Biology subjects

Chelini, G.

Publications and source records attributed to Chelini, G..

8 recordsLinked to original sources

bioRxiv2025

Automated assessment of the mouse body-language reveals pervasive behavioral disruption in a two-hit model of psychiatric vulnerability

The influence of early-life experiences is widely acknowledged as a crafting tool that sculpts complex behavioral patterns and well-being of living organisms. The use of preclinical models can provide invaluable insight into how a negative environmental push interplays with genetic make-up in shaping psychiatric vulnerability. However, the assessment of psychiatric traits in cross-species studies often relies on the use of surrogate metrics as a proxy for the internal state, limiting the interpretation to context-dependent outcomes. In this work, we exploited a validated computational tool for digitalized ethological screening to identify spontaneous hallmarks of altered behavioral functioning in a dual-hit mouse model of psychiatric vulnerability. To do so, mice carrying heterozygous deletion of the gene coding for Contactin-associated protein-like 2 (Cntnap2+/-) and their wild-type (WT) littermates were raised with limited bedding and nesting (LBN). These animals were compared to both WT and Cntnap2+/- mice raised in standard conditions, mapping their spontaneous behavior during freely-moving exploration. Our data show that descriptors of motility state or surrogate anxiety indicators largely failed in detecting subtle diversion from control conditions. By contrast, automated segmentation of the body-language revealed a significant impact of both genotype and early-life experience in shaping the spontaneous behavioral programming. Thus, using unsupervised clustering, we unveiled two alternative neurobehavioral profiles within our dataset. We found that one of the identified profiles largely overlapped with Cntnap2+/- mice raised with LBN, while the other was equally shared among controls. We conclude that the coincidence of early-life adversity and Cntnap2 haploinsufficiency drastically reshapes behavioral structure in rodents. SIGNIFICANCE STATEMENTEnhancing the predictive and face validity of preclinical models in psychiatric research remains a significant challenge due to the inherent heterogeneity and complexity of these conditions. While animal models are crucial for understanding the risk factors involved, replicating the full complexity of these conditions continues to pose difficulties. In this study, we use a tool for digitalized behavioral screening to investigate emotional hallmarks in a double-hit (environmental and genetic) mouse model of vulnerability for psychiatric disorder, glimpsing subliminal behavioral disturbances not captured with traditional assessments. Our findings highlight the effectiveness of novel computational tools in identifying subtle behavioral deviations and support the hypothesis that gene-environment interaction contributes to shape alternative behavioral structure in mice.

neuroscience↗

bioRxiv2024

Early-life scarcity adversity biases behavioral development toward a bipolar-like phenotype in mice heterozygous for CNTNAP2

The etiological complexity of psychiatric disorders arises from the dynamic interplay between genetic and environmental vulnerabilities. Among the environmental components, early-life adversities (ELA) are a major risk-factors for developing a psychiatric disorder. Yet, the mechanistic interaction between ELA and genetic vulnerability contributing to psychopathology is poorly understood. To fill this gap, we took advantage of the ideally controlled conditions of a pre-clinical approach. In this study we raised a mouse model with genetic predisposition to multiple psychiatric disorders (autism spectrum, schizophrenia, bipolar disorder), the Cntnap2+/- mouse, with limited bedding and nesting (LBN), a well-established paradigm to induce early-life stress in rodents. These mice were compared to LBN-raised Cntnap2+/+ littermates, as well as parallel groups of Cntnap2+/+ and Cntnap2+/- raised in standard conditions. Using a battery for behavioral phenotyping we show that ELA shapes non-overlapping phenotypic landscapes based on genetic predisposition. Specifically, we found that LBN-raised Cntnap2+/- mice develop a perseverative risk-taking behavior in the elevated plus maze and that this behavior is highly predictive of their success in the social interaction, assessed with the 3-chamber test. This finding suggests that the intrusion of anxiety into the social behavioral domain contributes to extreme gain- or loss-of function in social interaction, resembling a bipolar-like phenotype. Finally, we show that LBN promotes synaptic hypertrophy in the basolateral nucleus of the amygdala, but only in Cntnap2+/- raised in LBN this condition was found in combination with microglia abnormalities. We conclude that the interplay between ELA and Cntnap2 haploinsufficiency exacerbates bipolar-like behaviors in mice, and that this may be consequence of deficient synaptic homeostasis in the basolateral amygdala.

