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Stress is a major risk factor for the development of psychiatric disorders, including depression. However, its effects are not the same in all the subjects as only a portion of individuals exposed to stress will eventually develop negative mental outcomes, while others can be considered resilient. However, the biological processes underlying the development of a vulnerable or resilient phenotype are still poor understood. In order to cover this, we here used both transcriptomic and miRNomic based approaches in the ventral hippocampus of control (CON) and rats exposed to the chronic mild stress (CMS) paradigm, which were then divided into vulnerable (VULN) or resilient (RES) animals according to the sucrose consumption test. Transcriptomic analyses in VULN rats, compared to both the group of CON and RES animals, revealed the activation of inflammatory/immune-related pathways, specifically involved in antibodies and cytokine production, and the inhibition of pathways involved in protein synthesis. Conversely, transcriptomic data in RES animals suggested the activation of several pathways involved in neurotransmission. We then performed a mRNA-miRNA integration analysis by using miRComb R package, and we found that the most significant mRNA-miRNA pairs were involved in promoting the inflammatory status in VULN animals and, vice versa, by decreasing it in RES rats. Moreover, in VULN animals, the mRNA-miRNA combining analyses revealed the modulation of the olfactory sensory system, a key biological process that has been already found involved in the etiology of stress related disorders such as depression. Overall, our mRNA-miRNA integration-based approach identified distinct biological processes that are relevant for the development of a vulnerable or resilient phenotype in response to the negative effects of CMS exposure, which could allow the identification of novel targets for prevention or treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Competing Interests: The authors report no conflicts of interest.

A considerable proportion of patients with schizophrenia perform below population norms on standardized neuropsychological tests, and the performance of those performing within normal range is lower than predicted based on parental education. Cognitive impairment predates the onset of psychosis, is observed during symptom remission and in non-affected first-degree relatives of patients. At the present time, cognitive deficits are regarded as key features of schizophrenia, important determinants of poor psychosocial outcome and targets for both pharmacological and non-pharmacological treatment strategies. A group of eight key opinion leaders reviewed and discussed latest advances in scientific research and current good clinical practices on assessment, management, and treatment of CIAS. In the present paper they summarize the current evidence, identify main gaps between current knowledge and mental health services clinical practice, and provide practical recommendations to reduce the gap., Competing Interests: SB received advisory board, lecture, or consulting fees, outside the present work, from: Angelini, Janssen Pharmaceuticals, Lundbeck, Otsuka. RC received advisory board fees from Boehringer and was a speaker for Rovi. SG reports consulting fees from Gedeon Richter; honoraria from Angelini, Boehringer Ingelheim, Gedeon Richter, Janssen, Lundbeck, Otsuka, Recordati, Rovi; and participation on data safety monitoring boards with Angelini, Boehringer Ingelheim, Janssen, and Rovi. AM received advisory board or consultant fees from the following drug companies: Angelini, Rovi and Boehringer Ingelheim outside the submitted work. MR has received compensation as speaker/consultant from Angelini, Lundbeck, Otzuka, Sumitomo Pharma, and Sunovion, and he has received research grants from Sumitomo Pharma. PR has received honoraria as consultant for lectures from Angelini, Janssen, Lundbeck, and Otsuka. Furthermore, she is in the advisory board of Angelini. AV received advisory board, lecture, or consulting fees, outside the present work, from: Angelini, Innova Pharma-Recordati, Janssen Pharmaceuticals, Lundbeck, Otsuka, and Pfizer. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Vita, Barlati, Cavallaro, Mucci, Riva, Rocca, Rossi and Galderisi.)

Transcriptomic profiles are important indicators for molecular mechanisms and pathways involved in major depressive disorder (MDD) and its different phenotypes, such as immunometabolic depression. We performed whole-transcriptome and pathway analyses on 139 individuals from the observational, case-control, BIOmarkers in DEPression (BIODEP) study, 105 with MDD and 34 controls. We divided MDD participants based on levels of inflammation, as measured by serum high-sensitivity C-reactive protein (CRP), in n = 39 'not inflamed' (CRP < 1 mg/L), n = 31 with 'elevated CRP' (1-3 mg/L), and n = 35 with 'low-grade inflammation' (>3 mg/L). We performed whole-blood RNA sequencing using Illumina NextSeq 550 and statistical analyses with the Deseq2 package for R statistics (RUV-corrected) and subsequent pathway analyses with Ingenuity Pathway Analysis. Immunometabolic pathways were activated in individuals with CRP > 1 mg/L, although surprisingly the CRP 1-3 group showed stronger immune activation than the CRP > 3 group. The main pathways identified in the comparison between CRP < 1 group and controls were cell-cycle-related, which may be protective against immunometabolic abnormalities in this 'non-inflamed' depressed group. We further divided MDD participants based on exposure and response to antidepressants (n = 47 non-responders, n = 37 responders, and n = 22 unmedicated), and identified specific immunomodulatory and neuroprotective pathways in responders (especially vs. non-responders), which could be relevant to treatment response. In further subgroup analyses, we found that the specific transcriptional profile of responders is independent of CRP levels, and that the inhibition of cell-cycle-related pathways in MDD with CRP < 1 mg/L is present only in those who are currently depressed, and not in the responders. The present study demonstrates immunometabolic and cell-cycle-related transcriptomic pathways associated with MDD and different (CRP-based and treatment-based) MDD phenotypes, while shedding light on potential molecular mechanisms that could prevent or facilitate an individual's trajectory toward immunometabolic depression and/or treatment-non-responsive depression. The recognition and integration of these mechanisms will facilitate a precision-medicine approach in MDD., (© 2024. The Author(s).)

