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Introduction High-fat diet (HFD) consumption during pregnancy can shape fetal brain development, increasing susceptibility to mental disorders. Nevertheless, the mechanisms underlying these negative outcomes remain unclear. Objectives We hypothesize that mHFD induces inflammation and oxidative stress (OS) in the fetal brain, disrupting excitatory/inhibitory (E/I) balance in the adult brain. This results in altered hypothalamic-pituitary-adrenal (HPA) axis reactivity, emotional regulation, and cognitive function. We tested the ability of N-acetyl-cysteine (NAC) - a powerful anti-oxidant and anti-inflammatory compound - to counteract mHFD effects. Methods Our mHFD model consists of female C57BL/6N mice fed either HFD (fat 58%, carbohydrate 25.5%, and protein 16.4%) or control diet (CD, fat 10.5%, carbohydrate 73.1% and protein 16.4%) before and during pregnancy (13 weeks). After 5 weeks on diets, half of them received NAC (1g/kg) for 8 weeks, until delivery. Gene expression of Il-1b, Cd68, Tmem119, iNOS, and Arg1 was measured in fetal brains. Cognitive function and emotional phenotype were assessed in adult male and female offspring through the Morris Water Maze (MWM) and the Emergence test, respectively. HPA axis functionality was assessed by measuring plasma corticosterone levels by ELISA following acute stress. Gene expression of vesicular glutamate transporter 1 (Vglut1) and vesicular GABA transporter (Vgat) were assessed as markers of E/I balance. Results Exposure to mHFD induced inflammation and OS in the fetal brain of both sexes, by increasing Il-1b and iNOS/Arg1. Additionally, Cd68 and Tmem119 were specifically increased in females. In adulthood, mHFD reduced latency to emerge from the shelter in the Emergence test in both sexes. In females, mHFD impaired cognitive function, reducing time spent in the MWM target zone, and increased HPA reactivity in response to acute stress. Furthermore, mHFD decreased Vgat expression in both sexes, resulting in an imbalanced Vglut1/Vgat ratio towards excessive excitatory input. Maternal NAC supplementation rescued this imbalance. Conclusions Overall, these data show that mHFD increases inflammation and OS in fetal brains, with greater effects in female offspring, inducing alterations in the E/I neuronal balance with concomitant disruptions of the neuroendocrine system and the emotional and cognitive profiles during adulthood. The supplementation with NAC was effective in rescuing the E/I imbalance as well as the behavioral phenotype. Disclosure of Interest None Declared

Introduction Stressful experiences in utero can produce physiological changes which become embedded biological traces affecting fetal brain development and ultimately leading to increased vulnerability for psychiatric disorders. Objectives We hypothesized that stressors as diverse as maternal obesity and maternal psychophysical stress might disrupt fetal programming resulting in long-lasting effects on offspring brain development by acting through shared oxidative stress (OS)-mediated mechanisms. Methods We compared a mouse model (C57Bl/6N) of maternal high-fat diet (HFD) consumption (13 weeks, until delivery) to prenatal restraint stress (PNS) repeatedly administered during the last week of pregnancy. To counteract the negative effects of both stressors, the antioxidant N-acetyl-cysteine (NAC, 1 g/kg) was administered to female breeders for 8 weeks until delivery. Emotionality was assessed in adolescent male and female offspring through the elevated-plus-maze (EPM). Moreover, hippocampal gene expression levels of Brain-Derived-Neurotrophic-Factor (Bdnf ), Nuclear factor erythroid 2–related factor 2 (Nrf-2) and Kelch-like ECH-associated protein 1 (Keap-1) were measured, by qPCR, as markers of brain plasticity and antioxidant capacity. Results Prenatal exposure to both HFD and PNS enhanced behavioral disinhibition, increasing time spent in the open arms of the EPM and decreasing the frequency of risk-assessment behaviors, especially in female offspring. Moreover, both prenatal stressors led to decreased Bdnf (in females) and Nrf-2 levels, and disrupted Keap-1 levels. Prenatal NAC was able to counteract these effects on the brain. Conclusions Our data support the hypothesis of a “funnel effect” model explaining how different prenatal stressors result in long-term negative effects on the adolescent offspring, increasing risk assessment behaviors and affecting brain plasticity and antioxidant defenses. The beneficial preventive effects of NAC suggest that OS may be a common mechanism, playing a pivotal role in fetal programming of mental disorders. ERANET-NEURON-JTC-2018-Mental Disorders-“EMBED” and Bando Ricerca Indipendente ISS 2021-2023; MOMINFLAM. Unique signatures underlying placental-fetal brain crosstalk in maternal obesity to F Cirulli. Disclosure of InterestNone Declared

