Transcatheter Edge-to-Edge Mitral Valve Repair versus Minimally Invasive Mitral Valve Surgery: An Observational Study.

Background: Minimally invasive mitral valve surgery (MIC-MVS) has been established as preferred treatment of mitral regurgitation (MR), but mitral transcatheter edge-to-edge valve repair (M-TEER) is routinely performed in patients at high surgical risk and is increasingly performed in intermediate risk patients. Methods: From 2010 to 2021, we performed 723 M-TEER and 123 isolated MIC-MVS procedures. We applied a sensitivity analysis by matching age, left ventricular ejection fraction (LVEF), EuroSCORE II and etiology of MR. Results: Baseline characteristics showed significant differences in the overall cohort (p < 0.01): age 78.3 years vs. 61.5 years, EuroSCORE II 5.5% vs. 1.3% and LVEF 48.4% vs. 60.4% in M-TEER vs. MIC-MVS patients. Grade of MR at discharge was moderate/severe in 24.5% (171/697) in M-TEER vs. 6.5% (8/123) in MIC-MVS (p < 0.01). One-year survival was 91.5% (552/723) in M-TEER vs. 97.6% (95/123) in MIC-MVS (p = 0.04). A matching with 49 pairs (n = 98) showed comparable survival during follow-up, but a numerically higher mean mitral valve gradient of 4.1 mmHg (95% CI: 3.6-4.6) vs. 3.4 mmHg (95% CI: 3.0-3.8) in M-TEER (p = 0.04). Conclusions: Patients undergoing M-TEER had lower one-year survival than MIC-MVS, but differences disappeared after matching. Reduction in MR was less effective in M-TEER patients and postprocedural mitral valve gradients were higher.

Enhanced Risky Choice in Male Rats Elicited by the Acute Pharmacological Stressor Yohimbine Involves Prefrontal Dopamine D1 Receptor Activation.

BACKGROUND: Acute stress alters risk-based decision-making; however, the underlying neural and neurochemical substrates are underexplored. Given their well-documented stress-inducing effects in humans and laboratory animals, glucocorticoids such as cortisol and corticosterone and the α2-adrenoceptor antagonist yohimbine represent potent pharmacological tools to mimic some characteristics of acute stress. METHODS: Here, we analyzed the effects of the pharmacological stressors corticosterone and yohimbine given systemically on risk-based decision-making in male rats. Moreover, we investigated whether pharmacological stressor effects on risk-based decision-making involve dopamine D1 receptor stimulation in the dorsal prelimbic cortex (PL). We used a risk discounting task that requires choosing between a certain/small reward lever that always delivered 1 pellet and a risky/large reward lever that delivered 4 pellets with a decreasing probability across subsequent trials. RESULTS: Systemic administration of yohimbine increased the preference for the risky/large reward lever. By contrast, systemic single administration of corticosterone did not significantly promote risky choice. Moreover, co-administration of corticosterone did not enhance the effects of yohimbine on risky choice. The data further show that the increased preference for the risky/large reward lever under systemic yohimbine was lowered by a concurrent pharmacological blockade of dopamine D1 receptors in the PL. CONCLUSIONS: Our rodent data provide causal evidence that stimulation of PL D1 receptors may represent a neurochemical mechanism by which the acute pharmacological stressor yohimbine, and possibly nonpharmacological stressors as well, promote risky choice.

Pro-cognitive effects of the GlyT1 inhibitor Bitopertin in rodents.

