The oxytocin system mediates behavioral and neurobiological alterations associated with early adversity Diana Municchi, Camilla Mancini, Sofia Nutarelli, Marta Tiberi, Sebastian Luca D’Addario, Gilda Chilà, Alice Passeri, Greta Massa, Matteo Di Segni, Lucy Babicola, Sonia Canterini, Luisa Lo Iacono, Carlo Cifani, Simona Cabib, Massimiliano Renzi, Valerio Chiurchiù, Maria Teresa Viscomi, Rossella Ventura Molecular Psychiatry, 2026 Early life adversities (ELA) can significantly impact brain development and adult behavior, potentially increasing vulnerability to psychopathologies. Evidence shows that ELA exposure is significantly associated with dysfunctional Oxytocin (OXT), a neuropeptide strongly engaged in social behavior and linked to the processing of rewarding stimuli, such as drugs of abuse. Moreover, it has been recently demonstrated that peripheral OXT may be transported to the brain through several mechanisms, including Receptors for Advanced Glycation End-Products (RAGE), and the RAGE-mediated OXT transport has been shown to play a key critical role in mediating some aspects of social behavior, such as social bonding. However, how OXT system alterations induced by ELA could increase vulnerability to psychopathologies is still under investigation. To investigate this link, we exploit our model of early adversity (Repeated Cross-Fostering, RCF), known to increase the sensitivity to cocaine effects in adult C57BL/6 J (C57) female mice acting on the dopaminergic mesocorticolimbic system. Here, we show that in C57 females, RCF manipulation also impairs social recognition and impacts the OXT system by altering i) OXT levels in the brain and plasma; ii) the expression of RAGE; and iii) the expression of OXT receptor (OxtR). Notably, early restoring brain and plasmatic OXT levels via subcutaneous OXT injection during RCF manipulation counteracts the RCF-induced neurobiological alterations of the OXT system and prevents short and long-lasting behavioral alterations. These findings shed light on the mechanisms by which the oxytocinergic system mediates the long-term effects of early-life adversities on drug addiction vulnerability and social behavior.
The hypothalamus is an early site of mitochondrial failure and neuro-immune circuit disruption in amyotrophic lateral sclerosis Silvia Scaricamazza, Valentina Nesci, Gianmarco Fenili, Marta Tiberi, Anna Percio, Marco Rosina, Illari Salvatori, Flaminia Riggio, Niccolò Candelise, Luisa Pieroni, Viviana Greco, Valerio Chiurchiù, Alberto Ferri, Cristiana Valle Molecular Metabolism, 2026 BACKGROUND: Metabolic dysfunction is a defining feature of amyotrophic lateral sclerosis (ALS), emerging early and strongly associated with disease progression and prognosis. While systemic hypermetabolism is well documented, the central mechanisms underlying energy imbalance remain poorly understood. The hypothalamus, a key regulator of whole-body energy homeostasis, has recently been implicated in ALS, but its mechanistic contribution to metabolic failure and disease progression remains unclear. METHODS: We analyzed the hypothalamus SOD1-G93A mouse model using proteomics (ProteomeXchange ID: PXD070931), mitochondrial bioenergetic assays, immunofluorescence, flow cytometry, and gene expression to assess hypothalamic mitochondrial function, glial activation, and melanocortin system integrity. Limited analyses in the hFUS model confirmed the presence of key hypothalamic alterations, supporting a shared vulnerability across ALS models. In SOD1-G93A mice, the metabolic modulator trimetazidine (TMZ) was administered presymptomatically to evaluate effects on hypothalamic pathology, metabolic regulation, disease onset, and survival. FINDINGS: We provide the first evidence that mitochondrial bioenergetic defects arise specifically in the hypothalamus of ALS models before symptom onset. Proteomic profiling revealed dysregulation of mitochondrial pathways, while functional assays confirmed impaired bioenergetics in the hypothalamus. These deficits were accompanied by local pro-inflammatory activation of astrocytes and microglia, mitochondrial dysfunction in glial cells, and early disruption of the arcuate nucleus melanocortin system. Limited analyses in hFUS mice confirmed selective hypothalamic vulnerability. Early TMZ treatment in SOD1-G93A mice specifically restored hypothalamic bioenergetics, normalized local glial activation and melanocortin signaling, delayed disease onset, and extended survival. INTERPRETATION: These findings establish the hypothalamus as an early and selectively vulnerable site in ALS, where region-specific mitochondrial dysfunction contributes to metabolic and neuroinflammatory alterations. Targeting hypothalamic bioenergetics represents a promising therapeutic strategy.
