AIMS:Metabolic syndrome (MetS) is characterized by several metabolic alterations that may increase the risk of memory alterations. While metabolic consequences of MetS are well documented, its memory impact remains underexplored. This study aimed at investigating the progression of MetS-associated impairments and evaluating the therapeutic potential of URB597, a fatty-acid amide hydrolase inhibitor, that increases the N-acylethanolamine levels. MATERIALS AND METHODS:In Experiment 1, male Sprague-Dawley rats were fed a control (CTRL), high-fat (HF), high-carbohydrate (HC), or combined HF/HC diet for 12 weeks to identify the most effective model of MetS-induced metabolic and memory changes. In Experiment 2, rats received intranasal URB597 (0.1 mg/kg) for 10 weeks following the HF/HC diet to assess its therapeutic impact. Body weight, body mass index (BMI), and triglycerides were measured; memory function was assessed using the Object Recognition, Morris Water Maze, and Y-maze tasks. KEY FINDINGS:Results from Experiment 1 showed that the HF/HC diet induced metabolic dysfunctions and impairments in both recognition and long-term spatial memory, while short-term spatial memory remained intact. In Experiment 2, the prolonged diet reproduced the same metabolic and memory deficits observed in Experiment 1, and URB597 treatment reversed recognition memory impairments but did not improve spatial memory performance, suggesting a domain-specific vulnerability to MetS and to the treatment response. SIGNIFICANCE:These findings highlight memory deficits associated with MetS and point to N-acylethanolamine signaling as a potential modulatory pathway, with URB597 serving as a pharmacological tool to investigate its therapeutic relevance.

Living in a city brings a broad range of risks and protective factors to urban dwellers, yet how these factors interact within cities to impact their mental health remains unclear. Here, we integrate urban scaling and causal discovery to investigate how depression prevalence varies with the population size, and how urban determinants shape this relationship across 826 cities in the United States. Accounting for spatial dependence between cities, we find that depressive disorder scales sublinearly with population size, supporting the view that it is less likely to experience depression in more populous cities. The observed sublinear growth is accompanied by superlinear growth in several candidate determinants (including excessive drinking, single parenthood, and access to mental health providers), alongside sublinear growth in physical disability and street intersection density. Using causal discovery on population-adjusted data, we identify physical disability and excessive drinking as risk factors for depression, in contrast to economic prosperity and walkability that emerge as protective factors against depression. These findings highlight cities as systems intertwined with risks and protections, offering new insights that could inform system-oriented strategies to promote psychological well-being.

Background:The human gastrointestinal tract harbors trillions of microbes that act in synergy with the brain to regulate its homeostasis and function. This interplay holds promise for innovative dietary-based interventions to support cognitive and motivational processes or contrast their decline in disease. While probiotics have traditionally been used for such interventions, several limitations have hampered their suitability and incited interest in prebiotics. Fructans represent a valid prebiotic whereby they are abundant in several vegetables (e.g., chicory taproots) and increase short-chain fatty acids (SCFAs) production via fermentation by gut microbes. SCFAs have been reported to modulate gene expression in the brain via epigenetic mechanisms. Here, we investigated whether chicory taproots may represent a strategy to contrast cognitive and motivational impairments induced by chronic corticosterone administration. Methods:To test our hypothesis, we exposed C57BL/6 male mice (n = 18 per group) to corticosterone supplementation in drinking water and provided them with a fructan-rich diet (regular diet enriched with dried chicory taproots). Results:Consistent with our hypothesis, chicory taproot consumption promoted the growth of selected microbial species and increased SCFA concentrations. To verify the functional role of these modulations, using a comprehensive behavioral test battery, we observed that chicory taproots contrasted the cognitive and motivational consequences of chronic corticosterone exposure. These behavioral modifications were associated with a modulation of gene expression and its epigenetic regulators in brain regions relevant for cognition and motivation. Conclusions:These results highlight the role of prebiotics in preserving higher-order brain functions and offer insights into their therapeutic potential.