N-methyl-D-aspartate-receptor (NMDAR) hypofunction contributes to cognitive impairments in neuropsychiatric disorders such as schizophrenia. Reduced NMDAR signalling can be enhanced by increasing extracellular levels of the NMDAR co-agonist glycine through inhibition of its transporter (GlyT1). This may be one option to improve cognitive deficits or negative symptoms of schizophrenia. In this preclinical study, we aimed at investigating effects of the GlyT1-inhibitor Bitopertin on cognition, social function and motivation. Central target engagement was assessed by Bitopertin-induced changes in glycine levels in rats' cerebrospinal fluid (CSF) and prefrontal cortex (PFC). Behavioural effects of Bitopertin on recognition memory were evaluated using a social-recognition test in rats, while its effects on working memory were tested in a spontaneous alternation task in mice pre-treated with the NMDAR antagonist MK-801. Bitopertin was further investigated using a social interaction test in rats pre-treated with the NMDAR antagonist phencyclidine, and the effects on effortful motivation were explored in progressive ratio tasks in rats. Results show that Bitopertin increased glycine levels in CSF and PFC. Moreover, it enhanced recognition memory and reduced MK-801-induced working memory deficits. By contrast, Bitopertin had no significant effects on PCP-induced social interaction deficits, and it did not alter effort-related responding. Collectively, our data demonstrate that GlyT1 inhibition by Bitopertin increased CSF and extracellular glycine levels and advocated for pro-cognitive effects of GlyT1 inhibition both in intact and NMDAR antagonists-pre-treated rodents. Together, these findings support the use of GlyT1-inhibitors for the treatment of cognitive symptoms in pathologies characterized by NMDR hypofunction, such as schizophrenia.

Effects of GPR139 agonism on effort expenditure for food reward in rodent models: Evidence for pro-motivational actions.

Apathy, deficiency of motivation including willingness to exert effort for reward, is a common symptom in many psychiatric and neurological disorders, including depression and schizophrenia. Despite improved understanding of the neurocircuitry and neurochemistry underlying normal and deficient motivation, there is still no approved pharmacological treatment for such a deficiency. GPR139 is an orphan G protein-coupled receptor expressed in brain regions which contribute to the neural circuitry that controls motivation including effortful responding for reward, typically sweet gustatory reward. The GPR139 agonist TAK-041 is currently under development for treatment of negative symptoms in schizophrenia which include apathy. To date, however, there are no published preclinical data regarding its potential effect on reward motivation or deficiencies thereof. Here we report in vitro evidence confirming that TAK-041 increases intracellular Ca2+ mobilization and has high selectivity for GPR139. In vivo, TAK-041 was brain penetrant and showed a favorable pharmacokinetic profile. It was without effect on extracellular dopamine concentration in the nucleus accumbens. In addition, TAK-041 did not alter the effort exerted to obtain sweet gustatory reward in rats that were moderately food deprived. By contrast, TAK-041 increased the effort exerted to obtain sweet gustatory reward in mice that were only minimally food deprived; furthermore, this effect of TAK-041 occurred both in control mice and in mice in which deficient effortful responding was induced by chronic social stress. Overall, this study provides preclinical evidence in support of GPR139 agonism as a molecular target mechanism for treatment of apathy.

Effects of Motivational Downshifts on Specific Pavlovian-Instrumental Transfer in Rats.

BACKGROUND: Pavlovian stimuli predictive of appetitive outcomes can exert a powerful influence on the selection and initiation of action, a phenomenon termed outcome-selective Pavlovian-instrumental transfer (sPIT). Rodent studies suggest that sPIT is insensitive to motivational downshift induced by outcome devaluation, an effect that is, however, relatively underexplored. METHODS: Here we examined in detail the effects of distinct shifts in motivation from hunger to a state of relative satiety on sPIT in rats. RESULTS: A motivational downshift by outcome-specific devaluation immediately prior to testing markedly reduced overall lever responding and magazine entries but left intact the sPIT effect. A motivational downshift prior testing by (1) giving ad libitum rather than restricted access to maintenance diet in the home cage for 24 hours or by (2) a systemic blockade of hormone secretagogue receptor subtype 1A receptors to inhibit orexigenic actions of ghrelin both reduced overall lever responding and magazine entries. Moreover, these latter motivational downshifts reduced the sPIT effect; however, the sizes of the sPIT effects were still large. CONCLUSIONS: Collectively, our rodent findings indicate that major effects of various motivational downshifts are overall inhibition of lever pressing and magazine approach, possibly reflecting reduced general motivation. The observed effects of motivational downshifts on sPIT have implications with regard to the role of general motivating effects in sPIT and to the contribution of Pavlovian-instrumental interactions to excessive food seeking as well as obesity in humans.

