Neuroscience, Psychology, Pharmacology, Toxicology and Pharmaceutics
9
Scopus Publications
Scopus Publications
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.
Protocol for modeling earned-secure attachment in rodents using the repeated cross-fostering procedure with a significant alternative caregiver Camilla Mancini, Alice Passeri, Matteo Di Segni, Lucy Babicola, Rossella Ventura STAR Protocols, 2025 An earned-secure attachment (ESA) from a significant alternative caregiver (SAC) can mitigate the negative effects of the alteration of attachment bond. This protocol models clinical ESA in rodents using the repeated cross-fostering procedure with a SAC (RCF+SAC). We describe steps for housing of mice, the mating procedure, isolation of pregnant dam, and SAC introduction. We then detail the preparation of materials and environment for the RCF+SAC procedure and its subsequent execution. For complete details on the use and execution of this protocol, please refer to Mancini et al. 1
The role of motivation in eating disorders: understanding sex differences in the circuits Sofia Nasini, Antonino Casile, Brigitta Bonaldo, Camilla Mancini, Serafina Manila Guzzo, Luca Botticelli, Stefano Comai Frontiers in Behavioral Neuroscience, 2025 Motivated behaviors, such as reproduction and feeding, are essential for mammalian survival. Although these behaviors serve distinct evolutionary purposes, they share a common function: fulfilling specific biological needs. Their regulation involves distinct brain regions and is influenced by a complex interplay of neural circuits, with significant sex-based differences. Alterations in motivation represent critical components of effort-based decision-making processes in eating disorders (EDs). Importantly, the impairments in motivated behavior observed in EDs arise not from structural changes within the relevant brain regions but rather from functional alterations influenced primarily by gonadal hormones. These hormones play a pivotal role in the pathophysiology of EDs, driving sex-based differences in both the qualitative aspects of symptom presentation and developmental trajectories through intracellular genomic signaling pathways. The current review examines sex differences in motivated behavior within the context of EDs.
Secure attachment to caregiver prevents adult depressive symptoms in a sex-dependent manner: A translational study Camilla Mancini, Lucy Babicola, Gilda Chila, Matteo Di Segni, Diana Municchi, Sebastian Luca D’Addario, Elena Spoleti, Alice Passeri, Carlo Cifani, Diego Andolina, Simona Cabib, Fabio Ferlazzo, Marco Iosa, Rodolfo Rossi, Giorgio Di Lorenzo, Massimiliano Renzi, Rossella Ventura Iscience, 2024 Although clinically relevant, evidence for a protective effect of early secure attachment against the development of depressive symptoms in adulthood is still inconsistent. This study used a translational approach to overcome this limitation. The analysis of a non-clinical adult population revealed a moderating effect of secure attachment on depressive symptoms in women only. Thus, we tested the causal link between early attachment with caregiver and adult depressive-like phenotypes in a mouse model of early adversities that is especially effective in females. Repeated cross fostering (RCF) in the first postnatal days prevented the development of pups' secure attachment with the caregiver as tested in a rodent version of the "strange situation"-the standard human test-induced depressive-like behaviors and altered activity of the ventral tegmental area dopamine neurons in adulthood. Finally, a stable alternative caregiver during the RCF experience prevented all these effects, modeling human "earned attachment."
A mouse model of the 3-hit effects of stress: Genotype controls the effects of life adversities in females Lucy Babicola, Camilla Mancini, Cristina Riccelli, Matteo Di Segni, Alice Passeri, Diana Municchi, Sebastian Luca D'Addario, Diego Andolina, Carlo Cifani, Simona Cabib, Rossella Ventura Progress in Neuro Psychopharmacology and Biological Psychiatry, 2023 Helplessness is a dysfunctional coping response to stressors associated with different psychiatric conditions. The present study tested the hypothesis that early and adult adversities cumulate to produce helplessness depending on the genotype (3-hit hypothesis of psychopathology). To this aim, we evaluated whether Chronic Unpredictable Stress (CUS) differently affected coping and mesoaccumbens dopamine (DA) responses to stress challenge by adult mice of the C57BL/6J (B6) and DBA/2J (D2) inbred strains depending on early life experience (Repeated Cross Fostering, RCF). Three weeks of CUS increased the helplessness expressed in the Forced Swimming Test (FST) and the Tail Suspension Test by RCF-exposed female mice of the D2 strain. Moreover, female D2 mice with both RCF and CUS experiences showed inhibition of the stress-induced extracellular DA outflow in the Nucleus Accumbens, as measured by in vivo microdialysis, during and after FST. RCF-exposed B6 mice, instead, showed reduced helplessness and increased mesoaccumbens DA release. The present results support genotype-dependent additive effects of early experiences and adult adversities on behavioral and neural responses to stress by female mice. To our knowledge, this is the first report of a 3-hit effect in an animal model. Finally, the comparative analyses of behavioral and neural phenotypes expressed by B6 and D2 mice suggest some translationally relevant hypotheses of genetic risk factors for psychiatric disorders.
