Different stressors uniquely affect the expression of endocannabinoid-metabolizing enzymes in the central ring ganglia of Lymnaea stagnalis.

The endocannabinoid system (ECS) plays an important role in neuroprotection, neuroplasticity, energy balance, modulation of stress, and inflammatory responses, acting as a critical link between the brain and the body's peripheral regions, while also offering promising potential for novel therapeutic strategies. Unfortunately, in humans, pharmacological inhibitors of different ECS enzymes have led to mixed results in both preclinical and clinical studies. As the ECS has been highly conserved throughout the eukaryotic lineage, the use of invertebrate model organisms like the pond snail Lymnaea stagnalis may provide a flexible tool to unravel unexplored functions of the ECS at the cellular, synaptic, and behavioral levels. In this study, starting from the available genome and transcriptome of L. stagnalis, we first identified putative transcripts of all ECS enzymes containing an open reading frame. Each predicted protein possessed a high degree of sequence conservation to known orthologues of other invertebrate and vertebrate organisms. Sequences were confirmed by qualitative PCR and sequencing. Then, we investigated the transcriptional effects induced by different stress conditions (i.e., bacterial LPS injection, predator scent, food deprivation, and acute heat shock) on the expression levels of the enzymes of the ECS in Lymnaea's central ring ganglia. Our results suggest that in Lymnaea as in rodents, the ECS is involved in mediating inflammatory and anxiety-like responses, promoting energy balance, and responding to acute stressors. To our knowledge, this study offers the most comprehensive analysis so far of the ECS in an invertebrate model organism.

Behavioral and transcriptional effects of carnosine in the central ring ganglia of the pond snail Lymnaea stagnalis.

Carnosine is a naturally occurring endogenous dipeptide with well-recognized anti-inflammatory, antioxidant, and neuroprotective effects at the central nervous system level. To date, very few studies have been focused on the ability of carnosine to rescue and/or enhance memory. Here, we used a well-known invertebrate model system, the pond snail Lymnaea stagnalis, and a well-studied associative learning procedure, operant conditioning of aerial respiration, to investigate the ability of carnosine to enhance long-term memory (LTM) formation and reverse memory obstruction caused by an immune challenge (i.e., lipopolysaccharide [LPS] injection). Exposing snails to 1 mM carnosine for 1 h before training in addition to enhancing memory formation resulted in a significant upregulation of the expression levels of key neuroplasticity genes (i.e., glutamate ionotropic receptor N-methyl-d-aspartate [NMDA]-type subunit 1-LymGRIN1, and the transcription factor cAMP-response element-binding protein 1-LymCREB1) in snails' central ring ganglia. Moreover, pre-exposure to 1 mM carnosine before an LPS injection reversed the memory deficit brought about by inflammation, by preventing the upregulation of key targets for immune and stress response (i.e., Toll-like receptor 4-LymTLR4, molluscan defense molecule-LymMDM, heat shock protein 70-LymHSP70). Our data are thus consistent with the hypothesis that carnosine can have positive benefits on cognitive ability and be able to reverse memory aversive states induced by neuroinflammation.

Investigating the interactions between multiple memory stores in the pond snail Lymnaea stagnalis.

The pond snail Lymnaea stagnalis exhibits various forms of associative learning including (1) operant conditioning of aerial respiration where snails are trained not to open their pneumostome in a hypoxic pond water environment using a weak tactile stimulus to their pneumostome as they attempt to open it; and (2) a 24 h-lasting taste-specific learned avoidance known as the Garcia effect utilizing a lipopolysaccharide (LPS) injection just after snails eat a novel food substance (carrot). Typically, lab-inbred snails require two 0.5 h training sessions to form long-term memory (LTM) for operant conditioning of aerial respiration. However, some stressors (e.g., heat shock or predator scent) act as memory enhancers and thus a single 0.5 h training session is sufficient to enhance LTM formation lasting at least 24 h. Here, we found that snails forming a food-aversion LTM following Garcia-effect training exhibited enhanced LTM following operant condition of aerial respiration if trained in the presence of the food substance (carrot) they became averse to. Control experiments led us to conclude that carrot becomes a 'sickness' risk signal and acts as a stressor, sufficient to enhance LTM formation for another conditioning procedure.

A translational and multidisciplinary approach to studying the Garcia effect, a higher form of learning with deep evolutionary roots.