Dopamine D1 receptors in the medial orbitofrontal cortex support effort-related responding in rats.

Rodent studies on effort-related responding provide a tool to analyze basal aspects of motivation and to model psychiatric motivational dysfunctions reflecting low exertion of effort or reduced behavioral activation. It turned out that dopamine (DA) signaling in brain areas such as nucleus accumbens are essential in regulating effort-related motivational function and could play a major role in motivational dysfunction in psychiatric disorders. Recent rodent studies revealed that the medial orbitofrontal cortex (mOFC) is another key component of the neural circuitry regulating effort-related motivational function. The mOFC receives prominent DA input, however, the behavioral role of mOFC DA signaling is unknown. Here, we investigated whether DA signaling in the mOFC supports effort-related responding in rats. Results demonstrate that an intra-mOFC D1 receptor blockade markedly reduced effort-related responding in a progressive ratio task. Notably, the magnitude of this effect was comparable to the one caused by a systemic DA depletion induced by the VMAT-2 inhibitor tetrabenazine or by a satiety-induced motivational downshift. Collectively, our data show for the first time that D1 receptor activity in the mOFC plays a critical role in high effort responding. These results support findings in humans pointing to a role of the mOFC in effort-related responding. It is well known that the mOFC becomes dysfunctional in depression and schizophrenia. Our data point to the possibility that reduced mOFC DA activity could contribute to effort-related motivational symptoms in these disorders and support the notion that the DA system may be a drug target to treat effort-related motivational symptoms.

Role of the Medial Orbitofrontal Cortex and Ventral Tegmental Area in Effort-Related Responding.

The posterior subdivision of the medial orbitofrontal cortex (mOFC-p) mediates the willingness to expend effort to reach a selected goal. However, the neural circuitry through which the mOFC-p modulates effort-related function is as yet unknown. The mOFC-p projects prominently to the posterior ventral tegmental area (pVTA). Therefore, we analyzed the role of the mOFC-p and interactions with the pVTA in effort-related responding using a combination of behavioral, pharmacological, and neural circuit analysis methods in rats. Pharmacological inhibition of the mOFC-p was found to increase lever pressing for food under a progressive ratio (PR) schedule of reinforcement. These findings provide further support for a modulation of effort-related function by the mOFC-p. Then, we investigated effects of disconnecting the mOFC-p and pVTA on PR responding using unilateral pharmacological inhibition of both areas. This asymmetric intervention was also found to increase PR responding suggesting that the mOFC-p controls effort-related function through interactions with the pVTA. Possibly, a reduced excitatory mOFC-p drive on pVTA gamma-aminobutyric acid (GABA)ergic relays disinhibits VTA dopamine neurons which are known to support PR responding. Collectively, our findings suggest that the mOFC-p and pVTA are key components of a neural circuit mediating the willingness to expend effort to reach a goal.

[Subjectively Experienced Workload during Continuing Education in General Medicine and Demands on a Competence Center: A Cross-Sectional Study from Saxony-Anhalt]. / Subjektiv erlebte Arbeitsbelastung in der Weiterbildung Allgemeinmedizin und Anforderungen an ein Kompetenzzentrum ­ eine Querschnittsstudie aus Sachsen-Anhalt.

AIM OF THE STUDY: The expectations of trainees in training at Centers of Excellence are still partly unclear. Recent studies demonstrated the negative impact of high workload and stress on young doctors' mental health, a problem since the start of their careers. From trainees' point of view, are there differences in subjective occupational stress between inpatient and outpatient care sectors? How does a high subjective workload of general medicine trainees affect the demands made on the Centers of Excellence? METHOD: Design: cross-sectional study from March to June 2017 in Saxony-Anhalt Sample: every general medicine trainee registered with the KOSTA (n=221) Questionnaire: self-developed; content: demands on a Center of Excellence, sociodemographic parameters, biography of qualification, evaluation of previous postgraduate training in inpatient and outpatient care sectors, questionnaire about effort-reward-imbalance (ERI). RESULTS: In total, 73 responses from the trainees were received (33.0%). Every single response was included in the analysis. Occupational stress was specified on an averaging index from 1 (lowest) to 4 (highest). Higher workload was reported in the inpatient care sector (inpatient: 2.8 vs. outpatient: 2.1, p<0.01). The subjective workload was significantly increased by the amount of overtime work (inpatient: η²=18.3%, p=0.02, outpatient: η²=28.3%, p<0.01). Persons with above-average occupational stress tended to express a higher need for complete planning of qualification (percentage difference d%=0.31), mentoring (d%=0.15) and informal exchange with colleagues (d%=0.19). Trainees' feeling of occupational stress was proved to be independent of personal and demographic characteristics. CONCLUSION: General practice trainees need more mentoring with higher levels of occupational stress. This has to be considered when individual consulting is offered.