Robot integration in daily life demands research on both safety and social acceptance. Current methods focus on safety, but social factors are understudied. Moreover, existing studies lack deep analysis of human perception towards robot movement. Here, we present a novel navigation approach based on the combination of Game Theory and the Social Force Model (GTSFM) to bridge these gaps. We model navigation as a non-cooperative game to consider both pedestrians and robot as rational agents influencing each other’s choices. We evaluate the social acceptability of the GTSFM algorithm from both quantitative and qualitative perspectives. In both evaluations, the GTSFM is compared against two state-of-the-art algorithms: the social force model (SFM) and the optimal reciprocal collision avoidance (ORCA). According to the quantitative analysis performed in simulation, the GTSFM outperforms the SFM in all considered performance metrics and ensures higher performance than ORCA considering the smoothness of the trajectories and the proximity to pedestrians. The qualitative measurement is performed through a real-world experiment using a questionnaire administered to a pool of 76 participants. Our qualitative analysis revealed no statistically significant differences in performance between the algorithms tested. This lack of distinction may be due to unaccounted factors. The robot’s appearance and the limited velocity of the real robot could have obscured the distinction between the algorithms. These results represent a significant milestone in advancing the integration of robots into social environments also leave important hints for future research.

Exclusive breastfeeding (eBF) in infancy appears to offer a developmental advantage for children's brains compared to formula-fed counterparts. Existing research has predominantly focused on global brain measures (i.e., total white/grey matter volumes) or on limited sets of specific brain regions, in selected age groups, leaving uncertainties about the impact of eBF on the overall structural connectomes. In this cross-sectional study encompassing participants from childhood to adulthood, partial least squares correlations (PLSC) were employed to assess white and grey matter volumes. Furthermore, a network analytic approach was used to estimate the structural connectome based on cortical thickness data. The results revealed that eBF duration correlated with increased white matter volumes in children and with the volume of the medial orbital gyrus in adults. Structural connectome analyses demonstrated heightened anatomical connectivity in eBF children, evidenced by enhanced network density and local/global efficiency, along with increased node degree and local efficiency in frontal and temporal lobes. Similarly, eBF in adults was associated to an improved node connectivity in the frontal lobe. These findings imply a lasting impact of eBF on brain morphometry and structural connectivity. Childhood benefits include heightened white matter development, while in adulthood, eBF may contribute to reduced neural loss associated with aging and enhanced connectivity, particularly in frontal regions.

Causal discovery from urban data offers an unprecedented opportunity for research and practice in urban science. Whether they implement traditional regression analyses or more sophisticated tools for time series analysis, existing approaches to causal discovery consider cities to be statistically equivalent - an assumption that is seldom met in real urban systems, where cities dramatically differ in population size, land area, etc. In this study, we embrace the heterogeneity between cities within a novel approach to causal discovery that integrates urban scaling and information theory, towards the discovery of associations between urban processes. Our approach takes as input time series of salient urban variables for causal discovery, along with a set of static features that capture the heterogeneities within the system. Using a Cobb-Douglas function, we extract features-adjusted metropolitan indicators (FsAMIs) that mitigate spurious dependencies among variables due to the underlying variations in spatial features. Through the application of transfer entropy on FsAMIs, we ultimately perform model-free causal inference between urban processes. We validate our approach on synthetic datasets representative of a pair of time-varying urban mock variables and on two real-world open urban datasets related to climate change and infectious diseases. Results demonstrate that our framework outperforms the state of the art across diverse scenarios, minimizing false (positive and negative) inferences. Our methodology offers a powerful tool that advances data-driven urban policy and planning, leveraging open urban datasets to gain robust insight into relationships among urban variables.

Impulsivity has been proposed as a key driver of obesity. However, evidence linking impulsivity and obesity has relied on the study of individual factors, with limited account for the urban attributes of obesogenic environments. Here, we investigate the relationship between obesity and impulsivity through urban scaling and causal discovery. For 915 cities in the United States of America, we study the prevalence of obesity in adults, attention deficit hyperactivity disorder (ADHD) in children, and relevant urban features. We observe sublinear scaling of obesity and ADHD with population size, these disorders being less prevalent in larger cities. By applying a causal discovery tool to the deviations of cities from the urban scaling laws, we identify an influence of ADHD on obesity, moderated by lifestyle. The strength of these associations is confirmed by individual-level data on a cohort of 19,333 children, wherein we observe that ADHD modulates obesity both directly and indirectly.

Individuals with highly superior autobiographical memory (HSAM) challenge current memory knowledge, yet it remains unclear if their superior memory stems from impaired forgetting. Using a directed forgetting paradigm, we examined this in 12 individuals with HSAM and 30 controls. During fMRI, participants viewed single words followed by "remember" or "forget" instructions. Five minutes later, participants performed a memory recognition task with old (previously studied) and new words. Behaviorally, both groups showed similar forgetting effects, recognizing fewer to-be-forgotten than to-be-remembered words. However, at the neural level, HSAM individuals showed increased activity in the dorsal and ventral frontoparietal regions during initial word presentation, prior to memory instructions. During active forgetting, they also showed increased activity in the anterior and posterior midline regions. These findings suggest that HSAM individuals require additional neural resources for active forgetting to compensate for their enhanced initial processing of stimuli, enabling them to match the forgetting performance of controls.