TTV Viremia and Immune Responses Following Vaccination Against Mpox and Dengue Viruses Claudia Minosse, Pietro Giorgio Spezia, Sara Belladonna, Aurora Bettini, Giulia Matusali, Francesca Colavita, Stefania Notari, Linda Petrone, Marta Tiberi, Alessandro Rosario Cavasio, Valentina Mazzotta, Luigi Rosa, Eleonora Cimini, Daniele Focosi, Delia Goletti, Emanuele Nicastri, Andrea Antinori, Fabrizio Maggi Vaccines, 2026 Background: Torquetenovirus (TTV) viremia is increasingly recognized as a biomarker of host immune competence. We assessed the association between baseline TTV DNA levels and immune responses to the Mpox virus (MPXV) and dengue virus (DGV) vaccines in two prospective cohorts. Methods: A total of 248 individuals were enrolled, and TTV DNA was quantified before vaccination. Humoral and cellular responses to MVA-BN (for MPXV) and QDENGA (for DGV) vaccines were measured by using serology, neutralization assays, and interferon-γ ELISpot, and correlations with TTV viremia were investigated. Results: TTV DNA was detected in 81.2% of individuals, with a significantly higher prevalence and viral loads in the Mpox-Vac group than in the DGV-Vac group. Between both groups, the only significant association observed was an inverse correlation between pre-vaccination TTV load and DGV neutralizing antibody titers in the DGV-Vac group and was limited to the subset of TTV-positive individuals; no additional correlations with antibody and T responses were identified. For the Mpox-Vac group, stratified analyses in people living with HIV (PLWH) confirmed this lack of association. Conclusions: TTV viremia does not predict vaccine immunogenicity in immunocompetent or mildly immunosuppressed individuals. These results, which derive from within-cohort analyses and do not rely on direct comparisons between heterogeneous vaccine populations, support the role of TTV as a marker of immune status along a continuum of immunosuppression, with predictive value likely confined to populations with more severe immune impairment.
The DENGVAC study: Preliminary findings on the immunogenicity of the TAK-003 dengue vaccine Alessandra D’Abramo, Francesca Colavita, Laura Ponzetta, Patrizia De Marco, Serena Vita, Luigi Rosa, Silvia Cammisa, Eleonora Tartaglia, Laura Scorzolini, Eleonora Lalle, Eleonora Cimini, Stefania Notari, Marta Tiberi, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Linda Petrone, Fabrizio Maggi, Delia Goletti, Emanuele Nicastri Journal of Infection, 2026 OBJECTIVES: This study was designed to assess the safety and immunogenicity of the first dose of the TAK-003 dengue vaccine. The immune response profiles of vaccinated participants were compared among individuals who experienced or did not experience natural dengue infection in the past or as an acute infection. METHODS: In this single-centre prospective observational study, subjects were stratified into three groups: Group1-dengue seronegative; Group2-dengue seropositive; Group3-acute dengue infection. The assessments of vaccine-induced immunogenicity included: DENV-2 neutralizing antibodies, monocyte and dendritic cell (DC) phenotyping and T-cell response at baseline (T0) and 3 months (T3) post-vaccination (Group1 and 2) or post-infection (Group3). RESULTS: One hundred fifty subjects were enrolled at T0, and among them 80 subjects (median age 38 years, 50% male) were also evaluated at T3. Anti-DENV-2 neutralizing antibodies increased 26.9- and 9.19-fold in Group1 and 2, and 3.06-fold in Group3. Group1 showed increased monocytes and Group3 had reduced myeloid-DC and higher plasmacytoid-DC. Group1 and 2 exhibited DENV CD4 MP-induced T-cell responses similar to those observed in Group3. Notably, Group1 demonstrated a significantly greater T-cell response to the DENV CD8 MP than Group3. CONCLUSIONS: Preliminary data showed that TAK-003 vaccine is safe and immunogenic. The first vaccine dose elicits a functional antibody and a robust T-cell response. Further analyses on the current cohort are ongoing.
