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Autism spectrum disorder (ASD) is a neurodevelopmental disorder displaying the modification of complex human behaviors, characterized by social interaction impairments, stereotypical/repetitive activities and emotional dysregulation. In this study, fecal microbiota transplant (FMT) via gavage from autistic children donors to mice, led to the colonization of ASD-like microbiota and autistic behaviors compared to the offspring of pregnant females exposed to valproic acid (VPA). Such variations seemed to be tightly associated with increased populations of Tenericutes plus a notable reduction (p 0.001) of Actinobacteria and Candidatus S. in the gastrointestinal region of FMT mice as compared to controls. Indeed altered behaviors of FMT mice was reported when evaluated in the different maze tests (light dark, novel object, three chamber tests, novel cage test). Contextually, FMT accounted for elevated expression levels of the pro-inflammatory factors IL-1β, IL-6, COX-1 and TNF-α in both brain and small intestine. Villous atrophy and inflammatory infiltration (Caspase 3 and Ki67) were increased in the small intestine of FMT and VPA mice compared to controls. Moreover, the observed FMT-dependent alterations were linked to a decrease in the methylation status. Overall, findings of the present study corroborate a key role of gut microbiota in ASD. However, further investigations are required before any possible manipulation of gut bacteria with appropriate diets or probiotics can be conducted in ASD individuals.

The traditional Mediterranean diet (MD) is characterized by a high phenolic-rich food intake, including in particular vegetables and fruits, but also legumes, whole grain cereals, nuts, and extra virgin olive oil. Evidence for beneficial effects of polyphenols in humans depends on the amount consumed and on their bioavailability. Here, we evaluated the association between the estimated polyphenol intake by fruits and vegetables food source and serum biochemical parameters in healthy adolescents, recruited into the DIMENU research project. Categorizing adolescents into three groups according to their estimated total polyphenol intake, we found that adolescents who declared high consumption of polyphenols had a higher adherence to the MD and had a better serum lipid profile than adolescents consuming low amounts of polyphenols. Moreover, using human HepG2 liver cells treated with oleic acid as an in vitro model for studying lipid accumulation, we showed that intracellular lipid accumulation is alleviated by serum from adolescents consuming a polyphenol-rich diet following MD recommendations. Our data underline the importance of promoting adherence to the typical MD foods as a superior strategy to prevent metabolic and chronic diseases and to ensure a better quality of life among adolescents.

Current evidence supports the beneficial role of phytoestrogens in metabolic diseases, but their influences on spontaneous motor and anxiety behaviors plus neuroprotective effects have still not been completely elucidated. With the present study, neuro-behavioral activities were correlated to daidzein (DZ)-dependent expression changes of a high affinity catalytic receptor for several neurotrophins, and namely tropomyosin-related kinase B receptor (TrkB) in the cerebellar cortex of high-fat diet (HFD) hamsters (Mesocricetus auratus). Indeed, these changes appear to be tightly linked to altered plasma lipid profiles as shown by reduced low-density lipoproteins plus total cholesterol levels in DZ-treated obesity hamsters accounting for increased spontaneous locomotor together with diminished anxiety activities in novel cage (NCT) and light/dark box (LDT) tests. For this latter case, the anxiolytic-like hamsters spent more time in the light compartment, which was retained the aversive area of the LDT box. As for the evaluation of the neurotrophin receptor site, significantly elevated TrkB levels were also detected, for the first time, in the cerebellum of obese hamsters treated with DZ. In this condition, such a treatment widely led to an overall improvement of HFD-induced neurodegeneration damages, above all in the Purkinje and granular layers of the cerebellum. In this context, the notably active TrkB signaling events occurring in a DZ-dependent manner may turn out to be a key neuroprotective element capable of restoring normal emotional and spontaneously linked locomotor behaviors regulated by cerebellar cortical areas especially in obesity-related conditions.

Background: Obesity is now recognized as a worldwide health issue and has reached epidemic proportions, affecting both developed and developing countries. The World Obesity Federation stated that “Obesity is a chronic relapsing disease process”: as a result, obesity has been recognized internationally as a chronic disease. : The primary cause of the metabolic syndrome and increase of the cardiovascular risk have been identified in "sick fat", a condition then defined as adiposopathy. Heart attacks, strokes and renal failures are pathologies that have mid-risk factors such as dyslipidemia, hypertension and diabetes, which in turn are caused by obesity, whose primary risk factor is represented by the diet. The aim of the present review is to consider the importance of body composition, together with chronic inflammation and a new gut microbiota data that may turn out to be crucial elements of some target treatment of human obesity. Methods: In this review, we performed research using PubMed database reviewing the evidence in the literature of evidence information regarding the link between obesity and body composition in the development of metabolic disease via inflammation markers and in particular, the new role exerted by gut microbiota. Results: Several papers were evaluated searching for differences in fat mass and disease risk. We also identified the same papers dealing with differences in body composition and metabolic syndrome. Our attention focuses also on a new frontier of gut microbiota composition in the body weight decrease and anti-inflammatory effects. Conclusion: To the saving of lean mass, for the prevention of cardiometabolic diseases, also considering the relationship with obesity, it is necessary to reduce the inflammatory state, acting on the gut-microbiota and on the intestinal permeability. To improve the health of the intestinal flora, we propose a 4P medicine and treatment with probiotics, prebiotics, postbiotics, and polyphenols.