Exposure to adversities during early life stages (early life adversities - ELA), ranging from pregnancy to adolescence, represents a major risk factor for the vulnerability to mental disorders. Hence, it is important to understand the molecular and functional underpinning of such relationship, in order to develop strategies aimed at reducing the psychopathologic burden associated with ELA, which may eventually lead to a significant improvement in clinical practice. In this review, we will initially recapitulate clinical and preclinical evidence supporting the link between ELA and psychopathology and we will primarily discuss the main biological mechanisms that have been described as potential mediators of the effects of ELA on the psychopathologic risk, including the role for genetic factors as well as sex differences. The knowledge emerging from these studies may be instrumental for the development of novel therapeutic strategies aimed not only at correcting the deficits that emerge from ELA exposure, but also in preventing the manifestation of a full-blown psychopathologic condition. With this respect, we will specifically focus on adolescence as a key time frame for disease onset as well as for early therapeutic intervention. We believe that incorporating clinical and preclinical research data in the context of early life adversities can be instrumental to elucidate the mechanisms contributing to the risk for psychopathology or that may promote resilience. This will ultimately allow the identification of 'at risk' individuals who may benefit from specific forms of interventions that, by interfering with disease trajectories, could result in more benign clinical outcomes., Competing Interests: Declaration of competing interest M.A.R. has received compensation as speaker/consultant from Angelini, Lundbeck, Otzuka, Sumitomo Pharma, and Sunovion, and he has received research grants from Sumitomo Pharma. A.C. received compensation as a speaker from Sumitomo Pharma. All the other authors declare that there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Pietro Invernizzi consults for, advises and recieved grants from Calliditas, Ipsen, and Zydus. He consults for and advises Advanz. The remaining authors have no conflicts to report.

The biological mechanisms underlying the onset of major depressive disorder (MDD) have predominantly been studied in adult populations from high-income countries, despite the onset of depression typically occurring in adolescence and the majority of the world's adolescents living in low- and middle-income countries (LMIC). Taking advantage of a unique adolescent sample in an LMIC (Brazil), this study aimed to identify biological pathways characterizing the presence and increased risk of depression in adolescence, and sex-specific differences in such biological signatures. We collected blood samples from a risk-stratified cohort of 150 Brazilian adolescents (aged 14-16 years old) comprising 50 adolescents with MDD, 50 adolescents at high risk of developing MDD but without current MDD, and 50 adolescents at low risk of developing MDD and without MDD (25 females and 25 males in each group). We conducted RNA-Seq and pathway analysis on whole blood. Inflammatory-related biological pathways, such as role of hypercytokinemia/hyperchemokinemia in the pathogenesis of influenza (z-score = 3.464, p < 0.001), interferon signaling (z-score = 2.464, p < 0.001), interferon alpha/beta signaling (z-score = 3.873, p < 0.001), and complement signaling (z-score = 2, p = 0.002) were upregulated in adolescents with MDD compared with adolescents without MDD independently from their level of risk. The up-regulation of such inflammation-related pathways was observed in females but not in males. Inflammatory-related pathways involved in the production of cytokines and in interferon and complement signaling were identified as key indicators of adolescent depression, and this effect was present only in females., (© 2024. The Author(s).)

Background: The General Health Questionnaire-12 (GHQ-12) is a widely used screening tool for mental health assessment however its traditional scoring methods and cutoffs may not adequately capture the mental health complexities of younger populations., Methods: This study explores GHQ-12 responses from a sample of university students. Possible differences in means scores considering gender, age, academic field and degree course were assessed through t-test or one-way ANOVA as appropriate. To deeper understanding different levels of severity and individual item impact on general distress measurement, we applied Item-Response-Theory (IRT) techniques (two-parameters logistic model). We compared students' population with a population of workers who underwent a similar psychological evaluation., Results: A total of 3834 university students participated in the study. Results showed that a significant proportion (79%) of students reported psychological distress. Females and younger students obtained significantly higher average scores compared to others. IRT analysis found item-specific variations in mental distress levels, with more indicative items for short-term fluctuations and potential severe mental health concerns. Latent class analysis identified three distinct subgroups among students (including 20%, 37%, 43% of the participants respectively) with different levels of psychological distress severity. Comparison with a population of adults showed that students reported significantly higher scores with differences in the scale behavior., Conclusion: Our results highlighted the unique mental health challenges faced by students, suggesting a reevaluation of GHQ-12 applicability and cutoff scores for younger populations, emphasizing the need for accurate instruments in mental health evaluation., (© 2024. The Author(s).)

The transition to higher education at University is a critical moment for young adults to acquire unhealthy habits regarding physical activity (PA) and adherence to a healthy diet. Negative behaviors might be maintained in the years to come with a major risk of suffering from a Non-Communicable Disease. This study aims to determine the relationship between diet and PA in the student community of University of Milano-Bicocca. Students between 18 and 30 years old completed an online survey (6949 students). Two analyses of covariance (ANCOVA), chi-square tests of independence, and a binomial logistic regression were performed to examine the relationship between adequacy of food consumption and PA, in association also with sociodemographic characteristics. Data show a strong correlation between behaviors analyzed, with a proportional positive association between PA and healthy diet. Nevertheless, a third of the sample students incur in incorrect habits for both diet and PA. Further, students performing intensive PA have the healthiest food consumption in general but the worst red meat and pork intake. Accordingly, men practice more PA but have a less adequate diet, exactly contrary to women. In conclusion, policies promoting consciousness of well-being would transform Universities into healthy hubs for virtuous habits.

Exposure to early-life stress (ELS) has been related to an increased susceptibility to psychiatric disorders later in life. Although the molecular mechanisms underlying this association are still under investigation, glucocorticoid signaling has been proposed to be a key mediator. Here, we used two preclinical models, the prenatal stress (PNS) animal model and an in vitro model of hippocampal progenitor cells, to assess the long-term effect of ELS on FKBP5 , NR3C1 , NR3C2 , and FoxO1 , four stress-responsive genes involved in the effects of glucocorticoids. In the hippocampus of male PNS rats sacrificed at different time points during neurodevelopment (PND 21, 40, 62), we found a statistically significant up-regulation of FKBP5 at PND 40 and PND 62 and a significant increase in FoxO1 at PND 62. Interestingly, all four genes were significantly up-regulated in differentiated cells treated with cortisol during cell proliferation. As FKBP5 was consistently modulated by PNS at adolescence (PND 40) and adulthood (PND 62) and by cortisol treatment after cell differentiation, we measured a panel of miRNAs targeting FKBP5 in the same samples where FKBP5 expression levels were available. Interestingly, both miR-20b-5p and miR-29c-3p were significantly reduced in PNS-exposed animals (both at PND40 and 62) and also in the in vitro model after cortisol exposure. Our results highlight the key role of miR-20b-5p and miR-29c-3p in sustaining the long-term effects of ELS on the stress response system, representing a mechanistic link possibly contributing to the enhanced stress-related vulnerability to mental disorders.