Seminar program for postgraduate specialty training in general practice: proposal for a 5-year thematic catalogue.

Introduction: In different German regions, seminar programs have been conducted for General practice residents. In each region, selection and teaching of learning content is conducted in a different manner. So far, no structured, standardized curriculum has been implemented nationwide. We have investigated, if the development of a common 5-year program of learning topics is conceivable between the different university departments of General practice in Germany. Method: The seminar program working group of the DEGAM (German College of General Practitioners and Family Physicians) has conducted an online survey based on information gathered via preliminary telephone conference (n=7; physicians with postgraduate teaching experience) among all German university departments of General Practice and two non-university teaching institutions, identified via the internet. 884 topics were extracted from 14 Seminar programs. The topics were entered in a database, discussed and categorized: Practice management/practice work flow/standardized documentation forms/quality management (n=33 topics), common acute and chronic diseases, including disease management programs (n=29 topics), communication, neurological, psychological and psychiatric consultations (n=24 topics), common medical problems, including eye, ear, nose, throat, skin and pediatric problems (n=99 Topics) family physicians general approach, including epidemiology, shared decision making, test of time (n=42 Topics). These topics have been rated for priority and desirable number of teaching-units. Results: A catalogue of 111 topics was designed, encompassing 160 teaching units. There is a suggestion of wide topics collections plus an add-on catalogue. Conclusion: A proposal for a 5-year-thematic catalogue for postgraduate training of general practice residents in Germany has been developed. This newly developed curriculum has the potential to improve knowledge and skills that have not been covered during in-house and ambulatory general practice residencies.

Putamen Activation Represents an Intrinsic Positive Prediction Error Signal for Visual Search in Repeated Configurations.

We investigated fMRI responses to visual search targets appearing at locations that were predicted by the search context. Based on previous work in visual category learning we expected an intrinsic reward prediction error signal in the putamen whenever the target appeared at a location that was predicted with some degree of uncertainty. Comparing target appearance at locations predicted with 50% probability to either locations predicted with 100% probability or unpredicted locations, increased activation was observed in left posterior putamen and adjacent left posterior insula. Thus, our hypothesis of an intrinsic prediction error-like signal was confirmed. This extends the observation of intrinsic prediction error-like signals, driven by intrinsic rather than extrinsic reward, to memory-driven visual search.

Ghrelin receptor activation in the ventral tegmental area amplified instrumental responding but not the excitatory influence of Pavlovian stimuli on instrumental responding.

Pavlovian stimuli predictive of food are able to amplify instrumental responding for food. This phenomenon termed Pavlovian-instrumental transfer (PIT) critically depends on intact VTA function and mesoaccumbens dopamine transmission. Considerable evidence suggests that food-predictive stimuli can enhance the release of ghrelin, an orexigen hormone that promotes food-directed responding. The ventral tegmental area (VTA) appears to be a key region through which stimulation of ghrelin receptors (GHS-R1A) invigorates food-directed responding, in part by activating the mesoaccumbens dopamine system. Thus, it is conceivable that stimulation of GHS-R1A in the VTA can amplify PIT, i.e. stimulus-elicited increase in lever pressing for food. Here we examined in rats the effects of VTA ghrelin microinfusion on PIT. Our results demonstrate that ghrelin microinfusion into the VTA failed to enhance PIT suggesting that VTA GHS-R1A stimulation was unable to enhance the motivational significance of food-predictive stimuli. Consistent with previous studies, our results further indicate that intra-VTA ghrelin microinfusion invigorated instrumental responding under a progressive ratio schedule. These data provide support to the notion that VTA GHS-R1A stimulation increases the tendency to work for food.