Introduction Bipolar disorder (BD) is a psychiatric disease whose heterogeneity in phenotypic manifestations and disease severity hampers the diagnosis and the achievement of adequate therapeutic management. Increased pro-inflammatory cytokines and cortisol levels (CORT) have been observed in BD patients that might affect brain plasticity by decreasing Brain-Derived-Neurotrophic Factor (BDNF) levels. However, BD etiopathological mechanisms are still largely unclear and little is known about the interaction among these biomarkers and affective episodes. Objectives To assess changes in peripheral endocrine and inflammatory markers, CORT awakening response, BDNF and cytokines levels during an acute phase of the disease and during euthymia and to evaluate whether these changes might be exploited as a biosignature of the disease. Methods The study will be carried out on BD patients aged 18-65 who will be recruited during affective episodes (depressive, manic/hypomanic phase). In addition, a control group of 40 healthy subjects, age- and sex-matched will be also enrolled. All assessments will be carried out at the time of recruitment and after 3 and 6 months. Blood samples will be collected to evaluate cytokines (IL-1, IL-2, IL-6, IL-10, TNF-alpha, IFN-gamma) and BDNF. Hypothalamic-pituitary-adrenal (HPA) axis response will be assessed by measuring salivary cortisol levels upon awakening (cortisol awakening response – CAR). The psychopathological assessment will include the use of MADRS, YMRS and HAM-A for the assessment of psychiatric symptoms; PSP and C-SSRS for the assessment of global functioning and suicidal risk; IPSS and SRRS for the assessment of stress levels; CIRS for the evaluation of physical comorbidities. Results We expect that 1) changes in inflammatory markers can predict the onset of acute phases of BD; 2) to observe significant differences in the levels of pro-inflammatory cytokines, CORT and BDNF between BD patients (during euthymia) and control subjects. Conclusions Using a longitudinal approach, we will be able to evaluate whether the presence of affective symptoms in the BD patient is correlated with fluctuations in the levels of pro-inflammatory cytokines and chemokines, salivary cortisol and BDNF. Furthermore, the enrolment of control subjects will allow to evaluate if the inflammatory state and the activation of the HPA axis are steadily elevated in BD patients. “Funded by: Bando Ricerca Indipendente ISS 2021-2023 to A. Berry project code ISS20-9286e4091f8e” Disclosure of Interest None Declared

Introduction Maternal obesity may affect foetal programming representing a risk for adult mental health. Oxidative stress and inflammation associated with maternal obesity can alter the maturation of neuronal circuits affecting behaviour and mood. Objectives We investigated the emotional phenotype of male and female mouse offspring born from a high-fat diet (HFD) fed dams. We also tested the efficacy of N-acetyl-cysteine (NAC – an antioxidant) in preventing the negative effects of HFD. We focused on adolescence, an age of main vulnerability for the onset of psychopathology. Methods Female C57BL/6N mice were fed HFD for 13 weeks and, after 5 weeks, were also exposed to NAC (1 g/kg b.w.) via drinking water, until delivery. The neurodevelopment of offspring was assessed through the homing test. Emotionality was assessed in 35-45-day-old adolescent mice through elevated-plus-maze (EPM) and social interaction tests (SIT). Transcriptomic analysis of hippocampal tissue were performed to identify mechanisms of action of both HFD and NAC. Results NAC was effective in moderating body weight gain in HFD-fed dams. Neither HFD or NAC affected offspring development. Regardless of sex, prenatal HFD reduced exploration and decreased sociability, in EPM and SIT respectively. Prenatal HFD decreased hippocampal levels of BDNF in female offspring. Prenatal NAC administration prevented social anxiety and restored BDNF levels in the HFD group. Conclusions Data indicate long-term effects of maternal obesity on dams’ weight, offspring’s behaviour and hippocampal BDNF levels. These effects may be mediated by changes in oxidative stress as NAC was effective as a preventive agent. ERANET-NEURON-JTC 2018 (Mental Disorders) Project “EMBED”.