Lactoferrin (LF) and osteopontin (OPN) are bioactive milk proteins which can form heteroprotein complexes and complex coacervates. This research studied the effect of LF-OPN complexation and complex coacervation on the simulated infant gastrointestinal digestion of LF with subsequent examination of gut and bone health bioactivities in preclinical models. In an infant digestion model, the proteolytic profile of LF was unaltered by the pre-association of LF and OPN. Gastric proteolysis of LF was increased when the model gastric pH was reduced from 5.3 to 4.0, but less so when complexed with OPN. In a model of intestinal inflammation, undigested (79% inhibition) and gastric digestates (26% inhibition) of LF, but not gastrointestinal digestates, inhibited lipopolysaccharide (LPS)-induced NF-kappa B activation in intestinal epithelial cells. LF-OPN complexation sustained the inhibitory effect (21-43% of the undigested effect, depending on the type of complex) of LF after gastrointestinal digestion, suggesting that the peptides produced were different. In a neonatal rodent model used to study bone development, coacervating LF and OPN improved bone structures with a significant increase of trabecular proportion (BV/TV increase by 21.7%). This resulted in an 11.3% increase in stiffness of bones. Feeding the LF and OPN proteins in coacervate format also increased the levels of OPN, P1NP and M-CSF in blood, signifying a more pronounced impact on bone development. This research demonstrated that LF-OPN complexation and complex coacervation can delay simulated infant gastrointestinal digestion of LF and protect or improve the bioactivity of the proteins.

Type 2 Diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia, resulting from deficits in insulin secretion, insulin action, or both. Whilst the role of insulin in the peripheral nervous system has been ascertained in countless studies, its role in the central nervous system (CNS) is emerging only recently. Brain insulin has been lately associated with brain disorders like Alzheimer’s disease, obsessive compulsive disorder, and attention deficit hyperactivity disorder. Thus, understanding the role of insulin as a common risk factor for mental and somatic comorbidities may disclose novel preventative and therapeutic approaches. We evaluated general metabolism (glucose tolerance, insulin sensitivity, energy expenditure, lipid metabolism, and polydipsia) and cognitive capabilities (attention, cognitive flexibility, and memory), in adolescent, young adult, and adult male and female TALLYHO/JngJ mice (TH, previously reported to constitute a valid experimental model of T2DM due to impaired insulin signaling). Adult TH mice have also been studied for alterations in gut microbiota diversity and composition. While TH mice exhibited profound deficits in cognitive flexibility and altered glucose metabolism, we observed that these alterations emerged either much earlier (males) or independent of (females) a comprehensive constellation of symptoms, isomorphic to an overt T2DM-like phenotype (insulin resistance, polydipsia, higher energy expenditure, and altered lipid metabolism). We also observed significant sex-dependent alterations in gut microbiota alpha diversity and taxonomy in adult TH mice. Deficits in insulin signaling may represent a common risk factor for both T2DM and CNS-related deficits, which may stem from (partly) independent mechanisms.

Behavioural inflexibility is a symptom of neuropsychiatric and neurodegenerative disorders such as Obsessive-Compulsive Disorder, Autism Spectrum Disorder and Alzheimer's Disease, encompassing the maintenance of a behaviour even when no longer appropriate. Recent evidence suggests that insulin signalling has roles apart from its regulation of peripheral metabolism and mediates behaviourally-relevant central nervous system (CNS) functions including behavioural flexibility. Indeed, insulin resistance is reported to generate anxious, perseverative phenotypes in animal models, with the Type 2 diabetes medication metformin proving to be beneficial for disorders including Alzheimer's Disease. Structural and functional neuroimaging studies of Type 2 diabetes patients have highlighted aberrant connectivity in regions governing salience detection, attention, inhibition and memory. As currently available therapeutic strategies feature high rates of resistance, there is an urgent need to better understand the complex aetiology of behaviour and develop improved therapeutics. In this review, we explore the circuitry underlying behavioural flexibility, changes in Type 2 diabetes, the role of insulin in CNS outcomes and mechanisms of insulin involvement across disorders of behavioural inflexibility.

