strong evidence that the RNA cargo of extracellular vesicles can alter recipient cell gene expression and function. During the past decade, extracellular vesicles and their RNA cargo have become better defined, but many aspects of extracellular vesicle biology remain to be elucidated. These include selective cargo loading resulting in substantial differences between the composition of extracellular vesicles and source cells; heterogeneity in extracellular vesicle size and composition; and undefined mechanisms for the uptake of extracellular vesicles into recipient cells and the fates of their cargo. Further progress in unravelling the basic mechanisms of extracellular vesicle biogenesis, transport, and cargo delivery and function is needed for successful clinical implementation. This Review focuses on the current state of knowledge pertaining to packaging, transport and function of RNAs in extracellular vesicles and outlines the progress made thus far towards their clinical applications

Rodent models of depression-cardiovascular comorbidity : Bridging the known to the new

Numerous epidemiological studies have demonstrated a close and bidirectional association between depression and cardiovascular disorders (CVD). This comorbidity places a significant burden on individuals and the healthcare system. Not surprisingly, in the last two decades preclinical research in the field of depression and CVD has rapidly progressed. Multiple studies have demonstrated that aspects of human depression/cardiovascular comorbidity can be modeled in rodents exposed to chronic stress paradigms and that a depressive-like syndrome can be induced in rodent models of CVD. This research has provided insights into neural, autonomic, humoral, immune and circulatory mechanisms linking co-occurring mood and CVD. Recent investigations have started to address gender and individual differences in the vulnerability to both disorders and have begun to explore the efficacy of novel pharmacological interventions for the treatment of these comorbid conditions. This review discusses relatively well-established findings and the latest discoveries from rodent models of depression and CVD, with the aim of providing an up-to-date reference which may guide future studies of the relationship between mood and cardiovascular disturbances

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 \u3bcg/kg lipopolysaccharide \u2013 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 in neonatal patients with seizures

Objective: Seizures are frequently observed in neurological conditions affecting newborns. Since autonomic alterations are commonly associated with neonatal seizures (NS), we investigated the utility of heart rate variability (HRV) indexes of cardiac autonomic regulation for NS detection. Methods: HRV analysis was conducted on ECG tracings recorded during video-EEG monitoring in newborns with NS and matched-controls. The effects of gestational age on HRV were also evaluated. Results: Newborns with NS showed lower resting state HRV compared to controls. Moreover, seizure episodes were characterized by a short-lasting increase in vagal indexes of HRV. Pre-term newborns with NS had a lower HRV than full-term at rest. In pre-term newborns, no changes in HRV were observed before and during NS. On the contrary, full-term newborns showed significantly higher HRV before and during NS compared to the respective baseline values. Conclusion: Our data point to resting autonomic impairment in newborns with NS. In addition, an increment in HRV has been observed during NS only in full term newborns. Significance: Although these findings do not allow validation of HRV measures for NS prediction and detection, they suggest that a putative protective vagal mechanism might be adopted when an advanced maturation of autonomic nervous system is achieved

Nocturnal Heart Rate Variability Might Help in Predicting Severe Obstructive Sleep-Disordered Breathing

Obstructive sleep apnea (OSA) can have long-term cardiovascular and metabolic effects. The identification of OSA-related impairments would provide diagnostic and prognostic value. Heart rate variability (HRV) as a measure of cardiac autonomic regulation is a promising candidate marker of OSA and OSA-related conditions. We took advantage of the Physionet Apnea-ECG database for two purposes. First, we performed time- and frequency-domain analysis of nocturnal HRV on each recording of this database to evaluate the cardiac autonomic regulation in patients with nighttime sleep breathing disorders. Second, we conducted a logistic regression analysis (backward stepwise) to identify the HRV indices able to predict the apnea–hypopnea index (AHI) categories (i.e., “Severe OSA”, AHI ≥ 30; “Moderate-Mild OSA”, 5 ≥ AHI < 30; and “Normal”, AHI < 5). Compared to the “Normal”, the “Severe OSA” group showed lower high-frequency power in normalized units (HFnu) and higher low-frequency power in normalized units (LFnu). The standard deviation of normal R–R intervals (SDNN) and the root mean square of successive R–R interval differences (RMSSD) were independently associated with sleep-disordered breathing. Our findings suggest altered cardiac autonomic regulation with a reduced parasympathetic component in OSA patients and suggest a role of nighttime HRV in the characterization and identification of sleep breathing disorders

Reduced NPY Y1 receptor hippocampal expression and signs of decreased vagal modulation of heart rate in mice.

Central neuropeptide Y (NPY) signaling participates in the regulation of cardiac autonomic outflow, particularly via activation of NPY-Y1 receptors (Y1Rs). However, the specific brain areas and neural pathways involved have not been completely identified yet. Here, we evaluate the role of hippocampal Y1Rs in the modulation of the autonomic control of cardiac function using a conditional knockout mouse model. Radiotelemetric transmitters were implanted in 4-month-old male mice exhibiting reduced forebrain expression (rfb) of the Y1R (Npy1rrfb, n=10) and their corresponding controls (Npy1r2lox, n=8). ECG signals were recorded (i) during resting conditions, (ii) under selective pharmacological manipulation of cardiac vagal activity, and (iii) during acute and chronic psychosocial stress challenges, and analyzed via time- and frequency-domain analysis of heart rate variability. Npy1rrfb mice showed a lower Npy1r mRNA density in the dentate gyrus and in the CA1 region of the hippocampus. Under resting undisturbed conditions, Npy1rrfb mice exhibited (i) a higher heart rate, (ii) a reduced overall heart rate variability, and (iii) lower values of the indices of vagal modulation compared to Npy1r2lox counterparts. Following pharmacological vagal inhibition, heart rate was higher in control but not in Npy1rrfb mice compared to their respective baseline values, suggesting that tonic vagal influences on heart rate were reduced in Npy1rrfb mice. The magnitude of the heart rate response to acute stressors was smaller in Npy1rrfb mice compared to Npy1r2lox counterparts, likely due to a concurrent lower vagal withdrawal. These findings suggest that reduced Y1R expression leads to a decrease in resting vagal modulation and heart rate variability, which, in turn, may determine a reduced cardiac autonomic responsiveness to acute stress challenges