Competing Interests: Declaration of Competing Interest M.A.R. has received grants and served as consultant or CME speaker unrelated to this work for the following entities: Angelini, Exeltis, Lundbeck, Otzuka and Sumitomo Pharma. A.C. has served as CME speaker for Sumitomo Pharma.

Exposure to stressful experiences accounts for almost half of the risk for mental disorders. Hence, stress-induced alterations represent a key target for pharmacological interventions aimed at restoring brain function in affected individuals. We have previously demonstrated that lurasidone, a multi-receptor antipsychotic drug approved for the treatment of schizophrenia and bipolar depression, can normalize the functional and molecular impairments induced by stress exposure, representing a valuable tool for the treatment of stress-induced mental illnesses. However, the mechanisms that may contribute to the therapeutic effects of lurasidone are still poorly understood. Here, we performed a transcriptomic analysis on the prefrontal cortex (PFC) of adult male rats exposed to the chronic mild stress (CMS) paradigm and we investigated the impact of chronic lurasidone treatment on such changes. We found that CMS exposure leads to an anhedonic phenotype associated with a down-regulation of different pathways associated to neuronal guidance and synaptic plasticity within the PFC. Interestingly, a significant part of these alterations (around 25%) were counteracted by lurasidone treatment. In summary, we provided new insights on the transcriptional changes relevant for the therapeutic intervention with lurasidone, which may ultimately promote resilience., Competing Interests: Declaration of Competing Interest M.A.R. has received compensation as speaker/consultant from Angelini, Exeltis, Iqvia, Lundbeck, Otzuka, and Sumitomo Pharma, and he has received research grants from Sumitomo Pharma. All other authors declare that they have no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present for the first time a preclinical exploration of the effects of the promising natural atypical antipsychotic Methyl-2-Amino-3- Methoxybenzoate (MAM), a brain-penetrable protoalkaloid from the seed of the plant Nigella damascena. Using animal models related to hyperdopaminergic activity, namely the pharmacogenetic apomorphine (D2/D1 receptor agonist)-susceptible (APO-SUS) rat model and pharmacologically induced mouse and rat models of schizophrenia, we found that MAM reduced gnawing stereotypy and climbing behaviours induced by dopaminergic agents. This predicts antipsychotic activity. In line, MAM antagonized apomorphine-induced c-Fos and NPAS4 mRNA levels in post-mortem brain nucleus accumbens and dorsolateral striatum of APO-SUS rats. Furthermore, phencyclidine (PCP, an NMDA receptor antagonist) and 2,5-Dimethoxy-4-iodoamphetamine (DOI, a 5HT2A/2C receptor agonist) induced prepulse inhibition deficits, reflecting the positive symptoms of schizophrenia, which were rescued by treatment with MAM and atypical antipsychotics alike. Post-mortem brain immunostaining revealed that MAM blocked the strong activation of both PCP- and DOI-induced c-Fos immunoreactivity in a number of cortical areas. Finally, during a 28-day subchronic treatment regime, MAM did not induce weight gain, hyperglycemia, hyperlipidemia or hepato- and nephrotoxic effects, side effects known to be induced by atypical antipsychotics. MAM also did not show any cataleptic effects. In conclusion, its brain penetrability, the apparent absence of preclinical side effects, and its ability to antagonize positive and cognitive symptoms associated with schizophrenia make MAM an exciting new antipsychotic drug that deserves clinical testing., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: Noise-induced hearing loss is the most prevalent occupational disease worldwide and is historically associated with the Industrial Revolution. This study analyses early descriptions of this disorder during the pre-industrial period in the work of the Italian physician Bernardino Ramazzini (1633-1714)., Method: Primary and secondary historical literature were reviewed., Results: Ramazzini described hearing loss in corn millers and in coppersmiths and recognised that this disorder is irreversible and progressive when exposure to noise continues. He also seemed to describe tinnitus. He further suggested the use of earplugs as a preventive measure for these classes of workers. Ramazzini's anatomical and pathological knowledge appears to be based on ancient authors; he did not discuss contemporaneous medical authors' work on hearing function., Conclusion: Despite some limitations, Ramazzini's work appears pioneering for his time and represents an important milestone in the history of otolaryngology.

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).)

Exposure to stress can lead to long lasting behavioral and neurobiological consequences, which may enhance the susceptibility for the onset of mental disorders. However, there are significant individual differences in the outcome of stress exposure since only a percentage of exposed individuals may show pathological consequences, whereas others appear to be resilient. In this study, we aimed to characterize the effects of prenatal stress (PNS) exposure in rats at adolescence and to identify subgroup of animals with a differential response to the gestational manipulation. PNS adolescent offspring (regardless of sex) showed impaired emotionality in different pathological domains, such as anhedonia, anxiety, and sociability. However, using cluster analysis of the behavioral data we could identify 70% of PNS-exposed animals as vulnerable (PNS-vul), whereas the remaining 30% were considered resilient (PNS-res). At the molecular level, we found that PNS-res males show a reduced basal activation of the ventral hippocampus whereas other regions, such as amygdala and dorsal hippocampus, show significant PNS-induced changes regardless from vulnerability or resilience. Taken together, our results provide evidence of the variability in the behavioral and neurobiological effects of PNS-exposed offspring at adolescence. While these data may advance our understanding of the association between exposure to stress during gestation and the risk for psychopathology, the investigation of the mechanisms associated to stress vulnerability or resilience may be instrumental to develop novel strategies for therapeutic intervention., (© 2023. The Author(s).)