Animals, including humans, learn and remember to avoid a novel food when its ingestion is followed, hours later, by sickness - a phenomenon initially identified during World War II as a potential means of pest control. In the 1960s, John Garcia (for whom the effect is now named) demonstrated that this form of conditioned taste aversion had broader implications, showing that it is a rapid but long-lasting taste-specific food aversion with a fundamental role in the evolution of behaviour. From the mid-1970s onward, the principles of the Garcia effect were translated to humans, showing its role in different clinical conditions (e.g. side-effects linked to chemotherapy). However, in the last two decades, the number of studies on the Garcia effect has undergone a considerable decline. Since its discovery in rodents, this form of learning was thought to be exclusive to mammals; however, we recently provided the first demonstration that a Garcia effect can be formed in an invertebrate model organism, the pond snail Lymnaea stagnalis. Thus, in this Commentary, after reviewing the experiments that led to the first characterization of the Garcia effect in rodents, we describe the recent evidence for the Garcia effect in L. stagnalis, which may pave the way for future studies in other invertebrates and mammals. This article aims to inspire future translational and ecological studies that characterize the conserved mechanisms underlying this form of learning with deep evolutionary roots, which can be used to address a range of different biological questions.

Behavioral and Transcriptional Effects of Short or Prolonged Fasting on the Memory Performances of Lymnaea stagnalis.

INTRODUCTION: The Garcia effect, a solid learning paradigm, was used to investigate the molecular and behavioral effects induced by different lengths of fasting on the cognitive functions in the pond snail Lymnaea stagnalis, a valid model system. METHODS: Three experimental groups were used: moderately hungry snails, food-deprived for 1 day (D1 snails), severely hungry snails (D5 snails), fasting for 5 days, and satiated snails with ad libitum access to food (AL snails). In the Garcia effect, a single pairing of an appetitive stimulus with a heat stressor results in a learned taste-specific negative hedonic shift. D5 snails were injected with bovine insulin and D1 snails with the insulin receptor antibody (Ab). As a control group, AL snails were injected with saline. Gene expression analyses were performed by real-time PCR in snails' central nervous system (CNS). RESULTS: AL snails are "average learners," D1 snails are the best performers, whereas the D5 ones do not show the Garcia effect. Severely fasting snails injected with insulin 3 h before the training procedure show the Garcia effect, whereas injecting 1-day fasting snails with insulin receptor Ab blocks their ability to express memory. The differences in memory performances are associated with changes in the expression levels of selected targets involved in neuronal plasticity, energy homeostasis, and stress response. DISCUSSION: Our results suggest that short-term fasting creates an optimal internal state in L. stagnalis' CNS, allowing a spike in insulin release and an upregulation of genes involved in neuroplasticity. Long-term fasting, instead, upregulates genes involved in energy homeostasis and animal survival.

The dynamic interaction between symptoms and pharmacological treatment in patients with major depressive disorder: the role of network intervention analysis.

INTRODUCTION: The Major Depressive Disorder (MDD) is a mental health disorder that affects millions of people worldwide. It is characterized by persistent feelings of sadness, hopelessness, and a loss of interest in activities that were once enjoyable. MDD is a major public health concern and is the leading cause of disability, morbidity, institutionalization, and excess mortality, conferring high suicide risk. Pharmacological treatment with Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin Noradrenaline Reuptake Inhibitors (SNRIs) is often the first choice for their efficacy and tolerability profile. However, a significant percentage of depressive individuals do not achieve remission even after an adequate trial of pharmacotherapy, a condition known as treatment-resistant depression (TRD). METHODS: To better understand the complexity of clinical phenotypes in MDD we propose Network Intervention Analysis (NIA) that can help health psychology in the detection of risky behaviors, in the primary and/or secondary prevention, as well as to monitor the treatment and verify its effectiveness. The paper aims to identify the interaction and changes in network nodes and connections of 14 continuous variables with nodes identified as "Treatment" in a cohort of MDD patients recruited for their recent history of partial response to antidepressant drugs. The study analyzed the network of MDD patients at baseline and after 12 weeks of drug treatment. RESULTS: At baseline, the network showed separate dimensions for cognitive and psychosocial-affective symptoms, with cognitive symptoms strongly affecting psychosocial functioning. The MoCA tool was identified as a potential psychometric tool for evaluating cognitive deficits and monitoring treatment response. After drug treatment, the network showed less interconnection between nodes, indicating greater stability, with antidepressants taking a central role in driving the network. Affective symptoms improved at follow-up, with the highest predictability for HDRS and BDI-II nodes being connected to the Antidepressants node. CONCLUSION: NIA allows us to understand not only what symptoms enhance after pharmacological treatment, but especially the role it plays within the network and with which nodes it has stronger connections.

