Biology subjects

Manzoni, O. J.

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

12 recordsLinked to original sources

bioRxiv2026

Automated pup-level analysis reveals distinct effects of prenatal CBD and THC exposure on maternal retrieval

This study examined how prenatal CBD and {Delta}9-tetrahydrocannabinol (THC) exposure affects maternal caregiving in C57BL/6J mice. We developed the Machine-Automated Scoring of the Pup Retrieval Test (MAS-PRT) to overcome limitations of manual behavioral scoring. MAS-PRT integrates Multi-Animal DeepLabCut for dam and pup tracking with Detectron2 for dynamic nest reconstruction. Validated against 170 manually annotated retrieval trials, the pipeline showed high concordance with manual measurements and enabled reproducible extraction of encounter latency, retrieval latency, and locomotor trajectories. Prenatal exposure did not impair general nest-building or overall home-cage maternal care. However, pups from both CBD and THC groups showed reduced body weight at postnatal day 5. Cox proportional hazards modeling revealed divergent effects by compound: CBD-exposed dams exhibited a weight-dependent increase in probability of encountering and retrieving lighter pups, independent of pup sex. Spatial tracking further showed that dams traversed significantly shorter total trajectories when retrieving female progeny exposed to either compound. Longitudinal trial-by-trial analysis indicated intact task acquisition in controls and CBD dams, whereas THC dams displayed a flattened learning curve driven by lower retrieval latencies on initial trials. Together, these findings indicate that prenatal cannabinoid exposure does not produce generalized disruption of maternal care but instead induces compound-specific alterations in maternal reactivity, retrieval kinematics, and learning dynamics.

animal behavior and cognition↗

bioRxiv2023

Sexual differences in neuronal and synaptic properties across subregions of the mouse insular cortex

BackgroundThe insular cortex (IC) plays a pivotal role in processing interoceptive and emotional information, offering insights into sex differences in behavior and cognition. The IC comprises two distinct subregions: the anterior insular cortex (aIC), that processes emotional and social signals, and the posterior insular cortex (pIC), specialized in interoception and perception of pain. Pyramidal projection neurons within the IC integrate multimodal sensory inputs, influencing behavior and cognition. Despite previous research focusing on neuronal connectivity and transcriptomics, there has been a gap in understanding pyramidal neurons characteristics across subregions and between sexes. MethodsAdult male and female C57Bl/6J mice were sacrificed and tissue containing the IC was collected for ex vivo slice electrophysiology recordings that examined baseline sex differences in synaptic plasticity and transmission within aIC and pIC subregions. ResultsClear differences emerged between aIC and pIC neurons in both males and females: aIC neurons exhibited distinctive features such as larger size, increased hyperpolarization, and a higher rheobase compared to their pIC counterparts. Furthermore, we observed variations in neuronal excitability linked to sex, with male pIC neurons displaying a greater level of excitability than their female counterparts. We also identified region-specific differences in excitatory and inhibitory synaptic activity and the balance between excitation and inhibition in both male and female mice. Adult females demonstrated greater synaptic strength and maximum response in the aIC compared to the pIC. Lastly, synaptic long-term potentiation occurred in both subregions in males but was specific to the aIC in females. ConclusionsWe conclude that there are sex differences in synaptic plasticity and excitatory transmission in IC subregions, and that distinct properties of IC pyramidal neurons between sexes could contribute to differences in behavior and cognition between males and females. Highlights- Distinctions specific to sex are present within subregions of the insular cortex (IC) in C57Bl/6J mice. - Pyramidal neurons in the anterior IC (aIC) exhibited larger size and distinct electrical properties. Adult females exhibited stronger synaptic responses in the aIC. - Conversely, male posterior insular cortex neurons displayed increased excitability. - Synaptic long-term potentiation was observed in both subregions in males, but it was exclusive to the aIC in females. - Sex-based variations in various aspects of excitatory transmission within IC subregions could contribute to differences in behavior and cognition between males and females. Plain language summaryThis study investigates differences in the insular cortex (IC), a region of the brain responsible for emotions and sensory perceptions, between male and female mice. The IC has two parts: the front (aIC) deals with emotions and social cues, while the back (pIC) is focused on sensing pain and bodily sensations. We examined specific brain cells called pyramidal neurons in both aIC and pIC and discovered noteworthy distinctions between these neurons in adult male and female mice. Firstly, aIC neurons were larger and had unique electrical properties in both male and female mice. Males had more excitable pIC neurons compared to females, indicating that their neurons were more likely to transmit signals. We also explored how these neurons communicate with each other through connections known as synapses. In adult females, the aIC had stronger connections than the pIC. Finally, we observed that specific types of basic synaptic learning occurred exclusively in males in the aIC. These findings underscore significant disparities in the IC between males and females, offering valuable insights into the potential reasons behind variations in behaviors and emotions between sexes.