Femoroacetabular impingement (FAI) is a common source of hip pain affecting a wide range of subjects. In this work, we assessed two tests, namely the balance test and the MuscleLab test, in comparison with the flexion-abduction-external rotation (FABER) and flexion-adduction-internal rotation (FADIR) tests, in order to evaluate the functionality of the neural-musculoskeletal system of the subjects affected by FAI based on the measurement of biomechanical parameters. Our goal was to investigate the early detection of an altered hip joint and to monitor pathology progression over time. A total of 52 subjects, 29 females and 23 males, with an average age of 42 ± 13 years presenting hip impingement diagnosed using X-ray, were enrolled. Twenty-eight patients without signs of hip impingements were used as the control group. The balance test, which evaluates the capacity of a person to keep the orthostatic position against terrestrial gravity, and the MuscleLab test, which measures the force and power generated by active muscles during a movement, as well as FABER and FADIR tests, were performed in each subject. The balance and MuscleLab tests presented 100% sensitivity and higher sensitivity in FAI diagnosis, with 72.9% and 70.4%, respectively, in comparison with those obtained using FABER and FADIR tests, with 59.6% and 67.3%, respectively. The evaluation of the neural-musculoskeletal system using the balance and MuscleLab tests can help in the early detection of the severity of hip impingements and the assessment of non-operative treatments used over time.

Background: Antonio Scarpa (1752-1832) is generally remembered for his discoveries in the field of anatomy, but he also provided some important contributions to the history of surgery., Methods: We analyzed main treatises written by Scarpa, highlighting how he contributed to the development of modern surgery., Results: Scarpa made great innovations in three branches of surgery: abdominal surgery (hernia), orthopedics (clubfoot) and vascular surgery (aneurism). Furthermore, he contributed to the birth of modern ophthalmology.

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with reduced activity-dependent BDNF release in the brain and has been implicated in fear and anxiety disorders, including post-traumatic stress disorder. Exercise has been shown to have benefits in affective disorders but the role of BDNF Val66Met remains unclear. Male and female BDNF Val66Met rats were housed in automated running-wheel cages from weaning while controls were housed in standard cages. During adulthood, all rats underwent standard three-day fear conditioning testing, with three tone/shock pairings on day 1 (acquisition), and extinction learning and memory (40 tones/session) on day 2 and day 3. Expression of BDNF and stress-related genes were measured in the frontal cortex. Extinction testing on day 2 revealed significantly lower freezing in response to initial cue exposure in control Met/Met rats, reflecting impaired fear memory. This deficit was reversed in both male and female Met/Met rats exposed to exercise. There were no genotype effects on acquisition or extinction of fear, however chronic exercise increased freezing in all groups at every stage of testing. Exercise furthermore led to increased expression of Bdnf in the prefrontal cortex of females and its isoforms in both sexes, as well as increased expression of FK506 binding protein 51 (Fkpb5) in females and decreased expression of Serum/glucocorticoid-regulated kinase (Sgk1) in males independent of genotype. These results show that the Met/Met genotype of the Val66Met polymorphism affects fear memory, and that chronic exercise selectively reverses this genotype effect. Chronic exercise also led to an overall increase in freezing in all genotypes which may contribute to results., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The environmental disturbances in a critical neurodevelopmental period exert organizational effects on brain intrinsic plasticity including excitatory and inhibitory (E/I) neurotransmission those can cause the onset of psychiatric illness. We previously reported that treatment of neural precursor cells with N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 induced reduction of GABAergic interneuron differentiation, and these changes recovered by atypical antipsychotic blonanserin treatment in vitro. However, it remains unclear how this treatment affects neural circuit changes in hippocampus and amygdala, which might contribute to the prevention of onset process of schizophrenia. To elucidate the pathogenic/preventive mechanisms underlying prenatal environmental adversity-induced schizophrenia in more detail, we administered poly (I:C) followed by antipsychotics and examined alterations in social/cognitive behaviors, GABA/glutamate-related gene expressions with cell density and E/I ratio, and brain-derived neurotrophic factor (Bdnf) transcript levels, particularly in limbic areas. Treatment with antipsychotic blonanserin ameliorated impaired social/cognitive behaviors and increased parvalbumin (PV)-positive (+) cell density and its mRNA levels as well as Bdnf with long 3'UTR mRNA levels, particularly in the dorsal hippocampus, in rats exposed to maternal immune activation (MIA). Low dose of blonanserin and haloperidol altered GABA and glutamate-related mRNA levels, the E/I ratio, and Bdnf long 3'UTR mRNA levels in the ventral hippocampus and amygdala, but did not attenuate behavioral impairments. These results strongly implicate changes in PV expression, PV(+) GABAergic interneuron density, and Bdnf long 3'UTR expression levels, particularly in the dorsal hippocampus, in the pathophysiology and treatment responses of MIA-induced schizophrenia and highlight the therapeutic potential of blonanserin for developmental stress-related schizophrenia., Competing Interests: Declaration of competing interest None, (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Exposure to stress during early development may lead to altered neurobiological functions, thus increasing the risk for psychiatric illnesses later in life. One potential mechanism associated with those outcomes is the disruption of glial density and morphology, despite results from rodent studies have been conflicting. To address that we performed a systematic review and meta-analysis of rodent studies that investigated the effects of prenatal stress (PNS) and early life stress (ELS) on microglia, astrocyte, and oligodendrocyte density and morphology within the offspring. Our meta-analysis demonstrates that animals exposed to PNS or ELS showed significant increase in microglia density, as well as decreased oligodendrocyte density. Moreover, ELS exposure induced an increase in microglia soma size. However, we were unable to identify significant effects on astrocytes. Meta-regression indicated that experimental stress protocol, sex, age, and type of tissue analyzed are important covariates that impact those results. Importantly, PNS microglia showed higher estimates in young animals, while the ELS effects were stronger in adult animals. This set of data reinforces that alterations in glial cells could play a role in stress-induced dysfunctions throughout development., Competing Interests: Conflict of interest M.A.R. has received compensation as speaker/consultant from Angelini, Lundbeck, Otzuka and Sumitomo Pharma, and he has received research grants from Sumitomo Pharma. All the other authors declare no financial interests or potential conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The first half of the seventeenth century may be seen as the turning point of knowledge of human anatomy and physiology, as also demonstrated by the works by William Harvey (1578-1657) on the circulation of the blood. This article aims to present biographic context of the surgeon Gaspare Aselli (1581-1625) and his rather fortuitous discovery of the lacteals in Milan in 1622, that contributed to the comprehension of the lymphatic system. The experimentation on living animals ( anatomia animata , living anatomy), and particularly the vivisection used by Gaspare Aselli provided the basis for much of the subsequent investigation of the human physiology. In particular, the discovery of lymphatics challenged the basis of the Galenic doctrine, denying the liver the central role it had formerly been granted in transforming food into blood and revolutionized the ancient hepatocentrism in favor of the modern concept of cardiocentrism.

