Biology subjects

MANZONI, O. J.

Publications and source records attributed to MANZONI, O. J..

9 recordsLinked to original sources

bioRxiv2026

Prenatal Cannabidiol and Δ9-Tetrahydrocannabinol exposure lead to sex-specific disruptions in risk assessment and behavioral switching via divergent rewiring of the adult mPFC

BackgroundPrenatal cannabidiol (CBD) consumption is increasing, driven by a perception of safety relative to {Delta}9-tetrahydrocannabinol (THC). However, the neurodevelopmental risks of gestational CBD remain largely uncharacterized. MethodsUsing a sex-disaggregated framework, we investigated adult (P100-140) mouse offspring following in utero exposure (GD5-18; 3 mg/kg) to THC or CBD. Behavioral strategies were evaluated through risk-assessment and repetitive behavior tasks, coupled with targeted electrophysiological mapping of medial prefrontal cortex Layer 5 neurons, the primary hub for approach-avoidance arbitration. ResultsWe found that increased repetitive behavior was a universal feature of prenatal cannabinoids exposure. Alterations in risk appraisal emerged uniquely in CBD-exposed females and appeared dissociated from classical anxiety metrics. At the circuit level, THC and CBD were linked to an absence of endocannabinoid long-term depression (eCB-LTD). In males, CBD exposure coincided with a bidirectional plasticity collapse characterized by functional saturation, elevated AMPA/NMDA ratios, and slowed NMDAR activation kinetics. This ceiling effect may represent a top-down constraint on the prefrontal output circuit, potentially limiting the synaptic flexibility typically associated with adaptive behavioral transitions. In contrast, females exhibited compound-specific reorganizations of E/I balance. CBD-exposed females displayed a scaled-up architecture that preserved net E/I balance, whereas THC was associated with a pro-excitatory phenotype through the collapse of inhibitory control. ConclusionsDespite a shared loss of eCB-LTD, distinct synaptic remodeling might underlie divergent alterations in risk assessment and behavioral flexibility. This sex-specific circuit rewiring provides a neurobiological framework for the long-term behavioral risks associated with gestational cannabinoid exposure.

neuroscience↗

bioRxiv2026

Compound and sex specific medial prefrontal cortex rewiring after prenatal THC and CBD exposure

The growing perception of cannabinoids as benign has increased perinatal exposure to both {Delta}9-tetrahydrocannabinol (THC) and cannabidiol (CBD), yet their long-term effects on prefrontal circuitry remain incompletely defined. Here we used whole-cell and field electrophysiology in adult mice (P100-140) of both sexes to compare how in utero exposure to THC or CBD (GD5-18) remodels layer-5 pyramidal neurons in the medial prefrontal cortex (mPFC). We quantified intrinsic excitability, excitatory and inhibitory synaptic transmission, the net E/I ratio, spontaneous excitatory and inhibitory currents kinetics, and canonical forms of synaptic plasticity (endocannabinoid-mediated LTD and NMDA-dependent LTP). Both cannabinoids shifted the adult mPFC toward a more pro-excitatory state: the E/I ratio was altered in a compound- and sex-dependent manner, and endocannabinoid-mediated LTD was abolished across groups. THC recapitulated previously reported deficits, producing male-specific increases in intrinsic excitability and accelerating excitatory current kinetics in females, demonstrating a conserved cross-species vulnerability of prefrontal circuits to gestational THC. CBD produced distinct signatures: female offspring showed marked increases in spontaneous excitatory event frequency and amplitude, indicating large-scale reorganization of excitatory and inhibitory inputs, while male offspring exhibited a selective and profound impairment of LTP. The combination of universal eLTD loss and CBD-specific LTP impairment in males yields a bidirectional loss of plasticity: an emergent synaptic rigidity in which circuits are unable to potentiate or depress effectively. Together, these convergent and divergent effects establish that prenatal exposure to THC and CBD produces lasting, sex-dependent rewiring of mPFC circuitry. Our results caution that the non-intoxicating profile of CBD does not preclude durable developmental impact and underscore the importance of considering both compound identity and sex when assessing the neurodevelopmental risks of perinatal cannabinoid exposure.