neuroscience↗

bioRxiv2023

Adaptive Group Behavior of Fragile X Mice in Unfamiliar Environments

Fragile X Syndrome (FXS) stands out as a prominent cause of inherited intellectual disability and a prevalent disorder closely linked to autism. FXS is characterized by substantial alterations in social behavior, encompassing social withdrawal, avoidance of eye contact, heightened social anxiety, increased arousal levels, language deficits, and challenges in regulating emotions. Conventional behavioral assessments primarily focus on short-term interactions within controlled settings. In this study, we conducted a comprehensive examination of the adaptive group behavior of FXS mice over a three-day period, without introducing experimental interventions or task-based evaluations. The data unveiled intricate behavioral anomalies, with the most significant changes manifesting during the initial adaptation to unfamiliar environments. Notably, certain behaviors exhibited a gradual return to typical patterns over time. This dynamic FXS phenotype exhibited heightened activity, featuring increased exploration, amplified social interest, and an unconventional approach to social interactions characterized by a higher frequency of shorter engagements. These findings contribute to the growing understanding of social behavior in individuals with FXS and underscore the significance of comprehending their adaptive responses in various environmental contexts.

animal behavior and cognition↗

bioRxiv2023

Cell-Specific Disruptions in the Basolateral Amygdala-Accumbens Pathway of Fragile X Mice

Fragile X syndrome (FXS), a neurodevelopmental disorder caused by the inactivation of the FMR1 gene, is one of the most common causes of autism spectrum disorder (ASD). People with FXS and ASD often have difficulty regulating their emotions and behaving in a socially appropriate way. The specific neuronal circuits and synaptic dysfunctions involved in social deficits in FXS are not yet fully understood. The basolateral amygdala (BLA) to accumbens core (NAcC) pathway is central to normal social behavior, and we investigated the functionality of this pathway in a novel mouse model of FXS (Fmr1-/y::Drd1a-tdTomato). We used optogenetics to distinguish synapses between BLA neurons and spiny projection neurons (SPNs) in the NAcC. We found that the BLA-NAcC connection in FXS mice displayed heightened synaptic strength along with specific alterations in synaptic plasticity. In FXS, enhanced AMPA and NMDA postsynaptic currents elevated BLA-D2 SPN synaptic strength, while BLA-D1 SPNs increased firing probability occurred without altered transmission. This results in an overall increase in postsynaptic integration in both D1 and D2 SPN BLA-NAcC pathways compared to WT littermates. Further, the absence of FMRP leads to a specific deficit in long-term depression for BLA-D1 SPNs connections. The neurobiological changes identified in this study may underlie the susceptibility to stressors, socio-communicative difficulties, and altered reward-related processes that are characteristic of FXS pathology.

neuroscience↗

bioRxiv2023

Glutamatergic synaptic deficits in the prefrontal cortex of the Ts65Dn mouse model for Down syndrome

Down syndrome (DS), the most common form of intellectual disability, is a chromosomal disorder caused by having all or part of an extra chromosome 21, leading to intellectual disability. Contrary to the extensive research on the Ts65Dn mouse model of DS in the hippocampus, the synaptic foundation of prefrontal cortex (PFC) malfunction in individuals with DS, including working memory deficits, remains largely unclear. A previous study on mBACtgDyrk1a mice, which overexpress the Dyrk1a gene, showed that this overexpression negatively impacts spine density and synaptic molecular composition, causing synaptic plasticity deficits in the PFC. By comparing Ts65Dn mice, which overexpress multiple genes including Dyrk1a, and mBACtgDyrk1a mice, we aimed to better understand the role of different genes in DS. Results from electrophysiological experiments (i.e., patch-clamp and extracellular field potential recordings ex vivo) in Ts65Dn PFC male mice revealed modifications of intrinsic properties in layer V/VI pyramidal neurons and the synaptic plasticity range. Thus, long-term depression was abolished in Ts65Dn, while synaptic or pharmacological long-term potentiation were fully expressed in Ts65Dn mice. These results, illustrating the phenotypic divergence between the polygenic Ts65Dn model and the monogenic mBACtgDyrk1a model of DS, highlight the complexity of the pathophysiological mechanisms responsible for the neurocognitive symptoms of DS.

neuroscience↗

bioRxiv2022

In utero exposure to cannabidiol disrupts select early-life behaviors in a sex-specific manner