Peptide MegaPools Approach to Evaluate the Dengue-Specific CD4 and CD8 T-Cell Response Marta Tiberi, Linda Petrone, Andrea Salmi, Valentina Vanini, Gilda Cuzzi, Alessandra D’Abramo, Patrizia De Marco, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Emanuele Nicastri, Delia Goletti Pathogens, 2026 Background: Being central players in the adaptive immunity, the study of T-cell responses is crucial in both natural infections and vaccine-induced immunity. In this study, we assessed the antigen-specific T-cell responses to dengue virus (DENV) to identify the most immunogenic antigen for evaluating dengue-specific T-cell responses. Methods: Patients with dengue disease and subjects vaccinated with the QDENGA (TAK-003) vaccine (before and three months after vaccination) were enrolled. The T-cell-specific response was measured by ELISPOT and Activation Induced Markers (AIM) assay following PBMC stimulation either with DENV1-4 CD4 and CD8 MegaPools (MP) or serotype-specific DENV peptide pools at different concentrations. Results: We found that both DENV1-4 CD4 MP (at 1 µg/mL) and CD8 MP (at 5 µg/mL), which encompass all four DENV serotypes, elicited specific T-cell responses in patients with dengue infection independent of the infecting serotype. In contrast, selected serotype-specific DENV peptide pools have a lower ability to induce a measurable T-cell response. Moreover, DENV1-4 CD4 and CD8 MPs, at the highest concentrations, are suitable candidates to evaluate the dengue-specific T-cell response in vaccinated subjects. Conclusions: These findings support the use of the MP approach to investigate dengue-specific T-cell response to monitor the response during the infection and after vaccine administration.
Inflammatory Cytokine Signatures Are Associated With Disease Burden and Comorbidity of Episodic Migraine and Endometriosis Maria Albanese, Veronica Ceci, Giulia Carrera, Aikaterini Selntigia, Caterina Exacoustos, Marta Tiberi, Stefano Saracini, Alessandro Matteocci, Nicola Biagio Mercuri, Valerio Chiurchiù Neurology Neuroimmunology and Neuroinflammation, 2025 OBJECTIVES: The aim of this study was to characterize inflammatory cytokine profiles in women diagnosed with episodic migraine, endometriosis, or both conditions and to determine how these cytokine patterns relate to symptom severity and functional impact, to identify potential biological markers distinguishing comorbid cases from single-diagnosis cases. METHODS: Female patients with only episodic migraine, only endometriosis, or both conditions were enrolled. Plasma levels of proinflammatory cytokines were measured, and correlations with clinical parameters were analyzed. RESULTS: Women with episodic migraine had elevated levels of IL-1β, IL-6, and TNF-α compared with healthy controls, with even higher levels in those with both migraine and endometriosis, indicating a synergistic effect on systemic inflammation. IL-1β correlated with headache frequency and disability while IL-6 and TNF-α were linked to migraine severity and pain. Women with endometriosis alone did not show similar cytokine elevations, suggesting that inflammation is particularly amplified in comorbidity. Changes in leukocyte distribution further supported a unique immune activation profile in the comorbid group. DISCUSSION: These findings reveal novel biological evidence of a shared inflammatory endotype in women suffering from both conditions, which may contribute to the increased burden and comorbidity, highlighting the need for integrative diagnostic and management approaches.
Systemic inflammation accelerates neurodegeneration in a rat model of Parkinson’s disease overexpressing human alpha synuclein Mariangela Massaro Cenere, Marta Tiberi, Emanuela Paldino, Sebastian Luca D’Addario, Mauro Federici, Cecilia Giacomet, Debora Cutuli, Alessandro Matteocci, Francesca Cossa, Beatrice Zarrilli, Nicolas Casadei, Ada Ledonne, Laura Petrosini, Nicola Berretta, Francesca Romana Fusco, Valerio Chiurchiù, Nicola B. Mercuri Npj Parkinson S Disease, 2024 Increasing efforts have been made to elucidate how genetic and environmental factors interact in Parkinson’s disease (PD). In the present study, we assessed the development of symptoms on a genetic PD rat model that overexpresses human α-synuclein (Snca+/+) at a presymptomatic age, exposed to a pro-inflammatory insult by intraperitoneal injection of lipopolysaccharide (LPS), using immunohistology, high-dimensional flow cytometry, constant potential amperometry, and behavioral analyses. A single injection of LPS into WT and Snca+/+ rats triggered long-lasting increase in the activation of pro-inflammatory microglial markers, monocytes, and T lymphocytes. However, only LPS Snca+/+ rats showed dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), associated with a reduction in the release of evoked dopamine in the striatum. No significant changes were observed in the behavioral domain. We propose our double-hit animal as a reliable model to investigate the mechanisms whereby α-synuclein and inflammation interact to promote neurodegeneration in PD.