Background & Aims: Unhealthy lifestyles, such as chronic consumption of a Western Diet (WD), have been associated with increased systemic inflammation and oxidative stress (OS), a condition that may favour cognitive dysfunctions during aging. Polyphenols, such as rosmarinic acid (RA) may buffer low-grade inflammation and OS, characterizing the aging brain that is sustained by WD, promoting healthspan. The aim of this study was to evaluate the ability of RA to prevent cognitive decline in a mouse model of WD-driven unhealthy aging and to gain knowledge on the specific molecular pathways modulated within the brain., Methods: Aged male and female C57Bl/6N mice were supplemented either with RA or vehicle for 6 weeks. Following 2 weeks on RA they started being administered either with WD or control diet (CD). Successively all mice were tested for cognitive abilities in the Morris water maze (MWM) and emotionality in the elevated plus maze (EPM). Glucose and lipid homeostasis were assessed in trunk blood while the hippocampus was dissected out for RNAseq transcriptomic analysis., Results: RA prevented insulin resistance in males while protecting both males and females from WD-dependent memory impairment. In the hippocampus, RA modulated OS pathways in males and immune- and sex hormones-related signalling cascades (Lhb and Lhcgr genes) in females. Moreover, RA overall resulted in an upregulation of Glp1r, recently identified as a promising target to prevent metabolic derangements. In addition, we also found an RA-dependent enrichment in nuclear transcription factors, such as NF-κB, GR and STAT3, that have been recently suggested to promote healthspan and longevity by modulating inflammatory and cell survival pathways., Conclusions: Oral RA supplementation may promote brain and metabolic plasticity during aging through antioxidant and immune-modulating properties possibly affecting the post-reproductive hormonal milieu in a sex-dependent fashion. Thus, its supplementation should be considered in the context of precision medicine as a possible strategy to preserve cognitive functions and to counteract metabolic derangements., Competing Interests: Conflict of interest K.S. was employed by AnalytiCon Discovery GmbH, Potsdam, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All authors have approved the manuscript in its final form., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Maternal obesity has been recognized as a stressor affecting the developing fetal brain, leading to long-term negative outcomes comparable to those resulting from maternal psychological stress, although the mechanisms have not been completely elucidated. In this study, we tested the hypothesis that adverse prenatal conditions as diverse as maternal stress and maternal obesity might affect emotional regulation and stress response in the offspring through common pathways, with a main focus on oxidative stress and neuroplasticity. We contrasted and compared adolescent male and female offspring in two mouse models of maternal psychophysical stress (restraint during pregnancy - PNS) and maternal obesity (high-fat diet before and during gestation - mHFD) by combining behavioral assays, evaluation of the hypothalamic-pituitary-adrenal (HPA) axis reactivity, immunohistochemistry and gene expression analysis of selected markers of neuronal function and neuroinflammation in the hippocampus, a key region involved in stress appraisal. Prenatal administration of the antioxidant N-acetyl-cysteine (NAC) was used as a strategy to protect fetal neurodevelopment from the negative effects of PNS and mHFD. Our findings show that these two stressors produce overlapping effects, reducing brain anti-oxidant defenses (Nrf-2) and leading to sex-dependent impairments of hippocampal Bdnf expression and alterations of the emotional behavior and HPA axis functionality. Prenatal NAC administration, by restoring the redox balance, was able to exert long-term protective effects on brain development, suggesting that the modulation of redox pathways might be an effective strategy to target common shared mechanisms between different adverse prenatal conditions., (© 2023. The Author(s).)