Contains fulltext : 206959.pdf (Publisher’s version ) (Closed access) We have previously shown that the chromogranin A (CgA)-derived peptide catestatin (CST: hCgA352-372) inhibits nicotine-induced secretion of catecholamines from the adrenal medulla and chromaffin cells. In the present study, we seek to determine whether CST regulates dense core (DC) vesicle (DCV) quanta (catecholamine and chromogranin/secretogranin proteins) during acute (0.5-h treatment) or chronic (24-h treatment) cholinergic (nicotine) or peptidergic (PACAP, pituitary adenylyl cyclase activating polypeptide) stimulation of PC12 cells. In acute experiments, we found that both nicotine (60 muM) and PACAP (0.1 muM) decreased intracellular norepinephrine (NE) content and increased (3)H-NE secretion, with both effects markedly inhibited by co-treatment with CST (2 muM). In chronic experiments, we found that nicotine and PACAP both reduced DCV and DC diameters and that this effect was likewise prevented by CST. Nicotine or CST alone increased expression of CgA protein and together elicited an additional increase in CgA protein, implying that nicotine and CST utilize separate signaling pathways to activate CgA expression. In contrast, PACAP increased expression of CgB and SgII proteins, with a further potentiation by CST. CST augmented the expression of tyrosine hydroxylase (TH) but did not increase intracellular NE levels, presumably due to its inability to cause post-translational activation of TH through serine phosphorylation. Co-treatment of CST with nicotine or PACAP increased quantal size, plausibly due to increased synthesis of CgA, CgB and SgII by CST. We conclude that CST regulates DCV quanta by acutely inhibiting catecholamine secretion and chronically increasing expression of CgA after nicotinic stimulation and CgB and SgII after PACAPergic stimulation.

The global pandemic coronavirus disease (COVID-19) resulted in restrictions which forced adolescents to stay at home and influenced their food habits and lifestyles with potential negative health impact. This study aims to investigate the self-reported physical activity (PA) and eating habits related to the consumption of Mediterranean foods in a sample of adolescents during the COVID-19 lockdown enrolled into the DIMENU study. A web survey was launched for 91 adolescents (aged 15–17 years) to assess their adherence to the Mediterranean Diet using the KIDMED test and lifestyle habits using a questionnaire designed following recommendations by Italian National Institute of Health (ISS score). Our results indicate that most of the sample declared no changes in eating habits and PA without sex differences. After dividing the sample into active and sedentary groups based on the self-perceived PA, we found that KIDMED and ISS scores were significantly higher (p = 0.0028 and p = 0.0001, respectively) in active adolescents. Moreover, KIDMED was positively correlated with ISS only in active adolescents (r = 0.311, p = 0.0185). In conclusion, our data underline the impact of the PA on the Mediterranean diet adherence in adolescents during the lockdown, suggesting the usefulness of promoting wellness programs directed towards inactive individuals to increase their awareness on the importance of healthy lifestyles.

Hypertension is associated with inflammation and excessive production of catecholamines. Hypertensive patients have reduced plasma levels of CST (catestatin)—a bioactive cleavage product of the prohormone CgA (chromogranin A). In mouse models, hypertension symptoms can be reduced by administration of CST, but the role of CST in the regulation of cardiovascular function is unknown. In this study, we generated mice with KO (knockout) of the region of the CgA gene coding for CST (CST-KO) and found that CST-KO mice are not only hypertensive as predicted but also display left ventricular hypertrophy, have marked macrophage infiltration of the heart and adrenal gland, and have elevated levels of proinflammatory cytokines and catecholamines. Intraperitoneal injection with CST reversed these phenotypes, and ischemic preconditioning-induced cardioprotection was also abolished in CST-KO mice. Experiments with chlodronate depletion of macrophages and bone marrow transfer showed that macrophages produce CST and that the antihypertensive effects of CST are mediated, in part, via CST’s immunosuppression of macrophages as a form of feedback inhibition. The data thus implicate CST as a key autocrine attenuator of the cardiac inflammation in hypertension by reducing macrophage inflammation.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder featuring altered neuronal circuitry and consequently impaired social interactions, restrictive interests plus repetitive stereotypic activities. In the present study, differentiated behaviors of valproic (VPA) and propionic (PPA) acid-mediated autism rats were correlated to cerebral scaffolding proteins (Shank1,3) and BDNF expression variations. Sprague-Dawley offspring that received VPA during pregnancy displayed a notably diminished permanence (-78 %, p < 0.01) in the light chamber of light dark (LD) test, reduced exploratory tasks, i.e. grooming (-90 %) and rearing (-65 %). Moreover, they executed extremely greater climbing intervals (+300 %, p < 0.001) in novel cage (NC) test, plus exhibited an extremely reduced (-331 %) discrimination index in novel object recognition (NOR) test when compared to controls. PPA-treated postnatal days (PND) 12-16 rats also displayed anxiety-like behaviors, although in a less evident manner, as indicated by a moderate time (+55 %; p < 0.05) spent in dark chamber along with notable and moderate decreases in digging (-78 %) plus grooming (-52 %), respectively. Contextually, VPA- more than PPA supplied opposite Shank1,3 expression changes in cerebellum (CB; -62 %; +78 %), dorsomedial prefrontal cortex (DM-PFC; +95 % -76 %), respectively, while resulting extremely upregulated in hippocampus (HIP; +125 % - +155 %). Even BDNF resulted to be substantially and notably diminished in HIP (-85 %) and DM-PFC (-72 %), respectively, of VPA rats while it was only moderately reduced (-35 % to -45 %) in these same areas of PPA rats. The early altered brain-specific expression levels accounting for different behavioral performances may provide useful diagnostic indications and constitute valuable therapeutic strategies for autistic patients.