Early life adversity affecting the attachment bond alters ventral tegmental area transcriptomic patterning and behavior almost exclusively in female mice Luisa Lo Iacono, Camilla Mancini, Lucy Babicola, Marco Pietrosanto, Matteo Di Segni, Sebastian Luca D'Addario, Diana Municchi, Donald Ielpo, Tiziana Pascucci, Simona Cabib, Fabio Ferlazzo, Francesca R. D'Amato, Diego Andolina, Manuela Helmer-Citterich, Carlo Cifani, Rossella Ventura Neurobiology of Stress, 2021 Early life experiences that affect the attachment bond formation can alter developmental trajectories and result in pathological outcomes in a sex-related manner. However, the molecular basis of sex differences is quite unknown. The dopaminergic system originating from the ventral tegmental area has been proposed to be a key mediator of this process. Here we exploited a murine model of early adversity (Repeated Cross Fostering, RCF) to test how interfering with the attachment bond formation affects the VTA-related functions in a sex-specific manner. Through a comprehensive behavioral screening, within the NiH RDoC framework, and by next-generation RNA-Seq experiments, we analyzed the long-lasting effect of RCF on behavioral and transcriptional profiles related to the VTA, across two different inbred strains of mouse in both sexes. We found that RCF impacted to an extremely greater extent VTA-related behaviors in females than in males and this result mirrored the transcriptional alterations in the VTA that were almost exclusively observed in females. The sexual dimorphism was conserved across two different inbred strains in spite of their divergent long lasting consequences of RCF exposure. Our data suggest that to be female primes a sub-set of genes to respond to early environmental perturbations. This is, to the best of our knowledge, the first evidence of an almost exclusive effect of early life experiences on females, thus mirroring the extremely stronger impact of precocious aversive events reported in clinical studies in women.
Resilience to anhedonia-passive coping induced by early life experience is linked to a long-lasting reduction of Ih current in VTA dopaminergic neurons: Altered Ih current in the VTA of adult resilient-to-depression mice Sebastian Luca D'Addario, Matteo Di Segni, Ada Ledonne, Rosamaria Piscitelli, Lucy Babicola, Alessandro Martini, Elena Spoleti, Camilla Mancini, Donald Ielpo, Francesca R. D'Amato, Diego Andolina, Davide Ragozzino, Nicola B. Mercuri, Carlo Cifani, Massimiliano Renzi, Ezia Guatteo, Rossella Ventura Neurobiology of Stress, 2021 Exposure to aversive events during sensitive developmental periods can affect the preferential coping strategy adopted by individuals later in life, leading to either stress-related psychiatric disorders, including depression, or to well-adaptation to future adversity and sources of stress, a behavior phenotype termed “resilience”. We have previously shown that interfering with the development of mother-pups bond with the Repeated Cross Fostering (RCF) stress protocol can induce resilience to depression-like phenotype in adult C57BL/6J female mice. Here, we used patch-clamp recording in midbrain slice combined with both in vivo and ex vivo pharmacology to test our hypothesis of a link between electrophysiological modifications of dopaminergic neurons in the intermediate Ventral Tegmental Area (VTA) of RCF animals and behavioral resilience. We found reduced hyperpolarization-activated (Ih) cation current amplitude and evoked firing in VTA dopaminergic neurons from both young and adult RCF female mice. In vivo, VTA-specific pharmacological manipulation of the Ih current reverted the pro-resilient phenotype in adult early-stressed mice or mimicked behavioral resilience in adult control animals. This is the first evidence showing how pro-resilience behavior induced by early events is linked to a long-lasting reduction of Ih current and excitability in VTA dopaminergic neurons.
Xlr4 as a new candidate gene underlying vulnerability to cocaine effects Matteo Di Segni, Sebastian Luca D'Addario, Lucy Babicola, Donald Ielpo, Luisa Lo Iacono, Diego Andolina, Alessandra Accoto, Alessandra Luchetti, Camilla Mancini, Chiara Parisi, Mara D'Onofrio, Ivan Arisi, Rossella Brandi, Tiziana Pascucci, Carlo Cifani, Francesca R. D'Amato, Rossella Ventura Neuropharmacology, 2020