Cannabidiol (CBD), one of the main components of cannabis, is generally considered safe, despite the lack of studies on the possible consequences of its consumption during critical periods of neurodevelopment, including prenatal life. Although CBD crosses the placenta and its use during pregnancy is steadily increasing, the impact of gestational CBD exposure on early life is unknown. Here, we combined behavioral exploration and deep learning to assess how in utero exposure to low doses of CBD alters pre-weaning behaviors in mouse pups of both sexes. The data reveal that pups from CBD-treated dams exhibit sex-specific alterations in weight growth, homing behavior, and the syllabic repertoire of ultrasonic vocalizations. Thus, prenatal CBD is associated with alterations in innate behavioral responses and communication skills.

neuroscience↗

bioRxiv2020

Maternal exposure to the cannabinoid agonist WIN 55,12,2 during lactation induces lasting behavioral and synaptic alterations in the rat adult offspring of both sexes

Consumption of cannabis during pregnancy and the lactation period is a rising public health concern (Scheyer et al., 2019). We have previously shown that exposure to synthetic or plant-derived cannabinoids via lactation disrupts perinatal programming of the gamma-aminobutyric acid trajectory in the prefrontal cortex and early-life behaviors (Scheyer et al., 2020b). Recently, we described lasting behavioral and neuronal consequences of {Delta}9-tetrahydrocannabinol (THC) perinatal exposure via lactation (Scheyer et al., 2020a). Here, we extend upon these findings by testing the effects in offspring of maternal exposure to the synthetic cannabinoid agonist WIN 55,12,2 (WIN). The data demonstrate that rats exposed during lactation to WIN display social, cognitive and motivational deficits at adulthood. These behavioral changes were paralleled by a specific loss of endocannabinoid-mediated long-term depression in the prefrontal cortex and nucleus accumbens, while other forms of synaptic plasticity remained intact. Thus, similarly to THC, perinatal WIN exposure via lactation induces behavioral and synaptic abnormalities lasting into adulthood.

neuroscience↗

bioRxiv2020

Perinatal THC Exposure via Lactation Induces Lasting Alterations to Social Behavior and Prefrontal Cortex Function in Rats at Adulthood

Cannabis is the worlds most widely abused illicit drug and consumption amongst women during and surrounding the period of pregnancy is increasing. Previously, we have shown that cannabinoid exposure via lactation during the early postnatal period disrupts early developmental trajectories of prefrontal cortex maturation and induces behavioral abnormalities during the first weeks of life in male and female rat progeny. Here, we investigated the lasting consequences of this postnatal cannabinoid exposure on synaptic and behavioral parameters in the adult offspring of {Delta}9-tetrahydrocannabinol (THC)-treated dams. At adulthood, these perinatally THC-exposed rats exhibits deficits in social discrimination accompanied by an overall augmentation of social exploratory behavior. These behavioral alterations were further correlated with multiple abnormalities in synaptic plasticity in the prefrontal cortex, including lost endocannabinoid-mediated long-term depression (LTD), lost long-term potentiation and augmented mGlu2/3-LTD. Finally, basic parameters of intrinsic excitability at prefrontal cortex pyramidal neurons were similarly altered by the perinatal THC exposure. Thus, perinatal THC exposure via lactation induces lasting deficits in behavior and synaptic function which persist into adulthood life in male and female progeny.

neuroscience↗

bioRxiv2019

Cell-type and endocannabinoid specific synapse connectivity in the adult nucleus accumbens core

The nucleus accumbens (NAc) is a mesocorticolimbic structure that integrates cognitive, emotional and motor functions. Although its role in psychiatric disorders is widely acknowledged, the understanding of its circuitry is not complete. Here we combined optogenetic and whole-cell recordings to draw a functional portrait of excitatory disambiguated synapses onto D1 and D2 medium spiny neurons (MSNs) in the adult mouse NAc core. Comparing synaptic properties of ventral hippocampus (vHipp), basolateral amygdala (BLA) and prefrontal cortex (PFC) inputs revealed a hierarchy of synaptic inputs and feedforward inhibition that depends on the identity of the postsynaptic target MSN. Thus, the BLA is the dominant excitatory pathway onto D1 MSNs (BLA > PFC = vHipp) while PFC inputs dominate D2 MSNs (PFC > vHipp > BLA). Feedforward inhibition of MSN firing too, was input and cell-type specific: while minimal at vHipp-D1 and vHipp-D2 inputs; it inhibited with similar efficacy BLA-D1 or BLA-D2 inputs, was minimal at PFC-D1 but maximal at PFC-D2 inputs. We also tested the hypothesis that endocannabinoids endow excitatory circuits with pathway- and cell-specific plasticity. Thus, while CB1 receptors (CB1R) uniformly depress excitatory pathways irrespective of MSNs identity, TRPV1 receptors (TRPV1R) bidirectionally control inputs onto the NAc core in a pathway-specific manner. Finally, we show how the interplay of TRPV1R/CB1R shapes plasticity at identified BLA-NAc synapses. Together these data shed new light on synapse and circuit specificity in the adult NAc core and illustrate how endocannabinoids contribute to pathway-specific synaptic plasticity.\n\nSIGNIFICANCE STATEMENTWe examined the impact of connections from the ventral hippocampus (vHipp,) basolateral amygdala (BLA) and prefrontal cortex (PFC) onto identified medium spiny neurons (MSN) in the adult accumbens core. We found BLA inputs were strongest at D1 MSNs while PFC inputs dominate D2 MSNs. We evaluated the role of the endocannabinoid system in pathway- and cell-specific plasticity and found that CB1 receptors (CB1R) and TRPV1 receptors (TRPV1R) bidirectionally control synaptic transmission and plasticity onto accumbens MSNs in a pathway- and cell-specific manner. Finally, we clarify how the interplay of TRPV1R/CB1R shapes plasticity at identified BLA-NAc synapses.