At present, concerns are pointing to “tasteful” high-fat diets as a cause of conditioning physical-social states that through alterations of some key emotional- and nutritional-related limbic circuits such as hypothalamic and amygdalar areas lead to obesity states. Feeding and energetic homeostatic molecular mechanisms are part of a complex neuronal circuit accounting for this metabolic disorder. In an attempt to exclude conventional drugs for treating obesity, daidzein, a natural glycosidic isoflavone, which mimics estrogenic neuroprotective properties against increased body weight, is beginning to be preferred. In this study, evident anxiolytic-like behaviors were detected following treatment of high-fat diet hamsters with daidzein as shown by extremely evident (p

Hypertension (HTN) is a pandemic associated with inflammation and excessive production of catecholamines. Previous work has shown that hypertensive patients have reduced plasma levels of Catestatin (CST), a bioactive cleavage product of the prohormone Chromogranin A (CgA). Similarly, in mouse models, HTN symptoms can be reduced by administration of CST, but the role of CST in the regulation of cardiovascular function is unknown. In the present study, we generated mice with knockout (KO) of the region of the CgA gene coding for CST (CST-KO) and found that CST-KO mice are not only hypertensive as predicted, but also display left ventricular hypertrophy, have marked macrophage infiltration of the heart and adrenal gland, and have elevated levels of pro-inflammatory cytokines and catecholamines. Additionally, intraperitoneal injection with CST reverses these phenotypes, and ischemic pre-conditioning-induced cardioprotection was also abolished in CST-KO mice. To further explore the relationship between HTN, CST, and macrophages, experiments with chlodronate depletion of macrophages and bone-marrow transfer showed that macrophages produce CST and that the anti-hypertensive effects of CST are mediated in part via immunosuppression of macrophages by CST as a form of feedback inhibition. The data thus implicate CST as a key autocrine attenuator of the cardiac inflammation in HTN by reducing macrophage inflammation.

In adolescence, health status is influenced by several factors, including dietary pattern and physical activity (PA) which are crucial elements of lifestyle in terms of prevention and treatment of metabolic and chronic diseases. The current study aimed to explore the impact of the different intensity levels of PA along with the adherence to a Mediterranean diet (MD), on body composition indices and metabolic parameters in a cohort of adolescents, thereby investigating potential predictors of health behavior in youth. This cross-sectional study was carried out among 92 participants (44 girls and 48 boys, aged 14 to 17 years), which were divided into the following three groups according to intensity levels of PA: Group A (physical inactivity), Group B (moderate PA), and Group C (vigorous-intensity PA). The Questionnaire of Adherence to the Mediterranean Diet (KIDMED test) was used to assess both diet composition and adherence to a MD. All subjects underwent anthropometric measurements, bio-impedentiometric analysis for body composition parameters, and biochemical and hormonal measurements. The majority of adolescents (60.87%) had a medium adherence to the MD, and even a better distribution of food rates was found in adolescents performing vigorous-intensity PA. A comparison of anthropometric measurements and body composition parameters among groups showed that body mass index and fat mass (FM) were significantly lower while body cell mass (BCM), free fat mass (FFM), phase angle (PhA), and total body water (TBW) were higher in Group C adolescents as compared with those of Group A. In Group C, insulin resistance (HOMA-IR) was reduced and insulin levels were inversely associated with FFM (r = −0.454 and p = 0.004) and directly correlated with FM (r = 0.331 and p = 0.003). In the same Group C, we observed elevated serum irisin levels and lower lipid profile markers as compared with Group A. Interestingly, irisin negatively correlated with both total cholesterol (r = −0.428 and p = 0.04) and LDL (r = −0.468 and p = 0.02) in Group C. Finally, a receiver operator characteristic curve (ROC) analysis revealed irisin, LDL, HDL, and body composition variables (FFM, BMC, PhA, and TBW) as the most predictive measures for vigorous-intensity PA. Our results highlight the importance of developing healthy lifestyle programs that include improving the intensity of PA among a young population as a superior strategy for ensuring a better quality of life.

Adolescent nutrition and healthy dietary patterns, particularly the Mediterranean diet (MD), have been associated with improved health status and decreased risk of various chronic and metabolic diseases later in life. The aim of this study was to evaluate the impact of the Mediterranean food choices on lipid and glycemic metabolic profile in the total population and in adolescents grouped according to their physical activity (PA) levels at the time of recruitment (T0) and after six months from the administration of a personalized Mediterranean meal plan (T1). As part of the DIMENU study, 85 adolescents underwent measurements of lipid and glucose metabolic profile at T0 and T1. Using three positive items from KIDMED test related to the consumption of typical Mediterranean food (olive oil, fish, and nuts) and three negative items on dietary habits (going to fast-food, consuming biscuits, and candies), we categorized adolescents into six sets in which biochemical parameters were analyzed. In the total sample, significant reductions in serum total cholesterol, LDL, and glucose concentrations were observed for all the sets over the study period. Notably, active subjects, who had a better serum metabolic profile, showed significant improvements of glycemic control after 6 month follow up, while in sedentary adolescents and in those performing moderate PA significant reduction in glycemia, total cholesterol, and LDL was found in all sets. In conclusion, adopting the typical Mediterranean food choices led to a significant reduction in glucose and lipid profile in healthy adolescents, thus making the MD and PA a winning combination for health status.

It is already widely known that the different brain areas involved in blood pressure control, are highly vulnerable to the deleterious effects of this condition. Of particular concern are hypertensive and neuroinflammatory-dependent injuries that by modifying blood flow account for artery structural and functional alterations. It was thus our intention to establish if expression changes of some key brain neuroinflammatory factors like caspase-1,3, NF-kB, IL-1β and NLRP3, which are known to control blood pressure, are actively involved with inflammation regulatory events in a highly valuable spontaneously hypertensive rat (SHR) model. Indeed, notably increased (p 0.001) caspase-1, NLRP3 and IL-1β mRNA levels were detected in amygdalar plus hypothalamic areas of SHR. Contextually, similar up-regulated levels of these factors were also reported in brainstem nuclei with respect to the few hippocampal areas. This trend was supported by moderate increases (p 0.05) of NLRP3 in amygdalar and brainstem sites, while notably greater expression differences of NF-kB protein were observed in hippocampal and hypothalamic areas of SHR. At the same time, moderately increased levels of iNOS were typical of all of the above brain areas with the exception of the consistently (p 0.01) increased levels featured in the brainstem. Moreover, even immunohistochemical evaluations supplied notably and moderately increased cleaved caspase-3 cell levels in hippocampus and hypothalamus areas, respectively. Overall, evident hypertensive bouts correlated to neuroinflammatory events, especially in brain areas controlling blood pressure, tend to underlie the value of novel therapeutic approaches designed to improve brain blood flow and subsequently reduce hypertensive-dependent cerebral complications.

