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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”.