Public Preferences for Digital Health Data Sharing: Discrete Choice Experiment Study in 12 European Countries.

BACKGROUND: With new technologies, health data can be collected in a variety of different clinical, research, and public health contexts, and then can be used for a range of new purposes. Establishing the public's views about digital health data sharing is essential for policy makers to develop effective harmonization initiatives for digital health data governance at the European level. OBJECTIVE: This study investigated public preferences for digital health data sharing. METHODS: A discrete choice experiment survey was administered to a sample of European residents in 12 European countries (Austria, Denmark, France, Germany, Iceland, Ireland, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom) from August 2020 to August 2021. Respondents answered whether hypothetical situations of data sharing were acceptable for them. Each hypothetical scenario was defined by 5 attributes ("data collector," "data user," "reason for data use," "information on data sharing and consent," and "availability of review process"), which had 3 to 4 attribute levels each. A latent class model was run across the whole data set and separately for different European regions (Northern, Central, and Southern Europe). Attribute relative importance was calculated for each latent class's pooled and regional data sets. RESULTS: A total of 5015 completed surveys were analyzed. In general, the most important attribute for respondents was the availability of information and consent during health data sharing. In the latent class model, 4 classes of preference patterns were identified. While respondents in 2 classes strongly expressed their preferences for data sharing with opposing positions, respondents in the other 2 classes preferred not to share their data, but attribute levels of the situation could have had an impact on their preferences. Respondents generally found the following to be the most acceptable: a national authority or academic research project as the data user; being informed and asked to consent; and a review process for data transfer and use, or transfer only. On the other hand, collection of their data by a technological company and data use for commercial communication were the least acceptable. There was preference heterogeneity across Europe and within European regions. CONCLUSIONS: This study showed the importance of transparency in data use and oversight of health-related data sharing for European respondents. Regional and intraregional preference heterogeneity for "data collector," "data user," "reason," "type of consent," and "review" calls for governance solutions that would grant data subjects the ability to control their digital health data being shared within different contexts. These results suggest that the use of data without consent will demand weighty and exceptional reasons. An interactive and dynamic informed consent model combined with oversight mechanisms may be a solution for policy initiatives aiming to harmonize health data use across Europe.

A network study to differentiate suicide attempt risk profiles in male and female patients with major depressive disorder.

Suicide attempts are a possible consequence of Major Depressive Disorder (MDD), although their prevalence varies across different epidemiological studies. Suicide attempt is a significant predictor of death by suicide, highlighting its importance in understanding and preventing tragic outcomes. Researchers are increasingly recognizing the need to study the differences between males and females, as several distinctions emerge in terms of the characteristics, types and motivations of suicide attempts. These differences emphasize the importance of considering gender-specific factors in the study of suicide attempts and developing tailored prevention strategies. We conducted a network analysis to represent and investigate which among multiple neurocognitive, psychosocial, demographic and affective variables may prove to be a reliable predictor for identifying the 'suicide attempt risk' (SAR) in a sample of 81 adults who met DSM-5 criteria for MDD. Network analysis resulted in differences between males and females regarding the variables that were going to interact and predict the SAR; in particular, for males, there is a stronger link toward psychosocial aspects, while for females, the neurocognitive domain is more relevant in its mnestic subcomponents. Network analysis allowed us to describe otherwise less obvious differences in the risk profiles of males and females that attempted to take their own lives. Different neurocognitive and psychosocial variables and different interactions between them predict the probability of suicide attempt unique to male and female patients.