The mechanisms by which inflammation affects the different emotional moods are only partially known. Previous works have pointed to stress hormones like glucocorticoids plus the vascular factor endothelin-1 as key factors evoking stressful states especially in relation to endothelial dysfunctions. With this work, it was our intention to establish the role of pro- and anti-inflammatory cytokine expression variations towards depression-like behaviors and consequently the development of neurodegeneration events caused by endothelial damages in the hamster (Mesocricetus auratus). Such a rodent, which is considered a valuable animal model to test depression and anxiety states, exhibited a variety of depression-like behaviors including reduction in sucrose consumption, locomotion, and exploration (p

It is well established that the maintenance of energy expenditure is linked to active hypothalamic neural mechanisms controlling adaptive stimuli such as food intake. Variations of glucose levels and hormonal (leptin plus orexin-A) parameters, which are involved with energy homeostasis during different behavioral states, have not yet been fully defined. In this first study, behavioral analyses of an unpredictable stress model dealing with the actions of a sub-chronic administration of orexin-A (ORX-A) and the anti-hunger neuropeptide, i.e., leptin (LEP) within the hypothalamic suprachiasmatic (SCH) nucleus, were conducted on the valuable hibernating rodent (hamster; Mesocricetus auratus) model noted for its distinct depression and anxiety states. Treatment with LEP accounted for a notable reduction (p

Emerging studies are beginning to suggest that emotional states together with healthful measures constitute pertinent features of our lifestyle in which bad eating habits but more importantly what our gut has to host are causing great concern. It is well known that humans have established mutual relationships with a wide array of colonized microbes (collectively called gut microbiota) consisting of bacteria, fungi, eukaryotic parasites and viruses. The gut microbiota has exhibited a notable ability of communicating with the brain via a two-way system that includes the vagus nerve, immune sites, and a number of neurotransmitters. Interestingly, stressful along with obesity, cognitive, and brain developmental states are strongly influenced by microbiota homeostatic conditions. It was our aim to investigate behavioral and obesity effects evoked by treatment with probiotics via neuroinflammatory factors and namely IL-1β, NLRP3, Caspase-1 and NF-kB levels in the Syrian golden hamster. Following treatment with a high-fat diet (HFD), in the presence or absence of a multi-species probiotic formulation, hamsters were exposed to an unpredictable chronic mild stress (UCMS) test for 4 weeks. Independently of the diet, probiotics treatment markedly reduced stress-like behaviors in the different mazes. Moreover, probiotics decreased hypothalamic expression levels of the pro-neuroinflammatory factors like IL-1β, NLRP3, Caspase-1 and NF-kB, whereas HFD increased them. Contextually, they decreased plasmatic levels of IL-1β, NLRP3 and caspase-1 but not NF-kB. Our findings clearly support probiotics as a potentially valuable treatment strategy in obesity and anxiety, thereby proposing them for clinical treatments in patients with metabolic and mood disorders.

Interaction of the orexinergic (ORXergic) neuronal system with the excitatory (glutamate, l -Glu) or the inhibitory (GABA) neurosignaling complexes evokes major homeostatic physiological events. In this study, effects of the two ORXergic neuropeptides (ORX-A/B) on their receptor (ORX-2R) expression changes were correlated to feeding and grooming actions of the hibernating hamster ( Mesocricetus auratus ). Infusion of the central amygdala nucleus (CeA) with ORX-A caused hamsters to consume notable quantities of food, while ORX-B accounted for a moderate increase. Interestingly the latter neuropeptide was responsible for greater frequencies of grooming with respect to both controls and the hamsters treated with ORX-A. These distinct behavioral changes turned out to be even greater in the presence of l -Glu agonist (NMDA) while the α 1 GABA A receptor agonist (zolpidem, Zol) greatly reduced ORX-A-dependent feeding bouts. Moreover, ORX-A + NMDA mainly promoted greater ORX-2R expression levels with respect to ORX-A-treated hamsters while ORX-B + Zol was instead largely responsible for a down-regulatory trend. Overall, these features point to CeA ORX-2R sites as key sensory limbic elements capable of regulating eating and grooming responses, which may provide useful insights regarding the type of molecular mechanism(s) operating during feeding bouts.

Recently, there has been growing interest in the neurobiological role of some amygdalar neuromediators, such as GABA and orexins (ORX), that are responsible for stressful behaviors. Infusion of the major fear-related and panic-related basolateral amygdalar station, the lateral nucleus, with ORX-A and ORX-B, alone or in combination with the main α1-containing GABAA receptor agonist (zolpidem), modified anxiety states of the Syrian hamster. Single daily doses of ORX-A led to evident anxiogenic features, as pointed out by more time spent in the dark compartment of the light-dark exploration test, effects that were suppressed by zolpidem. Conversely, doses of ORX-B induced anxiolytic effects, whereas the concomitant administration of this neuropeptide with zolpidem strongly favored anxiogenic responses. In addition, these behavioral responses resulted in a widely correlated upregulation of the ORX-2 receptor in some key feeding and motor limbic areas, such as the ventromedial hypothalamic nucleus, central amygdalar nucleus, and hippocampal CA1 layer. Overall, these first indications on the differing anxiety states induced by ORX-A and ORX-B injected into the lateral amygdalar nucleus alone or in combination with zolpidem may constitute useful future therapeutic alternatives for the treatment of panic disorders as well as stressful behaviors.