Hydrogen Sulfide Modulates Astrocytic Toxicity in Mouse Spinal Cord Cultures: Implications for Amyotrophic Lateral Sclerosis Susanna De Stefano, Marta Tiberi, Illari Salvatori, Marco De Bardi, Juliette Gimenez, Mahsa Pirshayan, Viviana Greco, Giovanna Borsellino, Alberto Ferri, Cristiana Valle, Nicola B. Mercuri, Valerio Chiurchiù, Alida Spalloni, Patrizia Longone Antioxidants, 2024 Hydrogen sulfide (H2S), a known inhibitor of the electron transport chain, is endogenously produced in the periphery as well as in the central nervous system, where is mainly generated by glial cells. It affects, as a cellular signaling molecule, many different biochemical processes. In the central nervous system, depending on its concentration, it can be protective or damaging to neurons. In the study, we have demonstrated, in a primary mouse spinal cord cultures, that it is particularly harmful to motor neurons, is produced by glial cells, and is stimulated by inflammation. However, its role on glial cells, especially astrocytes, is still under-investigated. The present study was designed to evaluate the impact of H2S on astrocytes and their phenotypic heterogeneity, together with the functionality and homeostasis of mitochondria in primary spinal cord cultures. We found that H2S modulates astrocytes’ morphological changes and their phenotypic transformation, exerts toxic properties by decreasing ATP production and the mitochondrial respiration rate, disturbs mitochondrial depolarization, and alters the energetic metabolism. These results further support the hypothesis that H2S is a toxic mediator, mainly released by astrocytes, possibly acting as an autocrine factor toward astrocytes, and probably involved in the non-cell autonomous mechanisms leading to motor neuron death.
Lipid-associated macrophages reshape BAT cell identity in obesity Francesca Sciarretta, Andrea Ninni, Fabio Zaccaria, Valerio Chiurchiù, Adeline Bertola, Keaton Karlinsey, Wentong Jia, Veronica Ceci, Claudia Di Biagio, Ziyan Xu, Francesco Gaudioso, Flavia Tortolici, Marta Tiberi, Jiabi Zhang, Simone Carotti, Sihem Boudina, Paolo Grumati, Beiyan Zhou, Jonathan R. Brestoff, Stoyan Ivanov, Katia Aquilano, Daniele Lettieri-Barbato Cell Reports, 2024 Obesity and type 2 diabetes cause a loss in brown adipose tissue (BAT) activity, but the molecular mechanisms that drive BAT cell remodeling remain largely unexplored. Using a multilayered approach, we comprehensively mapped a reorganization in BAT cells. We uncovered a subset of macrophages as lipid-associated macrophages (LAMs), which were massively increased in genetic and dietary model of BAT expansion. LAMs participate in this scenario by capturing extracellular vesicles carrying damaged lipids and mitochondria released from metabolically stressed brown adipocytes. CD36 scavenger receptor drove LAM phenotype, and CD36-deficient LAMs were able to increase brown fat genes in adipocytes. LAMs released transforming growth factor β1 (TGF-β1), which promoted the loss of brown adipocyte identity through aldehyde dehydrogenase 1 family member A1 (Aldh1a1) induction. These findings unfold cell dynamic changes in BAT during obesity and identify LAMs as key responders to tissue metabolic stress and drivers of loss of brown adipocyte identity.
Frataxin deficiency shifts metabolism to promote reactive microglia via glucose catabolism Francesca Sciarretta, Fabio Zaccaria, Andrea Ninni, Veronica Ceci, Riccardo Turchi, Savina Apolloni, Martina Milani, Ilaria Della Valle, Marta Tiberi, Valerio Chiurchiù, Nadia D’Ambrosi, Silvia Pedretti, Nico Mitro, Cinzia Volontè, Susanna Amadio, Katia Aquilano, Daniele Lettieri-Barbato Life Science Alliance, 2024 Immunometabolism investigates the intricate relationship between the immune system and cellular metabolism. This study delves into the consequences of mitochondrial frataxin (FXN) depletion, the primary cause of Friedreich’s ataxia (FRDA), a debilitating neurodegenerative condition characterized by impaired coordination and muscle control. By using single-cell RNA sequencing, we have identified distinct cellular clusters within the cerebellum of an FRDA mouse model, emphasizing a significant loss in the homeostatic response of microglial cells lacking FXN. Remarkably, these microglia deficient in FXN display heightened reactive responses to inflammatory stimuli. Furthermore, our metabolomic analyses reveal a shift towards glycolysis and itaconate production in these cells. Remarkably, treatment with butyrate counteracts these immunometabolic changes, triggering an antioxidant response via the itaconate-Nrf2-GSH pathways and suppressing the expression of inflammatory genes. Furthermore, we identify Hcar2 (GPR109A) as a mediator involved in restoring the homeostasis of microglia without FXN. Motor function tests conducted on FRDA mice underscore the neuroprotective attributes of butyrate supplementation, enhancing neuromotor performance. In conclusion, our findings elucidate the role of disrupted homeostatic function in cerebellar microglia in the pathogenesis of FRDA. Moreover, they underscore the potential of butyrate to mitigate inflammatory gene expression, correct metabolic imbalances, and improve neuromotor capabilities in FRDA.