Objectives: During the first wave of the COVID-19 pandemic, the Region of Lombardy in Italy and its Regional Emergency Service (Azienda Regionale Emergenza Urgenza [AREU]) created a dedicated 24/7 free phone service to help the Lombard population. After an invitation from their professional order, local midwives collaborated on the AREU project as volunteers to address the needs of women from antenatal to postnatal periods. The aim of this article was to explore the experiences of midwives who volunteered in the AREU project., Study Design: This was a qualitative study using an interpretative phenomenological approach (IPA)., Methods: The experiences of midwives volunteering in AREU (N = 59) were explored using audio diaries. Written diaries were also offered as an alternative. Data collection took place between March and April 2020. Midwives were provided with semistructured guidance that indicated the main areas of interest of the study. The diaries were thematically analysed following a temporal criterion; a final conceptual framework was created from emerging themes and subthemes., Results: The following five themes were identified: (1) choosing to join the volunteer project, (2) the day-to-day difficulties, (3) strategies to cope with the unexpected, (4) professional relationships and (5) reflecting on the personal experience., Conclusions: This is the first study to investigate the experiences of Italian midwives who volunteered in a public health project during a pandemic/epidemic. According to participants, taking part in the volunteer activities was informed by and impacted on both their professional and personal lives. Overall, the experiences of midwives who volunteered in AREU were positive and of humanitarian value. Providing midwifery services within a multidisciplinary team for the benefit of public health represented both a challenge and personal/professional enrichment., (Copyright © 2023 The Royal Society for Public Health. All rights reserved.)

Rationale: Stress represents a major contributor to the development of mental illness. Accordingly, exposure of adult rats to chronic stress represents a valuable tool to investigate the ability of a pharmacological intervention to counteract the adverse effects produced by stress exposure., Objectives: The aim of this study was to perform a time course analysis of the treatment with the antipsychotic drug lurasidone in normalizing the anhedonic phenotype in the chronic mild stress (CMS) model in order to identify early mechanisms that may contribute to its therapeutic activity., Methods: Male Wistar rats were exposed to CMS or left undisturbed for 7 weeks. After two weeks of stress, both controls and CMS rats were randomly divided into two subgroups that received vehicle or lurasidone for five weeks. Weekly measures of sucrose intake were recorded to evaluate anhedonic behavior, and animals were sacrificed at different weeks of treatment for molecular analyses., Results: We found that CMS-induced anhedonia was progressively improved by lurasidone treatment. Interestingly, after two weeks of lurasidone treatment, 50% of the animals showed a full recovery of the phenotype, which was associated with increased activation of the prefrontal and recruitment of parvalbumin-positive cells that may lead to a restoration of excitatory/inhibitory balance., Conclusion: These results suggest that the capacity of lurasidone to normalize anhedonia at an early stage of treatment may depend on its ability to modulate the function of the prefrontal cortex., (© 2023. The Author(s).)

Background: Media communication during the covid-19 pandemic has been relevant for the population to receive information about the ongoing number of cases, deaths, and social restriction measures. Notably, the effects of the communication methods on young adults during the covid-19 pandemic have not been studied. Therefore the present study aimed to investigate the influence of communication modality about covid-19 on the perception of risk and judgment among young adults., Methods: A double-blind cross-sectional study was designed. Three hundred four subjects (age range19-25 years old) saw a 4-minute video concerning data communication on the covid-19 pandemic and compiled an online questionnaire about their perceptions. Two videos were randomized, one presenting the covid-19 data negatively (HARD video) while the other showed a positive ongoing resolution of the pandemic (SOFT video). Association tests and nominal logistic regression were used to evaluate differences in responses among the two groups., Results: The two videos lead to different reactions. Participants showed higher disagreement concerning the video content in the "SOFT" group compared to the "HARD" group. The responses of the "SOFT" group were more to be optimistic (OR=2.87, 95% CI 1.311-6.27) than those who had seen the "HARD" video. The sense of helplessness was lower in the "SOFT" compared "HARD" group (OR=3.02, 95% CI 1.311-6.96). The perception of fear was higher for the "HARD" group (OR=2.91, 95% CI 1.21-7-02)., Discussion: The modality of data presentation influenced the perception and feelings about the covid-19 pandemic. Likely, pre-existing perception of a pessimistic perspective was present in both groups; thus, the video did not lead to any change in the behavior., Conclusions: The phobic or counter-phobic reactions shown in the study participants highlighted the importance of the reliability of the information received and how previous feelings may influence the perception of the information.

