Biology subjects

Giua, G.

Publications and source records attributed to Giua, G..

5 recordsLinked to original sources

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↗

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.

neuroscience↗

bioRxiv2020

Prenatal THC does not affect female mesolimbic dopaminergic system in preadolescent rats

Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes towards it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to {Delta}9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype. This phenotype only reveals itself upon a single exposure to THC in males but not females. Here, we characterized the impact of PCE on female behaviors and mesolimbic dopamine system function by combining in vivo single-unit extracellular recordings in anesthetized animals and ex vivo patch clamp recordings, along with neurochemical and behavioral analyses. We find that PCE female offspring do not show any spontaneous or THC-induced behavioral disease-relevant phenotypes. The THC-induced increase of dopamine levels in nucleus accumbens was reduced in PCE female offspring, even when VTA dopamine activity in vivo and ex vivo did not differ compared to control. These findings indicate that PCE impacts mesolimbic dopamine function and its related-behavioral domains in a sex-dependent manner and warrant further investigations to decipher the mechanisms determining this sex-related protective effect from intrauterine THC exposure. HighlightsO_LIPCE female offspring do not manifest a disease-relevant phenotype C_LIO_LIPrenatal THC does not affect female dopaminergic neurons C_LIO_LIPCE female mesolimbic dopamine function is less responsive to acute THC C_LI

neuroscience↗