neuroscience↗

bioRxiv2025

Prenatal Cannabinoids Produce Sex Specific Changes in Risk Assessment and Shared Increases in Repetitive Behavior in Adult Offspring

The widespread perception of cannabinoids as harmless remedies has led to increasing use of both cannabidiol (CBD) and {Delta}9-tetrahydrocannabinol (THC) during pregnancy, yet their long-term impact on offspring behavior remains incompletely characterized. To directly compare these compounds, pregnant mice received daily CBD or THC (3 mg/kg, gestational days 5-18) and adult progeny of both sexes were evaluated (P90-120). To capture complementary dimensions of emotional and defensive responding, we employed the elevated plus maze (EPM) to quantify anxiety-related measures and ethological risk-assessment postures (e.g., stretch-attend) and the marble burying (MB) test to index repetitive/defensive behavior; together these assays provide convergent but distinct readouts that increase sensitivity to cannabinoid-induced effects. In the EPM, prenatal CBD exposure selectively increased stretch-attend postures in females, indicating heightened risk assessment; males were unaffected, and THC produced no comparable effect. Classical EPM indices--time in open or closed arms, preference for open-arms, and total distance traveled--were unchanged across groups, except that THC-exposed females exhibited hyperlocomotion. In contrast, marble burying was increased in both sexes following prenatal exposure to either CBD or THC, indicating a shared enhancement of repetitive/defensive responses. These results show that prenatal cannabinoid exposure yields enduring, sex-dependent alterations in adult behavior, with CBD selectively heightening female risk assessment and both cannabinoids increasing repetitive behavior across sexes, challenging the notion that CBD is a benign alternative to THC during gestation.

neuroscience↗

bioRxiv2024

Gestational CBD shapes insular cortex in adulthood

Many expectant mothers use CBD to alleviate symptoms like nausea, insomnia, anxiety, and pain, despite limited research on its long-term effects. However, CBD passes through the placenta, affecting fetal development and impacting offspring behavior. We investigated how prenatal CBD exposure affects the insular cortex (IC), a brain region involved in emotional processing and linked to psychiatric disorders. The IC is divided into two territories: the anterior IC (aIC), processing socioemotional signals, and the posterior IC (pIC), specializing in interoception and pain perception. Pyramidal neurons in the aIC and pIC exhibit sex-specific electrophysiological properties, including variations in excitability and the excitatory/inhibitory balance. We investigated ICs cellular properties and synaptic strength in the offspring of both sexes from mice exposed to low-dose CBD during gestation (E5-E18; 3mg/kg, s.c.). Prenatal CBD exposure induced sex-specific and territory-specific changes in the active and passive membrane properties, as well as intrinsic excitability and the excitatory/inhibitory balance, in the IC of adult offspring. The data indicate that in-utero CBD exposure disrupts IC neuronal development, leading to a loss of functional distinction between IC territories. These findings may have significant implications for understanding the effects of CBD on emotional behaviors in offspring.

neuroscience↗

bioRxiv2023

Cocaine-induced loss of LTD and social impairments are restored by fatty acid amide hydrolase inhibition