Recommendations for the surveillance of mental health problems in childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Survivors of childhood, adolescent, and young adult (diagnosed when <25 years of age) cancer are at risk of mental health problems. The aim of this clinical practice guideline is to harmonise international recommendations for mental health surveillance in survivors of childhood, adolescent, and young adult cancer. This guideline was developed by a multidisciplinary panel of experts under the sponsorship of the International Guideline Harmonization Group. We evaluated concordance among existing survivorship clinical practice guidelines and conducted a systematic review following evidence-based methods. Of 7249 studies identified, 76 articles from 12 countries met the inclusion criteria. Recommendations were formulated on the basis of identified evidence in combination with clinical considerations. This international clinical practice guideline strongly recommends mental health surveillance for all survivors of childhood, adolescent, and young adult cancers at every follow-up visit and prompt referral to mental health specialists when problems are identified. Overall, the recommendations reflect the necessity of mental health surveillance as part of comprehensive survivor-focused health care.

A flavonoid, quercetin, is capable of enhancing long-term memory formation if encountered at different times in the learning, memory formation, and memory recall continuum.

A major extrinsic factor influencing memory and neuro-cognitive performances across taxa is diet. Studies from vertebrates have shown the effects of a flavonoid rich diet on cognitive performance, but the mechanism underlying this action is still poorly understood. A common and abundant flavonoid present in numerous food substances is quercetin (Q). The present study provides the first support for Q-modulated enhancement of cognitive function in an invertebrate model, the pond snail Lymnaea stagnalis, after an operant conditioning procedure. We found that when snails were exposed to Q 3 h before or after a single 0.5 h training session, which typically results in memory lasting ~ 3 h, they formed a long-term memory (LTM) lasting for at least 24 h. Additionally, we assessed the effects of the combined presentation of a single reinforcing stimulus (at 24 h post-training or 24 h before training) and Q-exposure on both LTM formation and reconsolidation. That is, when applied within 3 h of critical periods of memory, Q regulates four different phases: (1) acquisition (i.e., a learning event), (2) consolidation processes after acquisition, (3) memory recall, and (4) memory reconsolidation. In all these phases Q-exposure enhanced LTM persistence.

Nature versus nurture in heat stress induced learning between inbred and outbred populations of Lymnaea stagnalis.

Changing environmental conditions often lead to microevolution of traits that are adaptive under the current selection pressure. Currently, one of the major selection pressures is the rise in temperatures globally that has a severe impact on the behavioral ecology of animals. However, the role of thermal stress on neuronal plasticity and memory formation is not well understood. Thermal tolerance and sensitivity to heat stress show variation across populations of the same species experiencing different thermal regimes. We used two populations of the pond snail Lymnaea stagnalis: one lab-bred W-snails and the other wild Delta snails to test heat shock induced learning and memory formation for the Garcia effect learning paradigm. In Garcia effect, a single pairing of a heat stressor (30 °C for 1h) with a novel taste results in a taste-specific negative hedonic shift lasting 24h as long-term memory (LTM) in lab bred W-snails. In this study we used a repeated heat stress procedure to test for increased or decreased sensitivity to the heat before testing for the Garcia effect. We found that lab-bred W-snails show increased sensitivity to heat stress after repeated heat exposure for 7days, leading to enhanced LTM for Garcia effect with only 15min of heat exposure instead of standard 1h. Surprisingly, the freshly collected wild snails do not show Garcia effect. Additionally, F1 generation of wild snails raised and maintained under laboratory conditions still retain their heat stress tolerance similar to their parents and do not show a Garcia effect under standard learning paradigm or even after repeated heat stressor. Thus, we found a differential effect of heat stress on memory formation in wild and lab bred snails. Most interestingly we also show that local environmental (temperature) conditions for one generation is not enough to alter thermal sensitivity in a wild population of L. stagnalis.

To eat or not to eat: a Garcia effect in pond snails (Lymnaea stagnalis).

Taste aversion learning is universal. In animals, a single presentation of a novel food substance followed hours later by visceral illness causes animals to avoid that taste. This is known as bait-shyness or the Garcia effect. Humans demonstrate this by avoiding a certain food following the development of nausea after ingesting that food ('Sauce Bearnaise effect'). Here, we show that the pond snail Lymnaea stagnalis is capable of the Garcia effect. A single 'pairing' of a novel taste, a carrot slurry followed hours later by a heat shock stressor (HS) is sufficient to suppress feeding response elicited by carrot for at least 24 h. Other food tastes are not suppressed. If snails had previously been exposed to carrot as their food source, the Garcia-like effect does not occur when carrot is 'paired' with the HS. The HS up-regulates two heat shock proteins (HSPs), HSP70 and HSP40. Blocking the up-regulation of the HSPs by a flavonoid, quercetin, before the heat shock, prevented the Garcia effect in the snails. Finally, we found that snails exhibit Garcia effect following a period of food deprivation but the long-term memory (LTM) phenotype can be observed only if the animals are tested in a food satiated state.