Exercise has been shown to be beneficial in reducing symptoms of affective disorders and to increase the expression of brain-derived neurotrophic factor (BDNF). The BDNF Val66Met polymorphism is associated with reduced activity-dependent BDNF release and increased risk for anxiety and depression. Male and female Val66Met rats were given access to running wheels from 3 weeks of age and compared to sedentary controls. Anxiety- and depression-like behaviors were measured in adulthood using the elevated plus maze (EPM), open field (OF), and forced swim test (FST). Expression of BDNF and a number of stress-related genes, the glucocorticoid receptor (Nr3c1), serum/glucocorticoid-regulated kinase 1 (Sgk1), and FK506 binding protein 51 (Fkbp5) in the hippocampus were also measured. Rats given access to running wheels developed high levels of voluntary exercise, decreased open-arm time on the EPM and center-field time in the OF, reduced overall exploratory activity in the open field, and increased immobility time in the FST with no differences between genotypes. Chronic exercise induced a significant increase in Bdnf mRNA and BDNF protein levels in the hippocampus with some of these effects being genotype specific. Exercise decreased the expression of Nr3c1 and Sgk1, but increased the expression of Fkbp5. These results suggest that chronic running-wheel exercise from adolescence increased anxiety and depression-like phenotypes in adulthood, independent of BDNF Val66Met genotype. Further studies are required to confirm that increased indices of anxiety-like behavior are independent from reduced overall locomotor activity., (© 2022 The Authors. Developmental Psychobiology published by Wiley Periodicals LLC.)

Promoting healthy behaviors throughout life is an essential prevention tool. Prior research showed that unhealthy behaviors tend to co-occur and interplay. However, which behaviors co-occur most frequently and which sociodemographic variables are associated with specific clusters of unhealthy behavior are still being determined. This study aimed to identify different lifestyle profiles and analyze their associations with sociodemographic factors in an Italian academic community to plan targeted initiatives to promote healthy lifestyles. A sample of 8715 adults from an Italian university (mean age = 26 years; range = 18-76; 30% male) participated in an online survey in 2019. Four health-related behaviors were evaluated: diet, physical activity, smoking, and alcohol consumption. Lifestyle profiles were identified through cluster analysis. Then, a multinomial logistic regression was performed to explore the association among lifestyle profiles, sociodemographic variables (age, gender, and academic role), and body mass index (BMI). Results showed that older age was associated with the probability of belonging to the profile characterized by smoke addiction and regular alcohol consumption but also with the healthiest diet. The younger the age, the greater the probability of belonging to the most physically active profile. Men were more likely than women to belong to the lifestyle profile with the most regular alcohol consumption and the highest physical activity. Lower BMI was associated with the most physically active profile. This study shed light on factors associated with different co-occurring health-related behaviors that should be considered in planning effective communication strategies and preventive health interventions within the academic community.

Stressful experiences early in life, especially in the prenatal period, can increase the risk to develop depression during adolescence. However, there may be important qualitative and quantitative differences in outcome of prenatal stress (PNS), where some individuals exposed to PNS are vulnerable and develop a depressive-like phenotype, while others appear to be resilient. PNS exposure, a well-established rat model of early life stress, is known to increase vulnerability to depression and a recent study demonstrated a strong interaction between transforming growth factor-β1 (TGF-β1) gene and PNS in the pathogenesis of depression. Moreover, it is well-known that the exposure to early life stress experiences induces brain oxidative damage by increasing nitric oxide levels and decreasing antioxidant factors. In the present work, we examined the role of TGF-β1 pathway in an animal model of adolescent depression induced by PNS obtained by exposing pregnant females to a stressful condition during the last week of gestation. We performed behavioral tests to identify vulnerable or resilient subjects in the obtained litters (postnatal day, PND > 35) and we carried out molecular analyses on hippocampus, a brain area with a key role in the pathogenesis of depression. We found that female, but not male, PNS adolescent rats exhibited a depressive-like behavior in forced swim test (FST), whereas both male and female PNS rats showed a deficit of recognition memory as assessed by novel object recognition test (NOR). Interestingly, we found an increased expression of type 2 TGF-β1 receptor (TGFβ-R2) in the hippocampus of both male and female resilient PNS rats, with higher plasma TGF-β1 levels in male, but not in female, PNS rats. Furthermore, PNS induced the activation of oxidative stress pathways by increasing inducible nitric oxide synthase (iNOS), NADPH oxidase 1 (NOX1) and NOX2 levels in the hippocampus of both male and female PNS adolescent rats. Our data suggest that high levels of TGF-β1 and its receptor TGFβ-R2 can significantly increase the resiliency of adolescent rats to PNS, suggesting that TGF-β1 pathway might represent a novel pharmacological target to prevent adolescent depression in rats., Competing Interests: The 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., (Copyright © 2022 Fidilio, Grasso, Caruso, Musso, Begni, Privitera, Torrisi, Campolongo, Schiavone, Tascedda, Leggio, Drago, Riva and Caraci.)

This article explores the relationship between the Catholic Church and animal magnetism. At the beginning of the nineteenth century, the Catholic Church had first tried to stem the rise of animal magnetism in a vague manner, but after a few decades, it eventually put a genuine veto in place. This measure was founded upon the dangers to morality and faith arising from the progressive polarization of the original doctrine in forms related to esotericism. Among the causes of the condemnation by the Congregation of the Holy Office, the primary ones were the naturalist interpretation of the miracles described in the Gospels and in the New Testament, and the possibility of falling under the control of a demonic spirit.

Rapastinel, formerly Glyx-13, is a novel positive allosteric modulator of the N-methyl-D-aspartate-receptor (NMDAR) that counteracts psychotomimetic actions of NMDAR antagonists. We set out to evaluate the effect of rapastinel alone or in combination with the global and GluN2B subunit-specific NMDAR antagonists MK-801 and Ro25-6981, respectively, on neuronal activation in relevant regions using c-fos brain mapping. Whereas rapastinel alone did not trigger significant c-fos expression beyond the prelimbic cortex, it strongly increased the c-fos expression induced by MK-801 in hippocampal, cingulate, and retrosplenial areas. Similar results were obtained when rapastinel was replaced by D-cycloserine. Our results reveal new interactions at network level between NMDAR modulators with possible implications regarding their therapeutic effects., (© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.)