N-methyl-D-aspartate receptors in the ventral tegmental area mediate the excitatory influence of Pavlovian stimuli on instrumental performance.

Pavlovian stimuli predictive of food can markedly amplify instrumental responding for food. This effect is termed Pavlovian-instrumental transfer (PIT). The ventral tegmental area (VTA) plays a key role in mediating PIT, however, it is yet unknown whether N-methyl-D-aspartate (NMDA)-type glutamate receptors in the VTA are involved in PIT. Here, we examined the effects of an NMDA-receptor blockade in the VTA on PIT. Immediately prior to PIT testing, rats were subjected to intra-VTA infusions of vehicle or of the NMDA-receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) (1, 5 µg/side). In rats that received AP-5 at the lower dose, the PIT effect was intact, i.e. presentation of the Pavlovian stimulus enhanced instrumental responding. By contrast, in rats that received AP-5 at the higher dose, the PIT effect was blocked. The data suggest that NMDA receptors in the VTA mediate the activating effects of Pavlovian stimuli on instrumental responding.

Neural structures involved in visual search guidance by reward-enhanced contextual cueing of the target location.

Spatial contextual cueing reflects an incidental form of learning that occurs when spatial distractor configurations are repeated in visual search displays. Recently, it was reported that the efficiency of contextual cueing can be modulated by reward. We replicated this behavioral finding and investigated its neural basis with fMRI. Reward value was associated with repeated displays in a learning session. The effect of reward value on context-guided visual search was assessed in a subsequent fMRI session without reward. Structures known to support explicit reward valuation, such as ventral frontomedial cortex and posterior cingulate cortex, were modulated by incidental reward learning. Contextual cueing, leading to more efficient search, went along with decreased activation in the visual search network. Retrosplenial cortex played a special role in that it showed both a main effect of reward and a reward×configuration interaction and may thereby be a central structure for the reward modulation of context-guided visual search.

Dopamine D1/D2 Receptor Activity in the Nucleus Accumbens Core But Not in the Nucleus Accumbens Shell and Orbitofrontal Cortex Modulates Risk-Based Decision Making.

BACKGROUND: It is well known that brain dopamine (DA) signals support risk-based decision making; however, the specific terminal regions of midbrain DA neurons through which DA signals mediate risk-based decision making are unknown. METHODS: Using microinfusions of the D1/D2 receptor antagonist flupenthixol, we sought to explore the role of D1/D2 receptor activity in the rat orbitofrontal cortex (OFC) and core and shell regions of the nucleus accumbens (AcbC and AcbS, respectively) in the regulation of risky choices. A risk-discounting task was used that involves choices between a certain small-reward lever that always delivered 1 pellet or a risky large-reward lever which delivered 4 pellets but had a decreasing probability of receiving the reward across 4 subsequent within-session trial blocks (100%, 50%, 25%, 12.5%). To validate task sensitivity to experimental manipulations of DA activity, we also examined the effects of systemic amphetamine and flupenthixol. RESULTS: Systemic amphetamine increased while systemic flupenthixol reduced risky choices. Results further demonstrate that rats that received intra-AcbC flupenthixol were able to track increasing risk associated with the risky lever but displayed a generally reduced preference for the risky lever across all trial blocks, including in the initial trial block (large reward at 100%). Microinfusions of flupenthixol into the AcbS or OFC did not alter risk-based decision making. CONCLUSIONS: Our data suggest that intra-AcbC D1/D2 receptor signaling does not support the ability to track shifts in reward probabilities but does bias risk-based decision making. That is, it increased the rats' preference for the response option known to be associated with higher risk-related costs.

Post-training glucocorticoid receptor activation during Pavlovian conditioning reduces Pavlovian-instrumental transfer in rats.