Long-term memory of configural learning is enhanced via CREB upregulation by the flavonoid quercetin in Lymnaea stagnalis.

Animals respond to acute stressors by modifying their behaviour and physiology. The pond snail Lymnaea stagnalis exhibits configural learning (CL), a form of higher order associative learning. In CL snails develop a landscape of fear when they experience a predatory cue along with a taste of food. This experience results in a suppression of the food response; but the memory only persists for 3 h. Lymnaea has also been found to upregulate heat shock proteins (HSPs) as a result of acute heat stress, which leads to the enhancement of memory formation. A plant flavonoid quercetin blocks the upregulation of HSPs when experienced prior to heat stress. Here, we used this blocking mechanism to test the hypothesis that HSP upregulation plays a critical role in CL. Snails experienced quercetin prior to CL training and surprisingly instead of blocking memory formation it enhanced the memory such that it now persisted for at least 24 h. Quercetin exposure either prior to or after CL enhanced long-term memory (LTM) up to 48 h. We quantified mRNA levels of the transcription factor CREB1 in the Lymnaea central nervous system and found LymCREB1 to be upregulated following quercetin exposure. The enhanced LTM phenotype in L. stagnalis was most pronounced when quercetin was experienced during the consolidation phase. Additionally, quercetin exposure during the memory reconsolidation phase also led to memory enhancement. Thus, we found no support of our original hypothesis but found that quercetin exposure upregulated LymCREB1 leading to LTM formation for CL.

LPS-induced histone H3 phospho(Ser10)-acetylation(Lys14) regulates neuronal and microglial neuroinflammatory response.

Epigenetic modifications of DNA and histone proteins are emerging as fundamental mechanisms by which neural cells adapt their transcriptional response to environmental cues, such as, immune stimuli or stress. In particular, histone H3 phospho(Ser10)-acetylation(Lys14) (H3S10phK14ac) has been linked to activation of specific gene expression. The purpose of this study was to investigate the role of H3S10phK14ac in a neuroinflammatory condition. Adult male rats received a intraperitoneal injection of lipopolysaccharide (LPS) (830 µg/Kg/i.p., n = 6) or vehicle (saline 1 mL/kg/i.p., n = 6) and were sacrificed 2 or 6 h later. We showed marked region- and time-specific increases in H3S10phK14ac in the hypothalamus and hippocampus, two principal target regions of LPS. These changes were accompanied by a marked transcriptional activation of interleukin (IL) 1ß, IL-6, Tumour Necrosis Factor (TNF) α, the inducible nitric oxide synthase (iNOS) and the immediate early gene c-Fos. By means of chromatin immunoprecipitation, we demonstrated an increased region- and time-specific association of H3S10phK14ac with the promoters of IL-6, c-Fos and iNOS genes, suggesting that part of the LPS-induced transcriptional activation of these genes is regulated by H3S10phK14ac. Finally, by means of multiple immunofluorescence approach, we showed that increased H3S10phK14ac is cell type-specific, being neurons and reactive microglia, the principal histological types involved in this response. Present data point to H3S10phK14ac as a principal epigenetic regulator of neural cell response to systemic LPS and underline the importance of distinct time-, region- and cell-specific epigenetic mechanisms that regulate gene transcription to understand the mechanistic complexity of neuroinflammatory response to immune challenges.

Ethical framework for FACILITATE: a foundation for the return of clinical trial data to participants.

This paper discusses the importance of return of clinical trial data to patients in the context of the FACILITATE project that aims to develop a participant-centric approach for the systematic return of individual clinical trial data. It reflects on the need for an ethical framework to support the return of clinical trial data. The discussion revolves around the developing FACILITATE ethical framework, specifically focusing on the ethical principles that form the foundation of the framework and guidance on how to implement those principles into practice.

Snails go on a fast when acetylsalicylic acid comes along with heat stress: A possible effect of HSPs and serotonergic system on the feeding response.