Studies have pointed to both α-amino-3-hydroxy-5- methyl-4-isoxazole propionic acid receptor (AMPAR) antago- nists and GABAA receptor (GABAAR) agonists as potent antistress agents. In this work, separate subchronic injections of the AMPAR antagonist, 6-ciano-7-nitroquinoxaline-2,3- dione (CNQX), and α1 GABAAR subunit agonist (Zol) within the central amygdala nucleus modified the elevated plus maze performances of hamsters exposed randomly to one of the following stressful conditions: food/water deprivation, forced swimming test, and permanence in cold room. Indeed, stressed hamsters treated with CNQX or Zol displayed a very great (p

Hypothermia is a physiological condition assuring brain protection against hypoxic-related damages. In this con- text, investigations carried out on the facultative hibernator Mesocricetusauratusprovedtobeveryusefulfor establishing thetypeofneurosignalingroleexertedbycerebral α-amino-3- hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subtypes during hypoxic/reperfusion injuries of the entrance (EN), torpor (TORP), and arousal (AROU) hi- bernating states. From the evaluation of the major AMPARs (GluR1 and GluR2), together with their scaffold proteins synapse-associated protein 97 kDa (SAP97) and PICK1, it resulted that GluR1 and SAP97 were mostly upregulated during the hypotensive (EN and TORP) states of the brainstem, amygdala, and hypothalamus, sites which are im- plicated with cardiovascular, motor, and sleep-wake events. In addition, elevated expression densities of the pro-apoptotic factor Bcl-2-associated X protein (Bax) resulted to be corre- lated to marked amino-cupric-silver stain signals during both hibernating states. Conversely, an increase of the neuroprotec- tive factor GluR2, together with PICK1 and the anti-apoptotic B cell lymphoma 2 (Bcl-2), appeared to be linked with re- duced argyrophilic signals in most of the above areas of the hypertensive AROU state. These first indications highlight distinct protective/degenerative measures of the above factors constituting key on/off switches during the various hibernat- ing states that may provide potential therapeutic bearings on sleeping disorders.

Several studies have pointed to the amygdala as a main limbic station capable of regulating different stressful states such as anxiety and depression. In this work it was our intention to determine the role of the central amygdala nucleus (CeA) on the execution of either anxiolytic and/or anti-depressant behaviors in the hibernating hamster (Mesocricetus auratus) via infusion of CeA with the antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) specific for α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) plus the specific agonist for α4 GABAAR i.e. 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP). Treatment with CNQX appeared to mainly prompt anti-depressant effects as shown by the achievements of swimming feats during forced swim test while THIP prevalently accounted for evident bouts of climbing when exposed to the same test. Moreover, even in the presence of the concomitant administration of both of these compounds, hamsters continued to spend more time in swimming despite this significant behavioral effect resulted to be numerically reduced for hamsters treated with only the α4 GABAAR agonist. Conversely, when these animals were tested in elevated plus maze (EPM), THIP tended to mostly favor anxiolytic activities as exhibited by stressed animals spending more time entering and remaining in EPM open arms. It was interesting to note that behavioral changes induced by both drugs appeared to be also responsible for glutamate receptor (GluR) expression differences as indicated by CNQX favoring an evident up-regulation of GluR2-containing neurons whereas THIP induced an up-regulation, this time of GluR1-containing neurons. Overall, the anti-depressant role of CNQX seems to be mostly attributed to elevated GluR2 levels while an anxiolytic-like effect of THIP was correlated to high GluR1values thereby proposing distinct GluRs as useful therapeutic sites against degenerative diseases such as depression-like behaviors.

Depletion of oxygen and glucose even for brief periods is sufficient to cause cerebral ischemia, which is a predominant worldwide cause of motor deficits with the reduction of life quality and subsequently death. Hence, more insights regarding protective measures against ischemic events are becoming a major research goal. Among the many neuronal factors, N-methyl-D-aspartate receptors (NMDAR), orexinergic neuroreceptors (ORXR), and sympatho-inhibitory neuropeptide catestatin (CST) are widely involved with ischemic episodes. In this study, it was possible to induce in vitro ischemic conditions of the hamster (Mesocricetus auratus) hippocampal and hypothalamic neuronal cultures, grown on a newly compartmentalized membrane system, via oxygen and glucose deprivation (OGD). These cultures displayed notably differentiated NMDARergic and ORXergic receptor expression activities along with evident brain-derived neurotrophic factor (BDNF) plus orexin A (ORX-A) secretion, especially under co-cultured conditions. Interestingly, addition of CST in OGD-insulted hippocampal cells accounted for upregulated GluN1 and ORX1R transcripts that in the case of the latter neuroreceptor was very strongly (p

At present neurobiological interests are directing more attention towards the major role of the amygdalar GABA(A) receptor on orexin-dependent behaviors. This telencephalic region has been widely studied especially in view of its control on various psychiatric disorders such as anxiety and depression. Recently, cross-talking relationships between these two specific neuroreceptor systems of the central-cortical amygdalar complex has been considered an important element for anxiety type of behaviors. In the present study, we investigated the effects of central amygdalar infusions with orexin-A, orexin-B±GABA(A) receptor α₂ subunit agonist (flunitrazepam) on elevated plus-maze and light-dark explorative behaviors of the facultative hibernating Syrian hamster. In a first case, it seemed that doses of orexin administered directly into the central nucleus were responsible for greater anxiogenic type of effects as shown by more time being spent both in the dark compartment and the closed arm of the elevated plus-maze, whereas, these effects were suppressed in the presence of flunitrazepam. At the cellular level, the effects of orexin accounted for evident argyrophilic reactions (neurodegeneration phenomena) including altered cell membrane and loss of cytoplasmic architecture in most amygdalar and hippocampal neuronal fields, while in the presence of flunitrazepam these reactions resulted to either be unappreciable or absent. Overall the actions of α₂-dependent inhibitory signals tend to corroborate, for the first time, a neuroprotective role against the over-excitatory orexinergic neurodegeneration reactions and thus its abnormal anxiety-like indications may prove to be therapeutically useful for orexin-dependent sleeping disorders.