neuroscience↗

bioRxiv2018

Sex differences in the behavioral and synaptic consequences of a single exposure to cannabinoid at puberty and adulthood

Heavy cannabis consumption among adolescents is associated with significant and lasting neurobiological, psychological and health consequences that depend on the age of first use. Chronic exposure to cannabinoid (CB) agonists during adolescence alters social behavior and prefrontal cortex (PFC) activity in adult rats. However, sex differences on social behavior as well as PFC synaptic plasticity after acute CB activation remain poorly explored. Here, we determined the consequences of a single CB activation differently affects PFC in males and females by assessing social behavior and PFC neuronal and synaptic functions in rats during pubertal or adulthood periods, 24h after a single in-vivo cannabinoid exposure (SCE). During puberty, SCE reduced play behavior in females but not males. In contrast, SCE impaired sociability in both sexes at adulthood. General exploration and memory recognition remained normal at both ages and both sexes. At the synaptic level, SCE ablated endocannabinoid-mediated long-term depression (eCB-LTD) in the PFC of females of both ages and heightened excitability of PFC pyramidal neurons at adulthood, while males were spared. In contrast, SCE was associated to impaired long-term potentiation in adult males. Together, the data indicate behavioral and synaptic sex differences in response to a single in-vivo exposure to cannabinoid at puberty and adulthood.

neuroscience↗

bioRxiv2018

Maternal cannabinoid exposure during lactation alters the developmental trajectory of prefrontal cortex GABA-currents in offspring

Cannabis is the most widely used illicit drug in the world, and its usage is increasing with its widespread legalization. Use of the drug by mothers during lactation may transfer active cannabinoids to the developing offspring, altering postnatal neurodevelopment during this critical period. During early life, GABA undergoes a functional switch from an excitatory to an inhibitory neurotransmitter due to reciprocal changes in expression of the K+/Cl- co-transporters KCC2 and NKCC1. Here, we characterize the functional GABA switch in the prefrontal cortex of both male and female rats. We show that treating rat dams with {Delta}9-THC or a synthetic cannabinoid during early lactation (PND01-10) retards KCC2 expression and delays the GABA switch in pups of both sexes via a CB1R-dependent mechanism. Our results indicate that the developmental trajectory of GABA in PFC neurons is significantly altered by perinatal exposure to cannabinoids through lactation during the early perinatal period.

neuroscience↗

bioRxiv2018

Sex specific endophenotypes of in-utero cannabinoid exposure

Cannabinoids can cross the placenta, thus may interfere with fetal endocannabinoid signaling during neurodevelopment, causing long-lasting deficits. Despite increasing cannabis consumption during pregnancy, the protracted consequences of prenatal cannabinoid exposure (PCE) remain incompletely understood. Here we report sex-specific differences in behavioral and neuronal deficits in the adult progeny of rat dams exposed to low doses of cannabinoids during gestation. In males, PCE reduced social interaction, ablated endocannabinoid long-term depression (LTD) and heightened excitability of prefrontal cortex pyramidal neurons, while females were spared. Group 1 mGluR and endocannabinoid signaling regulate emotional behavior and synaptic plasticity. Notably, sex-differences following PCE included levels of mGluR1/5 and TRPV1R mRNA. Finally, positive allosteric modulation of mGlu5 and enhancement of anandamide levels restored LTD and social interaction in PCE adult males. Together, these results highlight marked sexual differences in the effects of PCE and introduce strategies for reversing detrimental effects of PCE.

neuroscience↗