A novel food followed by sickness, causes a taste-specific conditioned aversion, known as the 'Garcia effect'. We recently found that both a heat shock stressor (30 °C for 1 h - HS) and the bacterial lipopolysaccharide (LPS) can be used as 'sickness-inducing' stimuli to induce a Garcia effect in the pond snail Lymnaea stagnalis. Additionally, if snails are exposed to acetylsalicylic acid (ASA) present in aspirin tablets before the LPS injection, the formation of the Garcia effect is prevented. Here, we hypothesized that exposing snails to crushed aspirin before the HS (ASA-HS) would prevent the HS-induced 'sickness state' and - therefore -the Garcia effect. Unexpectantly, the ASA-HS procedure induced a generalized and long-lasting feeding suppression. We thus investigate the molecular effects underlying this phenomenon. While the exposure to the HS alone resulted in a significant upregulation of the mRNA levels of the Heat Shock Protein 70 (HSP 70) in snails' central ring ganglia, the ASA-HS procedure induced an even greater upregulation of HSP70, suggesting that the ASA-HS combination causes a severe stress response that inhibits feeding. Additionally, we found that the ASA-HS procedure induced a significant downregulation of the mRNA levels of genes involved with the serotoninergic system which regulates feeding in snails. Finally, the ASA-HS procedure prevented HS-induced upregulation of the mRNA levels of key neuroplasticity genes. Our study indicates that two sickness-inducing stimuli can have different physiological responses even if behavioral outcomes are similar under some learning contexts.

Quercetin, the new stress buster: Investigating the transcriptional and behavioral effects of this flavonoid on multiple stressors using Lymnaea stagnalis.

Growing evidence suggests that a flavonoid-rich diet can prevent or reverse the effects of stressors, although the underlying mechanisms remain poorly understood. One common and abundant flavonoid found in numerous foods is quercetin. This study utilizes the pond snail Lymnaea stagnalis, a valid model organism for learning and memory, and a simple but robust learning paradigm-operant conditioning of aerial respiration-to explore the behavioral and transcriptional effects of different stressors on snails' cognitive functions and to investigate whether quercetin exposure can prevent stress effects on learning and memory formation. Our findings demonstrate that three different stressors-severe food deprivation, lipopolysaccharide injection (an inflammatory challenge), and fluoride exposure (a neurotoxic agent)-block memory formation for operant conditioning and affect the expression levels of key targets related to stress response, energy balance, and immune response in the snails' central ring ganglia. Remarkably, exposing snails to quercetin for 1 h before stress presentation prevents these effects at both the behavioral and transcriptional levels, demonstrating the potent stress-preventive properties of quercetin. Despite the evolutionary distance from humans, L. stagnalis has proven to be a valuable model for studying conserved mechanisms by which bioactive compounds like quercetin mitigate the adverse effects of various stressors on cognitive functions across species. Moreover, these findings offer insights into quercetin's potential for mitigating stress-induced physiological and cognitive impairments.

Time- and Region-specific Effect of Vortioxetine on Central LPS-induced Transcriptional Regulation of NLRP3 Inflammasome.

BACKGROUND: Inflammasome overactivation, multiprotein complexes that trigger inflammatory responses, plays a critical role in Major Depressive Disorder (MDD) pathogenesis and treatment responses. Indeed, different antidepressants alleviate depression-related behaviours by specifically counteracting the NLRP3 inflammasome signalling pathway. The immunomodulatory effects of vortioxetine (VTX), a multimodal antidepressant with cognitive benefits, were recently revealed to counter memory impairment induced by a peripheral lipopolysaccharide (LPS) injection 24 hours (h) postchallenge. METHODS: The potential link between VTX and NLRP3, along with other inflammasomes, remains unexplored. Hence, adult C57BL/6J male mice (n = 73) were fed with a standard or VTX-enriched diet (600 mg/kg of food, 28 days), injected with LPS (830 µg/kg) or saline, and sacrificed 6/24 h post-LPS. At these time-points, transcriptional effects of LPS and VTX's on NLRP3, NLRP1, NLRC4, AIM2 (inflammasomes), ASC and CASP1 (related subunits) and NEK7 mediator (NLRP3 regulator) were assessed in dorsal and ventral hippocampal subregions, frontal-prefrontal cortex and hypothalamus, brain regions serving behavioural-cognitive functions impaired in MDD. RESULTS: Varied expression patterns of inflammasomes were revealed, with long-term NLRP3 and ASC transcriptional changes observed in response to LPS. It was discovered that VTX counteracted the LPS-mediated NLRP3 and ASC upregulation in memory-related brain areas like the dorsal hippocampus at 24 h time-point, potentially via regulating NEK7 expression. No VTX-mediated transcriptional effects were observed on other inflammasomes, reinforcing a potentially specific modulation on the NLRP3 inflammasome signalling pathway. CONCLUSION: Thus, a novel VTX's molecular mechanism in modulating the NLRP3 inflammasome in a time- and area-specific manner in the brain was highlighted, with significant clinical implications in treating depression and cognitive impairments.