neuroscience↗

bioRxiv2024

N-acetylcysteine counteracts immune dysfunction and autistic-related behaviors in the Shank3b mouse model of Autism Spectrum Disorders

Autism Spectrum Disorder (ASD) includes a range of neurodevelopmental disabilities characterized by social interaction deficits, communication impairments, and repetitive behaviors. Previous studies have shown that pro-inflammatory conditions play a key role in ASD. Here we reported that increased levels of molecules related to inflammation are present in the cerebellum and peripheral blood (PB) of mice lacking Shank3b, established model of syndromic ASD. In parallel, immune dysfunction was documented in the bone marrow (BM) and spleen of mutant mice. N-acetylcysteine (NAC) treatment rescued inflammation in the cerebellum and PB, as well as impaired production of pro-inflammatory molecules in the BM and spleen. In addition, social impairment was counteracted in NAC-treated Shank3b-/- animals. Taken together, our study further confirms the key role of cerebellar inflammation in the establishment of ASD-related behaviors. Furthermore, our findings underscore the importance of considering ASD as a systemic disorder. Our findings therefore suggest that the interplay between oxidative stress and inflammation may support ASD-related behaviors in mice.

immunology↗

bioRxiv2023

The interplay between oxidative stress and inflammation supports autistic-related behaviors in mice

Autism Spectrum Disorder (ASD) is a highly prevalent neurodevelopmental condition characterized by social communication deficits and repetitive/restricted behaviors. Several studies showed that inflammation may contribute to ASD. Here we used RT-qPCR, RNA sequencing, immunohistochemistry, and flow cytometry to show that pro-inflammatory molecules were increased in the cerebellum and periphery of mice lacking Cntnap2 (Cntnap2-/-), a robust model of ASD. In parallel, oxidative stress was present in the cerebellum of mutant animals. Systemic treatment with N-acetyl-cysteine (NAC) rescued cerebellar oxidative stress and inflammation as well as motor and social impairments in Cntnap2-/- mice. This was accompanied by improved function of microglia cells in NAC-treated mutant animals. Intriguingly, social deficits, cerebellar inflammation and microglia dysfunction were induced by NAC in Cntnap2+/+animals. Our findings therefore suggest that the interplay between oxidative stress and inflammation may support ASD-related behaviors in mice.

immunology↗

bioRxiv2022

Automated decoding the mouse body-postures in a whisker nuisance test

Abnormal response to sensory stimuli characterizes multiple neuropsychiatric conditions. However, not many tools are currently available to assess somatosensory abnormalities in rodent models of brain disorders, limiting the possibilities to study cellular and molecular correlates of this phenotypic trait. To this goal, previous studies relied on the whisker nuisance test (WNt), in which freely moving mice are constantly stimulated on their whiskers using a wood stick for a set time. The whisker-guided response is then deconstructed in behavioral categories indicative of either anxiety or curiosity. Thus far, WNt was shown to be a valuable tool to investigate sensory-driven abnormalities in mouse models of autism spectrum disorders (ASD), demonstrating a solid translational validity. Nevertheless, assessment of behavioral response in the WNt is currently limited by the lack of an objective quantification method. To overcome this limitation, we developed WNt3R (Whisker Nuisance Test in 3D for Rodents), a MATLAB toolbox that uses the output of the open-source software DeepLabCut to determine discrete body postures associated with multiple ethologically-relevant behaviors. Our results show that behavioral modules identified using WNt3R reliably decode mouse body postures, outperforming the manual user, thus offering a novel and unbiased approach to study altered somatosensory function in rodents.

animal behavior and cognition↗

bioRxiv2022

A marmoset brain cell census reveals persistent influence of developmental origin on neurons