Background: Over the past few years, studies have increasingly focused on the development of mobile apps as complementary tools to existing traditional pharmacovigilance surveillance systems for improving and facilitating adverse drug reaction (ADR) reporting., Objective: In this research, we evaluated the potentiality of a new mobile app (vaxEffect@UniMiB) to perform longitudinal studies, while preserving the anonymity of the respondents. We applied the app to monitor the ADRs during the COVID-19 vaccination campaign in a sample of the Italian population., Methods: We administered vaxEffect@UniMiB to a convenience sample of academic subjects vaccinated at the Milano-Bicocca University hub for COVID-19 during the Italian national vaccination campaign. vaxEffect@UniMiB was developed for both Android and iOS devices. The mobile app asks users to send their medical history and, upon every vaccine administration, their vaccination data and the ADRs that occurred within 7 days postvaccination, making it possible to follow the ADR dynamics for each respondent. The app sends data over the web to an application server. The server, along with receiving all user data, saves the data in a SQL database server and reminds patients to submit vaccine and ADR data by push notifications sent to the mobile app through Firebase Cloud Messaging (FCM). On initial startup of the app, a unique user identifier (UUID) was generated for each respondent, so its anonymity was completely ensured, while enabling longitudinal studies., Results: A total of 3712 people were vaccinated during the first vaccination wave. A total of 2733 (73.6%) respondents between the ages of 19 and 80 years, coming from the University of Milano-Bicocca (UniMiB) and the Politecnico of Milan (PoliMi), participated in the survey. Overall, we collected information about vaccination and ADRs to the first vaccine dose for 2226 subjects (60.0% of the first dose vaccinated), to the second dose for 1610 subjects (43.4% of the second dose vaccinated), and, in a nonsponsored fashion, to the third dose for 169 individuals (4.6%)., Conclusions: vaxEffect@UniMiB was revealed to be the first attempt in performing longitudinal studies to monitor the same subject over time in terms of the reported ADRs after each vaccine administration, while guaranteeing complete anonymity of the subject. A series of aspects contributed to the positive involvement from people in using this app to report their ADRs to vaccination: ease of use, availability from multiple platforms, anonymity of all survey participants and protection of the submitted data, and the health care workers' support., (©Marzia Di Filippo, Alessandro Avellone, Michael Belingheri, Maria Emilia Paladino, Michele Augusto Riva, Antonella Zambon, Dario Pescini. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 04.11.2022.)

Competing Interests: The authors declared no conflicts of interest.

Neuroinflammation has emerged as an important factor in the molecular underpinnings of major depressive disorder (MDD) pathophysiology and in the mechanism of action of antidepressants. Among the inflammatory mediators dysregulated in depressed patients, interleukin (IL)-6 has recently been proposed to play a crucial role. IL-6 activates a signaling pathway comprising the JAK/STAT proteins and characterized by a specific negative feedback loop exerted by the cytoplasmic protein suppressor of cytokine signalling-3 (SOCS3). On these bases, here, we explored the potential involvement of IL-6 signaling in the ability of the antidepressant drug agomelatine to normalize the anhedonic-like phenotype induced in the rat by chronic stress exposure. To this aim, adult male Wistar rats were subjected to the chronic mild stress (CMS) paradigm and chronically treated with vehicle or agomelatine. The behavioral evaluation was assessed by the sucrose consumption test, whereas molecular analyses were performed in the prefrontal cortex. We found that CMS was able to stimulate IL-6 production and signaling, including SOCS3 gene and protein expression, but the SOCS3-mediated feedback-loop inhibition failed to suppress the IL-6 cascade in stressed animals. Conversely, agomelatine treatment normalized the stress-induced decrease in sucrose consumption and restored the negative modulation of the IL-6 signaling via SOCS3 expression and activity. Our results provide additional information about the pleiotropic mechanisms that contribute to agomelatine's therapeutic effects.

Rationale: Although the occurrence of stressful events is very common during life, their impact may be different depending on the experience severity and duration. Specifically, acute challenges may trigger adaptive responses and even improve the individual's performance. However, such a physiological positive coping can only take place if the underlying molecular mechanisms are properly functioning. Indeed, if these systems are compromised by genetic factors or previous adverse conditions, the response set in motion by an acute challenge may be maladaptive and even cause the insurgence or the relapse of stress-related psychiatric disorders., Objectives: On these bases, we evaluated in the rat brain the role of the antioxidant component of the redox machinery on the acute stress responsiveness and its modulation by potential detrimental or beneficial events., Methods: The expression of several antioxidant enzymes was assessed in different brain areas of adult male rats exposed to acute stress 3 weeks after a chronic immobilization paradigm with or without a concomitant treatment with the antipsychotic lurasidone., Results: The acute challenge was able to trigger a marked antioxidant response that, despite the washout period, was impaired by the previous adverse experience and restored by lurasidone in an anatomical-specific manner., Conclusions: We found that a working antioxidant machinery takes part in acute stress response and may be differentially affected by other experiences. Given the essential role of stress responsiveness in almost every life process, the identification of the underlying mechanisms and their potential pharmacological modulation add further translational value to our data., (© 2022. The Author(s).)

