Publications and outcomes

Fattore Liana , Landry Marc, Editorial: Understanding the link between environmental pollutants, brain & behavior, Frontiers in Psychiatry, Volume 17 – 2026, 2026

Open Access publication available here

Gugula, A., Sambak, P., Trenk, A. et al. Early-life adversity alters adult nucleus incertus neurons: implications for neuronal mechanisms of increased stress and compulsive behavior vulnerability. Neuropsychopharmacol. 50, 1406–1419 (2025)

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Abstract:

Early-life stress (ELS) arising from physical and emotional abuse disrupts normal brain development and impairs hypothalamic–pituitary–adrenal axis function, increasing the risk of psychopathological disorders and compulsive behaviors in adulthood. However, the underlying neural mechanisms remain unclear. The brainstem nucleus incertus (NI) is a highly stress-sensitive locus, involved in behavioral activation and stress-induced reward (food/alcohol) seeking, but its sensitivity to ELS remains unexplored. We used neonatal maternal separation stress in rats as a model for ELS and examined its impact on stress-related mRNA and neuropeptide expression in the NI, using fluorescent in situ hybridization and immunohistochemistry, respectively. Using whole-cell, patch-clamp recordings we determined the influence of ELS on the synaptic activity, excitability, and electrophysiological properties of NI neurons. Using c-Fos protein expression we also assessed the impact of ELS on the sensitivity of NI neurons to acute restraint stress in adulthood. ELS weakened the acute stress responsiveness of NI neurons, and caused dendritic shrinkage, impaired synaptic transmission and altered electrophysiological properties of NI neurons in a cell-type-specific manner. Additionally, ELS increased the expression of mRNA encoding corticotropin-releasing hormone receptor type 1 and the nerve-growth factor receptor, TrkA in adult NI. The multiple, cell-type specific changes in the expression of neuropeptides and molecules associated with stress and substance abuse in the NI, as well as impairments in NI neuron morphology and electrophysiology caused by ELS and observed in the adult brain, may contribute to the increased susceptibility to stress and compulsive behaviors observed in individuals with a history of ELS.

Giorgia Corli, Fabrizio De Luca, Sabrine Bilel, Marta Bassi, Elisa Roda, Paola Rossi, Liana Fattore, Carlo Alessandro Locatelli, Matteo Marti, Repeated treatment with JWH-018 progressively increases motor activity and aggressiveness in male mice: involvement of CB1 cannabinoid and D1/D2 dopaminergic receptors, European Journal of Pharmacology, Volume 998, 2025

Open Access publication available here

Abstract:

Rationale

To date, the exposure to Synthetic Cannabinoids (SCs) has been linked to unanticipated psychiatric symptoms such as agitation, psychosis, and aggressive behavior. In line with this, preclinical studies have shown that acute and long-term exposure to these compounds can result in psychostimulant effects that may be related to CB1-mediated and dopamine-dependent mechanisms.
 

Objectives

This study focuses on the progressive effects induced by repeated injection of 1-pentyl-3-(1-naphthoyl)indole JWH-018 (6 mg/kg, i.p.) on the locomotor activity and aggressive behavior in adult male ICR-CD1® mice. Thus, the interaction with the cannabinoid CB1 receptor-preferring antagonist/inverse agonist AM-251 (6 mg/kg, i.p.), the dopamine D1/5 receptor antagonist SCH23390 (0.1 mg/kg, i.p.), and the dopamine D2/3 receptor antagonist haloperidol (0.05 mg/kg, i.p.) have been evaluated. Expression and distribution of D1 and D2 receptors and tyrosine hydroxylase (TH) have been also investigated by immunohistochemistry on brain and cerebellar samples to explore potential neuroplastic events.
 

Results

The repeated treatment with JWH-018 lead to the exacerbation of unanticipated psychomotor agitation, progressively increasing spontaneous locomotion and aggressiveness. Pre-treatment with AM-251 prevents the effects induced by the SC first, third and seventh injection. SCH23390 and haloperidol significantly attenuate and fully prevent the effects induced by JWH-018 seventh injection when pre-administered, respectively, alone and in combination. Behavioral changes observed in JWH-018-treated mice are accompanied by alterations in cortical, hippocampal, striatal and cerebellar D1, D2 and TH gene expression levels.
 

Conclusion

The present results demonstrated that repeated treatment with high dosage of JWH-018 induces psycho-stimulants effects via both CB1 receptor-mediated and dopamine-dependent mechanisms.

Mañas-Ojeda, A., Hidalgo-Cortés, J., García-Mompó, C. et al. Activation of somatostatin neurons in the medial amygdala reverses long-term aggression and social deficits associated to early-life stress in male mice. Mol Psychiatry (2024).