The Impact of Music Therapy in a Pediatric Oncology Setting: An Italian Observational Network Study.

BACKGROUND: Music Therapy (MT) is a non-pharmacological, art-based intervention that employs music experiences within a therapeutic alliance to attend to clients' physical, emotional, cognitive, and social requirements. This is the first study aiming at investigating the impact of MT on the psychological facets of children suffering from cancer. METHODS: The study, combining the AQR and m-YPAS assessment tools, evaluated behavioral, sound-musical, and interactive parameters in pediatric oncology patients undergoing MT sessions during hospitalization. Fifty patients admitted to the Paediatric Oncology and Haematology Unit at Policlinico S. Orsola Hospital in Bologna, Italy, were enrolled, irrespective of their treatment regimen. Data collection occurred on the first day of the MT session between 3 p.m. and 5 p.m., with observations conducted by independent observers. In addition to traditional statistical analysis, network analysis was used to explore the combined interactions of all parameters, effectively discerning the distinctive roles played by each one during therapy sessions and their influence on all others. RESULTS: Network analysis highlighted distinct patterns of interactions among parameters during the various sessions, emphasizing the role of positive emotions and a calm setting, the child's ability to take the initiative in sessions, their sense of agency, and the parent's role in guiding them. Significant differences were recorded at each time point between all variables considered. CONCLUSIONS: The results of this innovative study may pave the way for future multicenter studies aimed at further exploring the role of MT in children undergoing both curative and palliative treatments for cancer.

Low TGF-ß1 plasma levels are associated with cognitive decline in Down syndrome.

Almost all individuals with Down's syndrome (DS) show the characteristic neuropathological features of Alzheimer's disease (AD) by the age of 40, yet not every individual with DS experiences symptoms of AD later in life. Similar to neurotypical developing subjects, AD in people with DS lasts for a long preclinical phase in which biomarkers follow a predictable order of changes. Hence, a prolonged asymptomatic period precedes the onset of dementia, underscoring the importance of identifying new biomarkers for the early detection and monitoring of cognitive decline in individuals with DS. Blood-based biomarkers may offer an alternative non-invasive strategy for the detection of peripheral biological alterations paralleling nervous system pathology in an early phase of the AD continuum. In the last few years, a strong neurobiological link has been demonstrated between the deficit of transforming growth factor-ß1 (TGF-ß1) levels, an anti-inflammatory cytokine endowed with neuroprotective activity, and early pro-inflammatory processes in the AD brain. In this clinical prospective observational study, we found significant lower plasma TGF-ß1 concentrations at the first neuropsychological evaluation (baseline = T0) both in young adult DS individuals (19-35 years) and older DS subjects without AD (35-60 years) compared to age- and sex-matched healthy controls. Interestingly, we found that the lower TGF-ß1 plasma concentrations at T0 were strongly correlated with the following cognitive decline at 12 months. In addition, in young individuals with DS, we found, for the first time, a negative correlation between low TGF-ß1 concentrations and high TNF-α plasma concentrations, a pro-inflammatory cytokine that is known to be associated with cognitive impairment in DS individuals with AD. Finally, adopting an ex vivo approach, we found that TGF-ß1 concentrations were reduced in parallel both in the plasma and in the peripheral blood mononuclear cells (PBMCs) of DS subjects, and interestingly, therapeutic concentrations of fluoxetine (FLX) applied to cultured PBMCs (1 µM for 24 h) were able to rescue TGF-ß1 concentrations in the culture media from DS PBMCs, suggesting that FLX, a selective serotonin reuptake inhibitor (SSRI) endowed with neuroprotective activity, might rescue TGF-ß1 concentrations in DS subjects at higher risk to develop cognitive decline.