Chronic stress represents a major contributor for the development of mental illness. This study aimed to investigate how animals exposed to chronic mild stress (CMS) responded to an acute stress (AS), as a vulnerability's challenge, and to establish the potential effects of the antipsychotic drug lurasidone on such mechanisms. Adult male Wistar rats were exposed or not (controls) to a CMS paradigm for 7 weeks. Starting from the end of week 2, animals were randomized to receive vehicle or lurasidone for 5 weeks. Sucrose intake was used to measure anhedonia. At the end, half of the animals were exposed to an acute stress before sacrifice. Exposure to CMS produced a significant reduction in sucrose consumption, whereas lurasidone progressively normalized such alteration. We found that exposure to AS produced an upregulation of Brain derived neurotrophic factor (Bdnf) in the prefrontal cortex of controls animals. This response was impaired in CMS rats and restored by lurasidone treatment. While in control animals, AS-induced increase of Bdnf mRNA levels was specific for Parvalbumin cells, CMS rats treated with lurasidone show a significant upregulation of Bdnf in pyramidal cells. Furthermore, when investigating the activation of different brain regions, CMS rats showed an impairment in the global response to the acute stressor, that was largely restored by lurasidone treatment. Our results suggest that lurasidone treatment in CMS rats may regulate specific circuits and mechanisms, which will ultimately contribute to boost resilience under stressful challenges., Competing Interests: Conflict of Iterest M.A.R. has received compensation as speaker/consultant from Angelini, Iqvia, Lundbeck, Otzuka, Sumitomo Pharma and Sunovion, and he has received research grants from Sumitomo Pharma and Sunovion. All other authors declare that they have no conflicts of interest., (Copyright © 2022 Elsevier B.V. and ECNP. All rights reserved.)

In preclinical psychiatry research, animals are central to modeling and understanding biological mechanisms of behavior and psychiatric disorders. We here present the first multimodal severity assessment of a genetically modified rat strain used in psychiatric research, lacking the dopamine transporter (DAT) gene and showing endophenotypes of several dopamine-associated disorders. Absence of the DAT leads to high extracellular dopamine (DA) levels and has been associated with locomotor hyperactivity, compulsive behaviors and stereotypies in the past. The German Animal Welfare Law, which is based on the EU Directive (2010/63/EU), requires a prospective severity assessment for every animal experiment, depending on the extent of the expected degree of pain, suffering, distress or lasting harm that the animals will experience. This should consider all procedures but also the impact of the genotype on the phenotype. Therefore, we examined multiple parameters indicating animal welfare, like burrowing behavior, social interaction, saccharin preference, baseline stress hormone levels and nesting behavior. Additionally, a footprint analysis was performed and home cage activity was analyzed for a more detailed characterization of locomotion. DAT KO rats demonstrated reduced burrowing, social interaction and saccharin preference. We also found pronounced stereotypies and alterations in the gait analysis in DAT KO rats. Moreover, we confirmed the hyperactivity and the impaired sensorimotor gating mechanisms to assure that our rats are exhibiting the correct phenotype. In conclusion, we provide evidence that DAT KO rats show alterations in natural behavior patterns and deduce that the marked stereotypies are a sign for coping difficulties, both indicating a negative influence of the genotype on wellbeing. We suggest to assess further rat models in an objectified severity assessment as previously done in mice to create a relative severity assessment based on scientific evidence. Until then, we propose the classification of homozygous DAT KO rats as "moderate" in accordance with the criteria of the EU directive 2010/63., Competing Interests: The 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., (Copyright © 2022 Mallien, Becker, Pfeiffer, Terraneo, Hahn, Middelman, Palme, Creutzberg, Begni, Riva, Leo, Potschka, Fumagalli, Homberg and Gass.)

Background: Exposure to traumatic experience represents one of the key environmental factors influencing the risk for several psychiatric disorders, in particular when suffered during childhood, a critical period for brain development, characterized by a high level of neuroplasticity. Abnormalities affecting neurotrophic factors might play a fundamental role in the link between childhood trauma (CT) and early life stress (ELS) and psychiatric disorders., Methods: A systematic review was conducted, considering genetic, biochemical and expression studies along with cognitive and brain structure imaging investigations, based on PubMed and Web of Science databases (available up until November 2021), to identify potential neuroplasticity related biomarkers associated both with CT/ELS and psychiatric disorders. The search was followed by data abstraction and study quality assessment (Newcastle-Ottawa Scale)., Results: 103 studies met our eligibility criteria. Among them, 65 were available for genetic, 30 for biochemical and 3 for mRNA data; 45 findings were linked to specific symptomatology/pathologies, 16 with various cognitive functions, 19 with different brain areas, 6 on methylation and 36 performed on control subjects for the Brain Derived Neurotrophic Factor (BDNF); whereas 4 expression/biochemical studies covered Neurotrophin 4 (NT-4), Vascular Endothelium Growth Factor (VEGF), Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), and Transforming Growth Factor β1 (TGF-β1)., Limitations: Heterogeneity of assessments (biological, psychological, of symptomatology, and CT/ELS), age range and ethnicity of samples for BDNF studies; limited studies for other neurotrophins., Conclusions: Results support the key role of BDNF (in form of Met allele) as biomarker, both at genetic and biochemical level, in mediating the effect of CT/ELS in psychiatric disorders, passing through specific cognitive functions and specific brain region architecture., (Copyright © 2022. Published by Elsevier B.V.)

The anatomic and medical knowledge of people throughout history is unexpectedly evident in some of the poems and texts written by intellectuals of the time. This article attempts to understand the conception of laryngology in the Middle Ages by analyzing the Divine Comedy , written by the Italian poet Dante Alighieri (1265-1321) at the beginning of the 14th century. In the text, Dante mentions the throat several times. He recognizes that the larynx has the dual functions of allowing respiration (dead souls recognize that the poet is alive through movement of his throat when breathing) and speech (souls with their throat cut cannot speak). However, Dante does not seem to know of the existence of vocal cords, thinking that it is the tongue that allows for word formation. In general, Dante's poem indicates that the anatomy and function of the throat were known during the medieval period, although this knowledge was not precise.

In the partition of the church of San Bernardino in Caravaggio (Lombardy), Fermo Stella (c. 1490-1562) depicted a cycle of frescoes of "The Passion of Christ". In the central panel, "The Crucifixion" one of the tortures of Christ, the sponge-bearer, shows a large goiter and other signs of hypothyroidism (macroglossia, expressionless face, and puffiness around the eyes), confirming that the Renaissance artists often represented sinful and wicked individuals as affected by thyroid diseases., (© 2021. Italian Society of Endocrinology (SIE).)

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.)