A growing body of evidence suggests that regular consumption of natural products might promote healthy aging; however, their mechanisms of action are still unclear. Rosmarinic acid (RA) is a polyphenol holding anti-inflammatory, antioxidant and neuroprotective properties. The aim of this study was to characterise the efficacy of an oral administration of RA in promoting healthspan in a mouse model of physiological aging. Aged C57Bl/6 male and female (24-month-old) mice were either administered with RA (500 mg/Kg) or a vehicle in drinking bottles for 52 days while 3-month-old mice receiving the same treatment were used as controls. All subjects were assessed for cognitive abilities in the Morris water maze (MWM) and for emotionality in the elevated-plus maze test (EPM). Brain-derived Neurotrophic Factor (BDNF) protein levels were evaluated in the hippocampus. Since the interaction between metabolic signals and cerebral functions plays a pivotal role in the etiopathogenesis of cognitive decline, the glycaemic and lipid profiles of the mice were also assessed. RA enhanced learning and memory in 24-month-old mice, an effect that was associated to improved glucose homeostasis. By contrast, the lipid profile was disrupted in young adults. This effect was associated with worse glycaemic control in males and with reduced BDNF levels in females, suggesting powerful sex-dependent effects and raising a note of caution for RA administration in young healthy adult subjects.

Obesity is a main risk factor for the onset and the precipitation of many non-communicable diseases. This condition, which is associated with low-grade chronic systemic inflammation, is of main concern during pregnancy leading to very serious consequences for the new generations. In addition to the prominent role played by the adipose tissue, dysbiosis of the maternal gut may also sustain the obesity-related inflammatory milieu contributing to create an overall suboptimal intrauterine environment. Such a condition here generically defined as "inflamed womb" may hold long-term detrimental effects on fetal brain development, increasing the vulnerability to mental disorders. In this review, we will examine the hypothesis that maternal obesity-related gut dysbiosis and the associated inflammation might specifically target fetal brain microglia, the resident brain immune macrophages, altering neurodevelopmental trajectories in a sex-dependent fashion. We will also review some of the most promising nutritional strategies capable to prevent or counteract the effects of maternal obesity through the modulation of inflammation and oxidative stress or by targeting the maternal microbiota.

Liquid chromatography coupled to mass spectrometry is a key metabolomics/metabonomics technology. Reversed-phase liquid chromatography (RPLC) is very widely used as a separation step, but typically has poor retention of highly polar metabolites. Here, we evaluated the combination of two alternative methods for improving retention of polar metabolites based on 6-aminoquinoloyl- N -hydroxysuccinidimyl carbamate derivatization for amine groups, and ion-pairing chromatography (IPC) using tributylamine as an ion-pairing agent to retain acids. We compared both of these methods to RPLC and also to each other, for targeted analysis using a triple-quadrupole mass spectrometer, applied to a library of ca. 500 polar metabolites. IPC and derivatization were complementary in terms of their coverage: combined, they improved the proportion of metabolites with good retention to 91%, compared to just 39% for RPLC alone. The combined method was assessed by analyzing a set of liver extracts from aged male and female mice that had been treated with the polyphenol compound ampelopsin. Not only were a number of significantly changed metabolites detected, but also it could be shown that there was a clear interaction between ampelopsin treatment and sex, in that the direction of metabolite change was opposite for males and females.