Considerable evidence suggests that glucocorticoid receptor activation can enhance memory consolidation in Pavlovian learning tasks. For instance, post-training injections of the synthetic glucocorticoid receptor agonist dexamethasone increased conditioned responding to reward-predictive Pavlovian stimuli. Here we explored whether post-training dexamethasone injections can enhance appetitive Pavlovian learning and amplify the ability of Pavlovian stimuli to invigorate instrumental behaviour, a phenomenon termed Pavlovian-instrumental transfer (PIT). Animals were given 8 training days with two sessions per day, an instrumental training session in the morning and a Pavlovian training session in the afternoon. Dexamethasone or vehicle injections were administered daily immediately after Pavlovian training sessions. In a subsequent transfer test, we measured the general PIT effect, i.e. the enhancement of lever pressing for expected reward during presentation of an appetitive Pavlovian stimulus predictive for the same reward. Repeated high-dose (1.2 mg/kg, i.p.) dexamethasone injections elicited pronounced body weight loss, markedly reduced instrumental performance and left Pavlovian learning unaltered, whereas repeated low-dose (3 µg/kg, i.p.) dexamethasone injections inhibited body weight gain, slightly reduced instrumental performance and left Pavlovian learning unaltered during training. Importantly, in rats subjected to high- and low-dose dexamethasone injections, the overall response rates and the PIT effect were reduced in the transfer test. Thus, dexamethasone given after Pavlovian training was not able to amplify the invigorating effects of Pavlovian stimuli on instrumental action. Considerable evidence suggests that body weight changes after repeated low- and high-dose dexamethasone treatment as observed here are associated with muscle atrophy that could impair response capabilities. However, our data suggest that impaired response capabilities are not a major factor accounting for reduced PIT in dexamethasone-treated animals.

Motivational states influence effort-based decision making in rats: the role of dopamine in the nucleus accumbens.

Decision-making policies are subject to modulation by changing motivational states. However, so far, little is known about the neurochemical mechanisms that bridge motivational states with decision making. Here we examined whether dopamine (DA) in the nucleus accumbens core (AcbC) modulates the effects of motivational states on effort-based decision making. Using a cost-benefit T-maze task in rats, we examined the effects of AcbC DA depletions on effort-based decision making, in particular on the sensitivity of effort-based decision making to a shift from a hungry to a sated state. The results demonstrated that, relative to sham controls, rats with AcbC DA depletion in a hungry as well as in a sated state had a reduced preference for effortful but large-reward action. This finding provides further support for the notion that AcbC DA regulates how much effort to invest for rewards. Importantly, our results further revealed that effort-based decision making in lesioned rats, as in sham controls, was still sensitive to a shift from a hungry to a sated state; that is, their preferences for effortful large-reward actions became lower after a shift from a restricted to a free-feeding regimen. These finding indicate that AcbC DA is not necessarily involved in mediating the effects of a shift in motivational state on decision-making policies.

Effort-based decision making in the rat: an [18F]fluorodeoxyglucose micro positron emission tomography study.

Decision making refers to the process by which subjects choose between competing courses of action based on the expected costs and benefits of their consequences. Lesion studies in rats suggest that the anterior cingulate cortex and the nucleus accumbens are key structures of a neural system that subserves effort-based decision making. Little is known about brain activation associated with effort-based decisions in intact rats. Using an open hypothesis approach, we used 2-deoxy-2[(18)F]fluoro-D-glucose positron emission tomography (FDG-PET) to assess regional metabolic changes in two conditions of an effort-based decision making task. In the "same effort" condition, male rats could choose between two response options associated with the same effort but different reward sizes, i.e., decision making was simply a function of reward size. By contrast, in the "different effort" condition, an integration of different efforts and reward sizes associated with the two response options was necessary before making a decision. Separate PET scans were performed from each condition. Subtractive analysis revealed that metabolic activity was increased in the different effort relative to the same effort condition in the left anterior cingulate, left orbitofrontal and prelimbic cortex region. Metabolic activity was decreased in the infralimbic cortex and septum region. Our findings suggest that making decisions on how much effort to invest to obtain greater rewards evokes changes of metabolic activity in multiple brain areas associated with cognitive, limbic, motor and autonomic functions. This study demonstrates that FDG-PET provides a tool to determine in rats regional brain metabolic activity in cognitive tasks.