The mammalian brain is composed of many brain structures, each with its own ontogenetic and developmental history. Transcriptionally-based cell type taxonomies reveal cell type composition and similarity relationships within and across brain structures. We sampled over 2.4 million brain cells across 18 locations in the common marmoset, a New World monkey primed for genetic engineering, and used single-nucleus RNA sequencing to examine global gene expression patterns of cell types within and across brain structures. Our results indicate that there is generally a high degree of transcriptional similarity between GABAergic and glutamatergic neurons found in the same brain structure, and there are generally few shared molecular features between neurons that utilize the same neurotransmitter but reside in different brain structures. We also show that in many cases the transcriptional identities of cells are intrinsically retained from their birthplaces, even when they migrate beyond their cephalic compartments. Thus, the adult transcriptomic identity of most neuronal types appears to be shaped much more by their developmental identity than by their primary neurotransmitter signaling repertoire. Using quantitative mapping of single molecule FISH (smFISH) for markers for GABAergic interneurons, we found that the similar types (e.g. PVALB+ interneurons) have distinct biodistributions in the striatum and neocortex. Interneuron types follow medio-lateral gradients in striatum but form complex distributions across the neocortex that are not described by simple gradients. Lateral prefrontal areas in marmoset are distinguished by high relative proportions of VIP+ neurons. We further used cell-type-specific enhancer driven AAV-GFP to visualize the morphology of molecularly-resolved interneuron classes in neocortex and striatum, including the previously discovered novel primate-specific TAC3+ striatal interneurons. Our comprehensive analyses highlight how lineage and functional class contribute to the transcriptional identity and biodistribution of primate brain cell types. One-Sentence SummaryAdult primate neurons are imprinted by their region of origin, more so than by their functional identity.

neuroscience↗

bioRxiv2021

Proteoglycan Clusters as a Site of Coordinated, Multi-Dendritic Plasticity

Experience-dependent learning depends on synaptic plasticity. While plasticity in individual synapses has been extensively investigated, the mechanisms underlying coordinated changes across sets of synapses on multiple dendrites, likely needed to encode effective adaptations to a salient stimulus, are not well understood. The extracellular matrix is uniquely well suited to fulfill this function, as rapid glia-driven remodeling of its local composition powerfully impact synaptic plasticity. We show that extracellular matrix microenvironments, named CS6 clusters, dynamically form around several dendrites in response to sensory stimuli in coincidence to stimulus-driven synaptic plasticity. CS6 clusters, formed by glia-dependent secretion of extracellular matrix components surrounding sets of adjacent dendrites, may represent a novel structure supporting coordinated synaptic plasticity. One Sentence SummaryExtracellular matrix clusters form microenvironments for coordinated multi-dendrite synaptic plasticity.

neuroscience↗

bioRxiv2020

Microglial Associated Circadian Rhythms of Perineuronal Net Composition

Perineuronal Nets (PNNs) are extracellular matrix (ECM) structures that envelop neurons and regulate synaptic functions. Long thought to be stable structures, PNNs have been recently shown to respond dynamically during learning, potentially regulating the formation of new synapses. We postulated that PNNs vary during sleep, a period of active synaptic modification. Notably, PNN components are cleaved by matrix proteases such as the protease cathepsin-S. This protease is diurnally expressed in the mouse cortex, coinciding with dendritic spine density rhythms. Thus, cathepsin-S may contribute to PNN remodeling during sleep, mediating synaptic reorganization. These studies were designed to test the hypothesis that PNN numbers vary in a diurnal manner in the rodent and human brain, as well as in a circadian manner in the rodent brain, and that these rhythms are disrupted by sleep deprivation. In mice, we observed diurnal and circadian rhythms of PNNs labeled with the lectin wisteria floribunda agglutinin (WFA+PNNs) in several brain regions involved in emotional memory processing. Sleep deprivation prevented the daytime decrease of WFA+ PNNs and enhances fear memory extinction. Diurnal rhythms of cathepsin-S expression in microglia were observed in the same brain regions, opposite to PNN rhythms. Finally, incubation of mouse sections with cathepsin-S eliminated PNN labeling. In humans, WFA+PNNs showed a diurnal rhythm in the amygdala and thalamic reticular nucleus (TRN). Our results demonstrate that PNNs vary in a circadian manner and this is disrupted by sleep deprivation. We suggest that rhythmic modification of PNNs may contribute to memory consolidation during sleep.

neuroscience↗