BackgroundA single usage of a drug of abuse can have lasting effects on both the brain and behavior, continuing even after the drug has been metabolized and eliminated from the body. A single dose of cocaine can abolish endocannabinoid-mediated long-term depression (eCB-LTD) in the nucleus accumbens (NAc) within 24 hours of administration. However, it is uncertain whether this altered neuroplasticity entails a behavioral deficit. MethodsOur study employed adult male mice to investigate the effects of a single dose of cocaine (20 mg/kg) on eCB-LTD, saccharin preference, and social interactions 24 hours after administration. We also examined the gene expression in components of the eCB system. The pharmacological increase of anandamide was evaluated using the fatty acid amide hydrolase (FAAH) inhibitor URB597 (1 mg/kg). ResultsAfter a single dose of cocaine, mice displayed altered plasticity, social interactions, and preference for saccharin and a reduction in mRNA levels of the anandamide-catabolizing enzyme NAPE-PLD. We discovered that the FAAH inhibitor URB597 (1 mg/kg) successfully reversed the cocaine-induced loss of eCB-LTD in the NAc and restored normal social interaction in cocaine-exposed mice, but it did not affect their saccharin preference. ConclusionsOverall, this research underlines the neuroplastic changes and subsequent behavioral alterations that occur after the initial use of cocaine, while also suggesting a potential role for anandamide in the early impairments caused by cocaine. The findings highlight the importance of understanding the mechanisms underlying the initiation of drug use and offer a potential therapeutic target.

neuroscience↗

bioRxiv2022

Dichotomous Intrinsic Properties of Adult Accumbens Medium Spiny Neurons Vanish in the Fragile X Mouse Model of Autism

Fragile X syndrome (FXS), the most common cause of autism and inherited intellectual disability, is caused by the mutation of a single gene, fmr1, which encodes the Fragile X mental retardation protein (FMRP). FXS patients suffer from cognitive, emotional, and social deficits indicative of dysfunction in the nucleus accumbens (NAc), a structure central to the control of social behavior. The major cell type of the NAc, medium spiny neurons (MSNs), are differentiated in two subtypes based on their expression of either dopamine D1 or D2 receptors, their connectivity, and associated behavioral functions. Understanding how the absence of FMRP differentially affects the cellular properties of MSNs is a necessary step to categorize FXS cellular endophenotypes. To address this question, we comprehensively compared the intrinsic passive and active properties of MSN subtypes identified in a novel Fmr1-/y :: Drd1a-tdTomato mouse model allowing in-situ identification of MSN subtypes in FXS mice. Although fmr1 transcripts and their gene product, FMRP, were found in both MSNs subtypes, the results suggest cell-autonomous functions for Fmr1. The opposite membrane properties and action potential kinetics that normally discriminate D1- from D2- MSNs in WT mouse is either reversed or abolished in Fmr1-/y :: Drd1a-tdTomato mice. Multivariate analysis shed light on the compound effects of Fmr1 ablation by revealing how the phenotypic traits that distinguish each cell type in WT are modified in FXS. Together these data show that in Fragile X mice the normal dichotomy that characterizes NAc D1- and D2-MSNs is thrown out of balance, leading to a uniform phenotype that could underlie selected aspects of the pathology.

neuroscience↗

bioRxiv2021

Cannabinoid during adolescence phenocopies reelin haploinsufficiency in prefrontal cortex synapses

In humans and rodents, the protracted development of the prefrontal cortex (PFC) throughout adolescence represents a time for marked vulnerability towards environmental adversities, such as stress or drug exposure. We previously showed that the extracellular matrix protein reelin is an instrumental synaptic modulator that shapes medial PFCs (mPFC) circuitry during maturation and is a critical mediator of the vulnerability to environmental stress. Emerging evidence highlight the role of the endocannabinoid system in the postnatal maturation of the PFC and reelin deficiency influences behavioral abnormalities caused by heavy consumption of THC during adolescence. Could the reelin-dependent maturation of prefrontal networks may be vulnerable to cannabinoid exposure during adolescence? To explore this hypothesis, we studied the effects of a single in-vivo exposure to a synthetic cannabinoid on reelin expression and mPFC functions in adolescent male mice. The results show that a single cannabinoid exposure mimics reelin haploinsufficiency by decreasing prefrontal reelin expression in a layer-specific pattern without changing its transcriptional levels. Furthermore, this treatment impeded synaptic plasticity: adolescent cannabinoid lowered long-term potentiation to the magnitude observed in age-matched reelin haploinsufficient males. Quantitative PCR analysis showed that changes in the mRNA levels of NMDARs does not account for the reduction of TBS-LTP. Together, the data show that exposure to cannabinoid during adolescence phenocopies reelin haploinsufficiency and further identifies reelin as a key component of the vulnerability of PFC to environmental insults.