Catestatin (CST), an endogenously small sympathoinhibitory peptide is capable of interfering with the major cerebral neuroreceptor-blocking site, i.e. γ-aminobutyric acidA receptor (GABAAR) system especially in limbic brain areas that are involved with feeding behaviors. The GABAARergic-related effects seem to derive from its interaction with other molecular neuroreceptors such as dopaminergic, ghrelin and leptinergic. In this context, the present study aimed to investigate probable feeding responses (eating and drinking) induced by treatment with CST and the GABAAR antagonist bicucullin (BIC) alone or simultaneously (CST+BIC) in the Syrian hibernating hamster (Mesocricetus auratus) model. Hamsters that received these compounds via intracerebroventricular infusions displayed notable variations of feeding and drinking bouts. In particular, an anorexigenic response was evident following treatment with CST while BIC evoked a significant increase of eating and drinking behaviors. Surprisingly when both agents were given simultaneously, a predominating anorexigenic response was detected as shown by evident CST-dependent reduction of feeding bouts. Contextually such behaviors, especially those following the combined treatment were tightly correlated with the significantly increased cerebral dopamine receptor 1 (D1) plus reduced ghrelin receptor (GhsR) and leptin receptor (LepR) transcript levels. Overall, the anorexigenic effect of CST deriving from its tight interaction with GABAARs activity plus D1 and GhsR transcripts tends to propose these neuronal elements as pivotal factors responsible for feeding disorders.

Recent evidences indicate that cerebral neurotrophic factors like vascular endothelial growth factor plus signaling pathways of the glutamatergic neuroreceptor system (L-Glu) are determinant modulators of depression-like states. In the present study, the type of interaction(s) exerted by the AMPAergic antagonist, 6-cyano-7-nitroquinoxalin-2,3-dione (CNQX) and the brain derived neurotrophic factor (BDNF) on depression-like behaviors in hamsters (Mesocricetus auratus) were investigated. Sub-chronic administration of BDNF in the hippocampal dentate gyrus (DG) of stressed hamsters was responsible for very evident (p

Brain ischemia is a major cause of death and the most common element of disability in the adult population worldwide. This phenomenon occurs when blood flow is reduced or interrupted in the various brain districts leading to oxygen and glucose deprivation (OGD), which by triggering a complex series of biochemical plus molecular mechanisms such as an exacerbated production of misfolded and oxidized proteins together with the breakdown of cellular integrity are responsible for neuronal cell death. Despite the mechanisms that underlie the triggering of ischemic insults are still unclear, numerous studies are pointing to excitotoxic glutamatergic neuronal signaling processes as key mediators of these events. Indeed, cultured neurons deriving from global cerebral ischemia appear to respond to OGD with a rapid internalization of α ‑ amino ‑ 3 ‑ hydroxy ‑ 5 ‑ methyl ‑ 4 ‑ isoxazolepropionic acid receptors (AMPAR) thereby suggesting them as critical components of OGD-induced cell death. It strongly seems that OGD-dependent neuronal ischemia occurs via GluR2-sites in which a switching from GluR2-containing Ca 2+ -impermeable receptors to GluR2-lacking Ca 2+ -permeable subtypes constitutes an important step. Interestingly attention regarding excitotoxicity-related ischemic events, aside being largely directed to the o veractivation of AMPARs, appear to be also tightly linked to the translocation of the pro-apoptotic protein Bax to the mitochondria accounting for the activation of the caspase factors. Although the brain is able to repair part of the neuronal damages and to restore the morpho-functional organization, cerebral ischemia more than ever continues to attract much attention especially due to its elevated mortality feature. In this review we analyzed the role played by GluR2 AMPAR subunit in the pathological processes that lead to neurodegenerative diseases with particular attention being paid to the assembly of the major synaptic AMPARs together with cellular events that feasibly account for ischemic brain damages. In this context, knowledge of the different molecular mechanisms operating under these conditions may surely provide helpful indications regarding the identification of new therapeutic targets for treating cerebral ischemia.

Chromogranin A knockout (Chga-KO) mice exhibit enhanced insulin sensitivity despite obesity. Here, we probed the role of the chromogranin A–derived peptide pancreastatin (PST: CHGA273–301) by investigating the effect of diet-induced obesity (DIO) on insulin sensitivity of these mice. We found that on a high-fat diet (HFD), Chga-KO mice (KO-DIO) remain more insulin sensitive than wild-type DIO (WT-DIO) mice. Concomitant with this phenotype is enhanced Akt and AMPK signaling in muscle and white adipose tissue (WAT) as well as increased FoxO1 phosphorylation and expression of mature Srebp-1c in liver and downregulation of the hepatic gluconeogenic genes, Pepck and G6pase. KO-DIO mice also exhibited downregulation of cytokines and proinflammatory genes and upregulation of anti-inflammatory genes in WAT, and peritoneal macrophages from KO mice displayed similarly reduced proinflammatory gene expression. The insulin-sensitive, anti-inflammatory phenotype of KO-DIO mice is masked by supplementing PST. Conversely, a PST variant peptide PSTv1 (PST-NΔ3: CHGA276–301), lacking PST activity, simulated the KO phenotype by sensitizing WT-DIO mice to insulin. In summary, the reduced inflammation due to PST deficiency prevented the development of insulin resistance in KO-DIO mice. Thus, obesity manifests insulin resistance only in the presence of PST, and in its absence obesity is dissociated from insulin resistance.