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Abstract: Early postnatal development is a critical period for the configuration of neural networks that support social and affective-like behaviors. In this sense, children raised in stressful environments are at high risk to develop maladaptive behaviors immediately or later in life, including anti-social and aggressive behaviors. However, the neurobiological bases of such phenomena remain poorly understood. Here we showed that, at long-term, maternal separation with early weaning (MSEW) decreased the density of somatostatin-expressing (SST+) neurons in the basolateral amygdala (BLA) of females and males, while their activity was only reduced in the medial amygdala (MeA) of males. Interestingly, only MSEW males exhibited long-term behavioral effects, including reduced sociability and social novelty preference in the 3-chamber test (3CH), decreased social interest in the resident-intruder test (RI), and increased aggressivity in both the RI and the tube dominance test (TT). To test whether the manipulation of MeASST+ neurons was sufficient to reverse these negative behavioral outcomes, we expressed the chemogenetic excitatory receptor hM3Dq in MSEW adult males. We found that the activation of MeASST+ neurons ameliorated social interest in the RI test and reduced aggression traits in the TT and RI assays. Altogether, our results highlight a role for MeASST+ neurons in the regulation of aggressivity and social interest and point to the loss of activity of these neurons as a plausible etiological mechanism linking early life stress to these maladaptive behaviors in later life.

Assaf, M.; Rouphael, M.; Bou Sader Nehme, S.; Soufia, M.; Alameddine, A.; Hallit, S.; Landry, M.; Bitar, T.; Hleihel, W. Correlational Insights into Attention-Deficit/Hyperactivity Disorder in Lebanon. Int. J. Environ. Res. Public Health 2024, 21, 1027.

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Abstract: Attention-Deficit/Hyperactivity Disorder (ADHD), a prevalent childhood neurodevelopmental disorder with complex etiology involving genetic and environmental factors, causes impairments across various life domains and substantial social and economic burden. Identifying correlates to prevent its onset and decrease its incidence is crucial. To our knowledge, our study represents the first case–control investigation of Lebanese ADHD patients to explore potential correlations between familial, maternal, and child health variables and ADHD to enhance understanding of its etiology and aid in prevention efforts. We recruited 61 Lebanese ADHD patients and 58 matched controls aged 6–24 years from all districts of Lebanon. The data to analyze were collected using a questionnaire. We employed statistical tests, including the independent samples t-test and the Chi-square test or Fisher’s exact test. We conducted a multivariate logistic regression analysis to identify the statistically significant factors explaining ADHD likelihood. We observed male predominance (68.9%) among patients. Maternal anemia during pregnancy (OR = 3.654; 95% CI [1.158–11.529]), maternal self-reported stress during pregnancy (OR = 3.268; 95% CI [1.263–8.456]), neonatal jaundice (OR = 5.020; 95% CI [1.438–17.532]), and familial history of ADHD (OR = 12.033; 95% CI [2.950–49.072]) were significantly associated with increased odds of the disorder. On the other hand, breastfeeding (OR = 0.263; 95% CI [0.092–0.757]) was identified as a protective factor against ADHD. This pilot study shed light on risk and protective factors associated with ADHD in the Lebanese population. The results are relevant, as some identified correlates could be avoidable. Further rigorous investigation is required to expand upon the observed correlations and to assist in early detection, prevention, and intervention strategies targeting ADHD. 

Nour-eddine Kaikai, Saadia Ba-M’hamed, Abderrazzak Ghanima, Mohamed Bennis,
« Exposure to metam sodium-based pesticide impaired cognitive performances in adult mice: Involvement of oxidative damage and glial activation », Toxicology and Applied Pharmacology, Volume 477, 2023, 116677

Open access publication available here

Abstract: Cognitive integrity is a critical aspect of neurological function, and a decline in cognitive function is a hallmark of neurotoxicity. Oxidative stress is a significant pathological feature contributing to cognitive deficits that can arise from exposure to environmental pollutants such as pesticides. Among these, Metam sodium-based pesticides (MS-BP) are an emergent type of pesticide widely used in the agriculture and public health sectors for controlling pests and diseases. Our prior research has shown that animals exposed to MS-BP during the early stages of brain development caused cognitive impairments. In the present study, we tested whether exposure to this compound in a fully matured brain would affect cognitive performance and induce oxidative damage to the central nervous system. In this context, adult mice received chronic treatment with increasing doses of MS-BP and subjected to a set of behavioral paradigms. Following behavioral assessment, oxidative stress and glial activation were evaluated. Our main findings showed that MS-BP chronic exposure impaired recognition and short- and long-term memory. These alterations were accompanied by increased superoxide dismutase activity and malondialdehyde level and a marked decrease in catalase activity in specific brain areas. Moreover, exposure to MS-BP is associated with a significant rise in the density of astrocytic and microglial markers, indicating a possible glial cell response within the prefrontal cortex and hippocampus. The present work demonstrated that MS-BP altered cognitive performance likely through oxidative damage to the brain.