Prenatal stress (PNS) affects foetal programming and, through an interaction with subsequent challenges, can increase vulnerability to mood and metabolic disorders. We have previously shown that, following PNS, adult male rats are characterized by increased vulnerability to a metabolic stressor experienced at adulthood (8-week-high-fat diet-HFD). In this study, we specifically assessed whether PNS might interact with an adult metabolic challenge to induce an inflammatory phenotype. Changes in the expression levels of inflammatory (Il-1β, Tnf-α, Il-6) and of stress response mediators (Nr3c1, Fkbp5) as well as of mood and metabolic regulators (Bdnf, Ghs-R) were investigated in the hippocampus, prefrontal cortex and hypothalamus, brain regions involved in the pathogenesis of depression and prone to inflammation in response to stress. Overall, PNS reduced the expression of Bdnf and Tnf-α, while HFD administered at adulthood counteracted this effect suggesting that PNS impinges upon the same pathways regulating responses to a metabolic challenge at adulthood. Furthermore, HFD and PNS affected the expression of both Nr3c1 and Fkbp5, two neuroendocrine mediators involved in the response to stress, metabolic challenges and in the modulation of the emotional profile (as shown by the correlation between Fkbp5 and the time spent in the open arms of the elevated plus-maze). Overall, these results indicate that the same metabolic and neuroendocrine effectors engaged by PNS are affected by metabolic challenges at adulthood, providing some mechanistic insight into the well-known comorbidity between mood and metabolic disorders., (© 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Adverse stressful experiences in utero can redirect fetal brain development, ultimately leading to increased risk for psychiatric disorders. Obesity during pregnancy can have similar effects as maternal stress, affecting mental health in the offspring. In order to explain how similar outcomes may originate from different prenatal conditions, we propose a "funnel effect" model whereby maternal psychological or metabolic stress triggers the same evolutionarily conserved response pathways, increasing vulnerability for psychopathology. In this context, the placenta, which is the main mother-fetus interface, appears to facilitate such convergence, re-directing "stress" signals to the fetus. Characterizing converging pathways activated by different adverse environmental conditions is fundamental to assess the emergence of risk signatures of major psychiatric disorders, which might enable preventive measures in risk populations, and open up new diagnostics, and potentially therapeutic approaches for disease prevention and health promotion already during pregnancy., (Copyright © 2022. Published by Elsevier Ltd.)

Over the last decades a decrease in mortality has paved the way for late onset pathologies such as cardiovascular, metabolic or neurodegenerative diseases. This evidence has led many researchers to shift their focus from researching ways to extend lifespan to finding ways to increase the number of years spent in good health; "healthspan" is indeed the emerging concept of such quest for ageing without chronic or disabling diseases and dysfunctions. Regular consumption of natural products might improve healthspan, although the mechanisms of action are still poorly understood. Since preclinical studies aimed to assess the efficacy and safety of these compounds are growing, we performed a systematic review and meta-analysis on the effects of natural products on healthspan in mouse and rat models of physiological ageing. Results indicate that natural compounds show robust effects improving stress resistance and cognitive abilities. These promising data call for further studies investigating the underlying mechanisms in more depth., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Maternal obesity plays a key role in the health trajectory of the offspring. Although research on this topic has largely focused on the potential of this condition to increase the risk for child obesity, it is becoming more and more evident that it can also significantly impact cognitive function and mental health. The mechanisms underlying these effects are starting to be elucidated and point to the placenta as a critical organ that may mediate changes in the response to stress, immune function and oxidative stress. Long-term effects of maternal obesity may rely upon epigenetic changes in selected genes that are involved in metabolic and trophic regulations of the brain. More recent evidence also indicates the gut microbiota as a potential mediator of these effects. Overall, understanding cause-effect relationships can allow the development of preventive measures that could rely upon dietary changes in the mother and the offspring. Addressing diets appears more feasible than developing new pharmacological targets and has the potential to affect the multiple interconnected physiological pathways engaged by these complex regulations, allowing prevention of both metabolic and mental disorders., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

Aim of this study was to characterize the effects of oral trehalose administration (2%w/v) on healthspan in old mice. Trehalose was administered in drinking water for 1 month to male and female C57BL/6N mice aged 25-months. After behavioral phenotyping (grip strength, beam walking and rotarod tests), autophagy (LC3-II/actin) and oxidative stress were tested in the cerebral cortex and gastrocnemius muscle. The latter parameter was indirectly assessed by evaluating carbonyl groups added to proteins as a result of oxidative reactions, in addition to central levels of NRF2 protein, a transcription factor that regulates the expression of antioxidant enzymes. In comparison with sex-matched controls, trehalose-treated males performed better in motor planning and coordination tasks. This behavioral phenotype was associated with an activation of the ubiquitin-proteasome system, autophagy and antioxidant defences in cerebral cortex. Independently from trehalose administration, females were characterized by better motor performance and showed higher levels of ubiquitinated proteins and NRF2 in cerebral cortex, suggesting an up-regulation of basal antioxidant defences. In conclusion, trehalose was effective in counteracting some aspects of age-related decay, with specific effects in male and female subjects., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)