Cigarette smoking causes insulin resistance. However, nicotine induces anti-inflammation and improves glucose tolerance in insulin-resistant animal models. Here, we determined the effects of nicotine on glucose metabolism in insulin-sensitive C57BL/J6 mice. Acute nicotine administration (30 min) caused fasting hyperglycemia and lowered insulin sensitivity acutely, which depended on the activation of nicotinic-acetylcholine receptors (nAChRs) and correlated with increased catecholamine secretion, nitric oxide (NO) production, and glycogenolysis. Chlorisondamine, an inhibitor of nAChRs, reduced acute nicotine-induced hyperglycemia. qRT-PCR analysis revealed that the liver and muscle express predominantly β4 > α10 > α3 > α7 and β4 > α10 > β1 > α1 mRNA for nAChR subunits respectively, whereas the adrenal gland expresses β4 > α3 > α7 > α10 mRNA. Chronic nicotine treatment significantly suppressed expression of α3-nAChR (predominant peripheral α-subunit) in liver. Whereas acute nicotine treatment raised plasma norepinephrine (NE) and epinephrine (Epi) levels, chronic nicotine exposure raised only Epi. Acute nicotine treatment raised both basal and glucose-stimulated insulin secretion (GSIS). After chronic nicotine treatment, basal insulin level was elevated, but GSIS after acute saline or nicotine treatment was blunted. Chronic nicotine exposure caused an increased buildup of NO in plasma and liver, leading to decreased glycogen storage, along with a concomitant suppression of Pepck and G6Pase mRNA, thus preventing hyperglycemia. The insulin-sensitizing effect of chronic nicotine was independent of weight loss. Chronic nicotine treatment enhanced PI-3-kinase activities and increased Akt and glycogen synthase kinase (GSK)-3β phosphorylation in an nAChR-dependent manner coupled with decreased cAMP response element–binding protein (CREB) phosphorylation. The latter effects caused suppression of Pepck and G6Pase gene expression. Thus, nicotine causes both insulin resistance and insulin sensitivity depending on the duration of the treatment.

Chromogranin A (Chga) is abundant in (neuro) endocrine cells, and its derived peptide catestatin (CST) acts as an antihypertensive, cardioprotective, pro-angiogenic, and insulin-sensitizing peptide...

Hibernation is a physiological state that by putting vital biological processes at rest enables mammals to protect all organs, especially the brain against ischemic insults and reperfusion injuries. Earlier studies have highlighted the role of hypothalamic (HTH) sites like the periventricular nucleus (Pe) toward sleep-wake and cardiovascular activities of hibernators. In the present work, infusions of Pe with the orexigenic neuropeptide orexin-A (ORX-A) or the novel anti-obesity sympathoinhibitory neuroactive peptide catestatin (CST) have been correlated to differing feeding and motor behaviors in the facultative hibernating hamster Mesocricetus auratus. Behavioral observations showed that treatment with CST provided an anti-obesity activity via the reduction of food intake and body weight for all hibernating states, while ORX-A promoted orexigenic events during mainly the entrance phase. Moreover, hamsters treated with this neuropeptide during the entrance and the arousal hypertensive phases also featured elevated ORX 2 receptor (ORX2R) levels in the third layer of the parietal cortex and lateral HTH (LH), areas involved with feeding, motor plus sleep-wake rhythms. Conversely, ORX-A down-regulated ORX2Rs in the ventromedial (VMH) and supraoptic (SO) HTH nuclei that are associated with anorexigenic effects. Even CST induced mixed ORX2R expression patterns in mostly HTH areas like the evident down-regulation in LH along with the up-regulation in VMH and SO. Overall treatments, especially ORX-A+CST led to reduced neurodegenerative phenomena in HTH supporting their importance together with ORX2Rs in preserving hemodynamic activities, feeding and sleep-wake rhythms of this diencephalic station, which may supply useful therapeutic indications for treating cardiovascular disturbances linked with brain dysfunctions.

Recent interferences of hemodynamic functions via modified brain neuronal mechanisms have proven to be major causes of dementia and sleeping disorders. In this work, cerebral expression differences of the neuroactive vesicular chromogranin A (CgA) and distinct α GABAAR subunits were detected in the facultative hibernating hamster. In particular, damaged neuronal fields of hypotensive torpor (TORP) state were correlated to elevated CgA and GABAAR α1, α4 mRNA levels in the paraventricular hypothalamic nucleus (PVN), central amygdalar nucleus (CeA) plus solitary tractus nucleus (NTS). Conversely, few neurodegeneration signals of hypertensive arousal (AROU) state, accounted for mostly lower CgA levels in the same areas. This state also provided increased α2-containing sites in amygdala, hippocampal and NTS neurons together with elevated α4-containing receptors in the periventricular hypothalamic nucleus (Pe). Interestingly in our hibernating model, CgA appeared to preferentially feature inhibitory neurosignals as indicated by preliminary perfusion of amygdalar sites with its highly specific antihypertensive derived peptide (catestatin) promoting GABA-dependent sIPSCs. Overall, evident neuronal damages plus altered expression capacities of CgA and α1-, α2-, α4-GABAARs in CeA, Pe, PVN as well as NTS during both hibernating states corroborate for the first time key molecular switching events guaranteeing useful cardiovascular rescuing abilities of neurodegenerative disorders.

Recently, environmental stimuli on different neurobiological events, via participation of distinct amygdalar (AMY) ORXergic fibers have aroused wide interests in view of their ability to modify neuronal linked stressful and physiological homeostatic conditions. Results of the present study indicate that ORXergic (ORX-A/B) circuits of the facultative hibernating golden hamster (Mesocricetus auratus) central AMY (CeA) and basolateral AMY (BlA) nuclei constitute major sites of feeding behaviors. Indeed, hamsters after treatment of BlA with ORX-A frequently ingested greater quantities of food as compared to controls, while ORX-B in CeA induced a very (p0.001) great consumption of water. The same nuclei treated separately with either ORX-A or ORX-B ± the selective α(1) GABA(A) benzodiazepine receptor agonist (zolpidem) dedicated less time to eating and drinking sessions. Conversely, hamsters that received the same neuropeptides but this time with the glutamatergic agonist NMDA displayed greater hyperphagic effects above all for ORX-A. When behavioral changes were compared to the expression of the specific ORXergic receptor (ORX-2R), an up-/down-regulating pattern was detected in some limbic areas (AMY, hippocampus and hypothalamus) following treatment with ORX-A or ORX-B plus NMDA. Overall, indications deriving from this study strongly point to hamster BlA-enriched ORX-A fibers in combination with either inhibitory or excitatory signals as main targets of hyperphagic responses while CeA ORX-B activities in presence of these same neuronal signals predominantly induced drinking motivational behaviors. The distinct behavioral activities of these two neuropeptides may have useful clinical bearings toward psychiatric and sleeping disorders such as bulimia and narcolepsy.