Prefrontostriatal circuitry regulates effort-related decision making.

The anterior cingulate cortex (ACC), the basolateral amygdala (BLA), and the dopamine in the nucleus accumbens (NAc) are part of a neural system that is critically involved in making decisions on how much effort to invest for rewards. In the present study, we sought to identify functional interactions between ACC and NAc regulating effort-based decision making. Rats were tested in a T-maze cost-benefit task in which they could either choose to climb a barrier to obtain a large reward (LR) in one arm or a small reward in the other arm without a barrier. Experiment 1 revealed that bilateral excitotoxic lesions of the core subregion of the NAc impaired effort-based decision making, that is, reduced the preference for the high effort-LR option when having the choice to obtain a low reward with little effort. Experiment 2 showed that disconnection of the ACC and NAc core using an asymmetrical excitotoxic lesion procedure impaired effort-based decision making. The present data provide evidence that effort-based decision making is governed by an interconnected neural system that requires serial information transfer between ACC and NAc core.

Molecular analysis of homocysteic acid-induced neuronal stress.

Hyperhomocysteinemia is a risk factor for vascular and neuronal lesions often observed with concomitant high levels of homocysteic acid. In contrast to homocysteine, homocysteic acid induces calcium influx into neurons, with characteristics of an excitotoxic glutamatergic agonist at elevated concentrations. On the molecular level this is correlated to fast modifications of proteins (phosphorylation and proteolysis). Within the homocysteic acid induced molecular signature we focused in more detail on phosphorylation of two proteins implicated as risk factors in schizophrenia and neurodegeneration: Dihydropyrimidinase related protein and 14-3-3 protein isoforms. Among the identified proteins there are known chaperones and oxidative metabolism enzymes, but a few are new in context of neuronal stress: Lasp-1, a vitamin D associated factor and an expressed sequence with features of a Rho GDP dissociation inhibitor. Moreover, we detect a specific proteolytic processing of heat shock protein 70 and proteindisulfide isomerase, which is abolished by vitamins (folic acid, vitamin B12, and vitamin B6), which also decrease elevated intracellular calcium levels induced by homocysteic acid.

Influence of regular voluntary exercise on spontaneous and social stress-affected sleep in mice.

To investigate the impact of regular physical exercise on sleep, we assessed sleep-wake behaviour in male C57BL/6N mice with and without long-term access (i.e. 4 weeks) to a running wheel. We studied sleep-wake behaviour during undisturbed conditions as well as after social stress. The exercising mice ran approximately 4 km/day, which affected their physical constitution, their spontaneous sleep-wake pattern and their endocrine and sleep responses to stress. When compared with the control mice, exercising animals had more muscle substance, less body fat and heavier adrenal glands. At baseline, exercising mice showed fewer, but longer-lasting, sleep episodes (indicating improved sleep consolidation) and less rapid-eye-movement sleep. In both control and exercising mice, mild social stress (elicited by a 15-min social conflict) evoked elevated plasma levels of adrenocorticotrophic hormone and corticosterone, an increase in non-rapid-eye-movement sleep, an enhancement of low-frequency activity in the electroencephalogram within non-rapid-eye-movement sleep (indicating increased sleep intensity) and a decrease in wakefulness. However, as compared with the control animals, exercising mice responded to social stress with higher corticosterone levels, but not adrenocorticotrophic hormone levels, suggesting an increased sensitivity of their adrenal glands to adrenocorticotrophic hormone. Moreover, in control mice, social stress increased rapid-eye-movement sleep in parallel to non-rapid-eye-movement sleep, whereas this stressor selectively decreased rapid-eye-movement sleep in exercising animals. Corticosterone is known to decrease rapid-eye-movement sleep. Therefore, changes in the regulation of the hypothalamic-pituitary-adrenocortical axis as a result of the long-term exercise may contribute to the observed differences in spontaneous and social stress-affected sleep. In conclusion, regular exercise appears to increase sleep quality and reverses the effects of mild social stress on rapid-eye-movement sleep.