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bioRxiv2021

Sex-specific divergent maturational trajectories in the post-natal rat basolateral amygdala

The basolateral amygdala (BLA), the part of the amygdala complex involved in the transduction of perceptual stimuli into emotion, undergoes profound reorganization at adolescence in rodents and humans. How cellular and synaptic plasticity evolve throughout postnatal development in both sexes is only partially understood. We used a cross-sectional approach to compare the morphology, neuronal, and synaptic properties of BLA neurons in rats of both sexes at adolescence and adulthood. While BLA pyramidal neurons from rats of both sexes displayed similar current-voltage relationships, rheobases, and resting potentials during pubescence, differences in these parameters emerged between sexes at adulthood: BLA neurons were more excitable in males than females. During pubescence, BLA neuron excitability was highest in females and unchanged in males; male action potentials were smaller and shorter than females and fast afterhyperpolarizations were larger in males. During post-natal maturation, no difference in spine density was observed between groups or sexes but spine length increased and decreased in females and males, respectively. A reduction in spine head diameter and volume was observed exclusively in females. Basic synaptic properties also displayed sex-specific maturational differences. Stimulus-response relationships and maximal fEPSP amplitudes where higher in male adolescents compared with adults but were similar in females of both ages. Spontaneous excitatory postsynaptic currents mediated by AMPA receptors were smaller in BLA neurons from adolescent female compared with their adult counterparts but were unchanged in males. These differences did not directly convert into changes in overall synaptic strength estimated from the AMPA/NMDA ratio, which was smaller in adolescent females. Finally, the developmental courses of long-term potentiation and depression (LTP, LTD) were sexually dimorphic. LTP was similarly present during the adolescent period in males and females but was not apparent at adulthood in females. In contrast, LTD followed an opposite development: present in adolescent females and expressed in both sexes at adulthood. These data reveal divergent maturational trajectories in the BLA of male and female rats and suggest cellular substrates to the BLA linked sex-specific behaviors at adolescence and adulthood.

neuroscience↗

bioRxiv2020

Sex-specific maturational trajectory of endocannabinoid plasticity in the rat prefrontal cortex

The prefrontal cortex (PFC) develops until early adulthood in rodents and humans, but how synaptic plasticity evolves throughout postnatal development is not known. Here, we used a cross-sectional approach to establish the postnatal maturational trajectories of intrinsic properties and synaptic plasticity in the PFC of rats of both sexes. We found that while layer 5 PFC pyramidal neurons from rats of both sexes displayed similar current-voltage relationships, rheobases and resting potentials across all age groups, excitability was lower in female adults compared to the other developmental stages. NMDAR-dependent long-term potentiation and mGluR2/3-mediated long-term depression (LTD) were equally expressed at the juvenile, pubescent and adult developmental stages in animals of both sexes. However, the developmental course of endocannabinoid (eCB)-mediated LTD was sexually dimorphic. First, eCB-LTD emerged during the juvenile period in females. However, although CB1Rs were functional in both sexes at all developmental stages, eCB-LTDs first emerged during pubescence in male. Second, eCB-LTD engaged distinct receptors in males and females depending on their developmental stages. Female rats employ both CB1R and TRPV1R to produce eCB-LTD at the juvenile stage but solely CB1R at pubescence followed by only TRPV1R at adulthood. In contrast, in pubescent and adult males eCB-LTD always and exclusively depended on CB1R. Pharmacological blockade of 2AGs principal degrading enzyme allowed incompetent male juvenile synapses to express eCB-LTD. The data reveal different maturational trajectories in the PFC of male and female rats and provide new cellular substrates to the sex-specific behavioral and synaptic abnormalities caused by adolescent exposure to cannabinoids.

neuroscience↗