To date, many scientific attempts have been directed towards the development of experimental models for the identification of neuronal mechanisms evoking cardiovascular and hemodynamic dysfunctions. The spontaneously hypertensive rat (SHR), a genetic model of essential hypertension, has become a valuable rodent for the characterization of molecular markers in hypertensive-related diseases. Recently, growing interests have also been directed to a new experimental paradigm i.e. hibernation, a physiological state consenting the hamster (Mesocricetus auratus) to activate protective mechanisms against ischemic-like complications during the arousal phase. With this intention, the present review will focus attention on specific neurosignaling systems involved with the preservation of hemodynamic conditions in those brain areas that play a pivotal role on such a feature. It is widely known that healthy neurons conserve their structural and responsiveness properties in presence of a constant blood supply, which is assured by their coupling to microvessels and perivascular astrocytes as well as by secretory proteins such as chromogranin A (CgA). So, it will be interesting to establish if this protein alone or with the participation of excitatory/inhibitory neurosignals is capable of influencing some brain areas controlling cardiovascular conditions in both SHRs and hibernating hamsters. In this context, the present work will deliver the most important findings regarding neuronal CgA and its cross-talking ability with major inhibitory (GABA/adenosine) and/or excitatory (glutamate) neuroreceptor systems in relation to hypertensive/hypotensive states of both animal models. Indications deriving from such approaches may provide clinically useful insights regarding their role as protective factors of hemodynamic and neurological disorders.

Background Excitatory transmitting mechanisms are proving to play a critical role on neuronal homeostasis conditions of facultative hibernators such as the Syrian golden hamster. Indeed works have shown that the glutamatergic system of the main olfactory brain station (amygdala) is capable of controlling thermoregulatory responses, which are considered vital for the different hibernating states. In the present study the role of amygdalar glutamatergic circuits on non-hibernating (NHIB) and hibernating (HIB) hamsters were assessed on drinking stimuli and subsequently compared to expression variations of some glutamatergic subtype mRNA levels in limbic areas. For this study the two major glutamatergic antagonists and namely that of N-methyl-D-aspartate receptor (NMDAR), 3-(+)-2-carboxypiperazin-4-yl-propyl-1-phosphonate (CPP) plus that of the acid α-amine-3-hydroxy-5-metil-4-isoxazol-propionic receptor (AMPAR) site, cyano-7-nitro-quinoxaline-2,3-dione (CNQX) were infused into the basolateral amygdala nucleus. Attempts were made to establish the type of effects evoked by amygdalar glutamatergic cross-talking processes during drinking stimuli, a response that may corroborate their major role at least during some stages of this physiological activity in hibernators. Results From the behavioral results it appears that the two glutamatergic compounds exerted distinct effects. In the first case local infusion of basolateral complexes (BLA) with NMDAR antagonist caused very great (p < 0.001) drinking rhythms while moderately increased feeding (p < 0.05) responses during arousal with respect to moderately increased drinking levels in euthermics. Conversely, treatment with CNQX did not modify drinking rhythms and so animals spent more time executing exploratory behaviors. These same antagonists accounted for altered glutamatergic transcription activities as displayed by greatly reduced GluR1, NR1 and GluR2 levels in hippocampus, ventromedial hypothalamic nucleus (VMN) and amygdala, respectively, plus a great (p < 0.01) up-regulation of GluR2 in VMN of hibernators. Conclusion We conclude that predominant drinking events evoked by glutamatergic mechanisms, in the presence of prevalently down regulated levels of NR1/2A of some telencephalic and hypothalamic areas appear to constitute an important neuronal switch at least during arousal stage of hibernation. The establishment of the type of glutamatergic subtypes that are linked to successful hibernating states, via drinking stimuli, may have useful bearings toward sleeping disorders.

Background The structural arrangement of the γ-aminobutyric acid type A receptor (GABAAR) is known to be crucial for the maintenance of cerebral-dependent homeostatic mechanisms during the promotion of highly adaptive neurophysiological events of the permissive hibernating rodent, i.e the Syrian golden hamster. In this study, in vitro quantitative autoradiography and in situ hybridization were assessed in major hypothalamic nuclei. Reverse Transcription Reaction-Polymerase chain reaction (RT-PCR) tests were performed for specific GABAAR receptor subunit gene primers synthases of non-hibernating (NHIB) and hibernating (HIB) hamsters. Attempts were made to identify the type of αβγ subunit combinations operating during the switching ON/OFF of neuronal activities in some hypothalamic nuclei of hibernators. Results Both autoradiography and molecular analysis supplied distinct expression patterns of all α subunits considered as shown by a strong (p < 0.01) prevalence of α1 ratio (over total α subunits considered in the present study) in the medial preoptic area (MPOA) and arcuate nucleus (Arc) of NHIBs with respect to HIBs. At the same time α2 subunit levels proved to be typical of periventricular nucleus (Pe) and Arc of HIB, while strong α4 expression levels were detected during awakening state in the key circadian hypothalamic station, i.e. the suprachiasmatic nucleus (Sch; 60%). Regarding the other two subunits (β and γ), elevated β3 and γ3 mRNAs levels mostly characterized MPOA of HIBs, while prevalently elevated expression concentrations of the same subunits were also typical of Sch, even though this time during the awakening state. In the case of Arc, notably elevated levels were obtained for β3 and γ2 during hibernating conditions. Conclusion We conclude that different αβγ subunits are operating as major elements either at the onset of torpor or during induction of the arousal state in the Syrian golden hamster. The identification of a brain regional distribution pattern of distinct GABAAR subunit combinations may prove to be very useful for highlighting GABAergic mechanisms functioning at least during the different physiological states of hibernators and this may have interesting therapeutic bearings on neurological sleeping disorders.