Cognitive flexibility involves the capability to switch between different perspectives and implement novel strategies upon changed circumstances. The Wisconsin Card Sorting Test (in humans) and the Attentional Set-Shifting Task (ASST, in rodents) evaluate individual capability to acquire a reward-associated rule and subsequently disregard it in favour of a new one. Both tasks entail consecutive stages wherein subjects discriminate between: two stimuli of a given category (simple discrimination, SD); the stimuli of SD confounded by an irrelevant stimulus of a different category (compound discrimination, CD); different stimuli belonging to the SD category (intradimensional shift, IDS); and two stimuli of the confounding category (extradimensional shift, EDS). The ASST is labour intensive, not sufficiently standardised, and prone to experimental error. Here, we tested the validity of a new, commercially available, automated version of ASST (OPERON) in two independent experiments conducted in: different mouse strains (C57BL/6 and CD1 mice) to confirm their differential cognitive capabilities (Experiment 1); and an experimental model of chronic stress (administration of corticosterone in the drinking water; Experiment 2). In both experiments, OPERON confirmed the findings obtained through the manual version. Just as in Experiment 1 both versions captured the deficit of C57BL/6 mice on the reversal of the CD (CDR), so also in Experiment 2 they provided analogous evidence that corticosterone treated mice have a remarkable impairment in the IDS. Thus, OPERON capitalises upon automated phenotyping to overcome the limitation of the manual version of the ASST while providing comparable results.

Breast milk (BM) is the optimal source of nutrition for mammals' early life. It exerts multiple benefits, including the development of cognitive capabilities and protection against several diseases like obesity and infection of the respiratory tract. However, which components of BM are involved in individual development has remained elusive. Sialylated human milk oligosaccharides (HMOs) may constitute a valid candidate, whereby they represent the principal source of sialic acid and act as building blocks for brain development. We hypothesize that the reduced availability of two HMOs, sialyl(alpha2,6)lactose (6 ' SL) and sialyl(alpha2,3)lactose (3 ' SL), may impair attention, cognitive flexibility, and memory in a preclinical model and that the exogenous supplementation of these compounds may contrast the observed deficits. We evaluated cognitive capabilities in a preclinical model exposed to maternal milk containing reduced concentrations of 6 ' SL and 3 ' SL during lactation. To modulate their concentrations, we utilized a preclinical model characterized by the absence of genes that synthesize 3 ' SL and 6 ' SL (B6.129-St3gal4(tm1.1Jxm) and St6gal1(tm2Jxm), double genetic deletion), producing milk lacking 3 ' SL and 6 ' SL. Then, to ensure exposure to 3 ' SL-6 ' SL-poor milk in early life, we adopted a cross-fostering protocol. The outcomes assessed in adulthood were different types of memory, attention and information processing, some of which are part of executive functions. Then, in the second study, we evaluated the long-term compensatory potential of the exogenous oral supplementation of 3 ' SL and 6 ' SL during lactation. In the first study, exposure to HMO-poor milk resulted in reduced memory and attention. Specifically, it resulted in impaired working memory in the T-maze test, in reduced spatial memory in the Barnes maze, and in impaired attentional capabilities in the Attentional set-shifting task. In the second part of the study, we did not observe any difference between experimental groups. We hypothesize that the experimental procedures utilized for the exogenous supplementation may have impacted our ability to observe the cognitive read-out in vivo. This study suggests that early life dietary sialylated HMOs play a crucial role in the development of cognitive functions. Future studies are needed to clarify if an exogenous supplementation of these oligosaccharides may compensate for these affected phenotypes.

Beside its involvement in somatic dysfunctions, altered insulin signalling constitutes a risk factor for the development of mental disorders like Alzheimer's disease and obsessive-compulsive disorder. While insulin-related somatic and mental disorders are often comorbid, the fundamental mechanisms underlying this associ-ation are still elusive. Studies conducted in rodent models appear well suited to help decipher these mechanisms. Specifically, these models are apt to prospective studies in which causative mechanisms can be manipulated via multiple tools (e.g., genetically engineered models and environmental interventions), and experimentally dissociated to control for potential confounding factors. Here, we provide a narrative synthesis of preclinical studies investigating the association between hyperglycaemia - as a proxy of insulin-related metabolic dysfunctions - and impairments in working and spatial memory, and attention. Ultimately, this review will advance our knowledge on the role of glucose metabolism in the comorbidity between somatic and mental illnesses.