Biology subjects

Contestabile, A.

Publications and source records attributed to Contestabile, A..

9 recordsLinked to original sources

bioRxiv2026

Individual behavioral signatures shape processing of context-dependent social fear

Context processing is an essential function in the cognitive repertoire of numerous species, including humans and mice, allowing them to learn from their environment and adapt their future behavior. Impairments or alterations in context processing are hypothesized to represent one of the core etiological mechanisms underlying trauma- and stressor-related disorders such as post-traumatic stress disorder (PTSD). Individual behavioral traits are key determinants of post-stress responses; however, how they influence distinct phases of contextual encoding and processing remains incompletely understood. This knowledge gap is further exacerbated by the limited availability of contextual fear protocols based on social stress, even though the latter is among the most frequent and impactful forms of stress exposure. Here, based on social defeat paradigms, we establish a longitudinal social conditioned place aversion (sCPA) protocol that leads to avoidance of the defeat-associated chamber in adult male mice. Prior characterization of mice according to anxiety-related phenotypes revealed that mice displaying high novelty-induced thigmotaxic (i.e. high anxiety-like) behavior showed lasting long-term memory of the defeat-associated chamber as denoted by persistent avoidance. On the other hand, lower levels of exploration/locomotor behaviors prior to stress exposure predicted greater avoidance of the defeat-associated chamber in the short-term. Finally, we reveal that inhibiting the activity of VTAVgat neurons during conditioning sessions abolished sCPA acquisition, while disrupting the predictive ability of locomotor/exploratory profiles derived prior to the sCPA. Our data establishes a robust temporally structured social stress-based conditioning protocol and reveals how prior individual anxiety- and exploration/locomotion-related traits influence distinct stages of context processing.

animal behavior and cognition↗

bioRxiv2024

Anxa1+ dopamine neuron vulnerability defines prodromal Parkinson's disease bradykinesia and procedural motor learning impairment

Progressive degeneration of dopamine neurons (DANs) defines Parkinsons disease (PD). However, the identity and function of the most vulnerable DAN populations in prodromal PD remain undefined. Here, we identify substantia nigra DANs with Annexin A1 (Anxa1) expression as selectively vulnerable across multiple prodromal PD models and significantly reduced in patient-derived DANs. We found that Anxa1+ DANs have a unique functional profile, as they do not signal reward or reinforce actions, and they are not necessary for motivated behavior. Instead, activity of Anxa1+ DAN axons correlates with vigorous movements during self-paced exploration, yet their silencing only disrupts a subset of action sequences that mirror a PD bradykinesia profile. Importantly, Anxa1+ DANs are essential for procedural learning in a maze task and for motor learning of dexterous actions. These findings establish the early vulnerability of Anxa1+ DANs in PD, whose function can explain prodromal bradykinesia and impairments in procedural motor learning.

neuroscience↗

bioRxiv2024

A striosomal accumbens pathway drives compulsive seeking behaviors through an aversive Esr1+ hypothalamic-habenula circuit.

The lateral hypothalamic area (LHA) integrates external stimuli with internal states to drive the choice between competing innate or value-driven motivated behaviors. Projections from the LHA to the lateral habenula (LHb) shape internal states, with excitatory estrogen receptor 1-expressing (Esr1+) LHA-LHb neurons driving aversive responses and sustained negative states. Here, we identify and functionally characterize a specific projection from the nucleus accumbens (ACB) that targets Esr1+ LHA-LHb neurons. Using cell-type-specific tracing of monosynaptic inputs, single-nucleus RNA sequencing, and neuroanatomical mapping, we demonstrate that the Esr1+ LHA-LHb pathway receives a major input from a striosomal Tac1+/Tshz1+/Oprm1+ ACB neuron subtype. Intersectional cell-type-specific and input-output defined optogenetic manipulation of this ACB-LHA-LHb pathway revealed its role in signaling aversion after repeated activation, with the negative behavioral state being dependent on recruitment of Esr1+ LHA-LHb neurons. Importantly, we found that activation of the D1+ ACB-LHA pathway drives reward-independent compulsive-like seeking behaviors, expressed as compulsive digging or poking behaviors. We found that these complex yet stereotyped behaviors compete with highly motivated states and can override the need for natural rewards or social stimuli. Our findings reveal a discrete striosomal Tac1+ ACB projection targeting the aversive Esr1+ LHA-LHb pathway as a key circuit that promotes compulsive seeking behaviors over goal-directed actions.

neuroscience↗

bioRxiv2023

Heterogeneous subpopulations of GABAAR-responding neurons coexist in physiological and pathological mature neuronal networks at increasing scales of complexity

GABA is the main inhibitory neurotransmitter in adults. Depolarizing/excitatory GABA responses have been well characterized at the level of neuronal-population average during typical neurodevelopment and partially in pathology. However, no investigation has specifically assessed whether a mosaicism of cells with either depolarizing/excitatory or hyperpolarizing/inhibitory GABAergic responses exists in adult animals in health/disease. Here, we showed that such mosaicism is present both in adult WT and Down syndrome (DS) mice, as assessed at increasing scales of neuronal-network complexity (cultures, brain- slices, behaving mice). Nevertheless, WT mice presented a lower percentage of cells with depolarizing GABA than DS mice. Restoring the mosaicism of hyperpolarizing and depolarizing GABA-responding neurons to WT levels rescued anxiety behaviour in DS mice. We also found heterogeneous GABAergic responses in mature control and trisomic human iPSC-derived neurons. Thus, a heterogeneous population of GABA-responding cells exists in physiological/pathological conditions in mature mouse and human neurons, possibly contributing to disease-associated behaviours.

neuroscience↗

bioRxiv2021

Inhibition of TRPV4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism

Autism spectrum disorder is a neurodevelopmental disease characterized by social deficits and repetitive behaviors. The high heterogeneity of the disease may be explained by gene and environmental interactions and potential risk factors include immune dysfunctions and immune-mediated co-morbidities. Mutations in the SHANK3 gene have been recognized as a genetic risk factor for ASD. While heterozygous SHANK3 mutations are usually the types of mutations associated with idiopathic autism in patients, heterozygous deletion of Shank3 gene in mice does not commonly induce ASD-related behavioural deficit. Here, we used in-vivo and ex-vivo approaches to demonstrate that region-specific neonatal downregulation of Shank3 in the NAc promotes D1R-MSN hyperexcitability and upregulates Trpv4 to impair social behaviour. Interestingly, genetically vulnerable Shank3+/- mice, when challenged with Lipopolysaccharide to induce inflammatory response, showed similar circuit and behavioural alterations that were rescued by acute Trpv4 inhibition. Altogether our data demonstrate shared molecular and circuit mechanisms between ASD-relevant genetic alterations and environmental insults, which ultimately lead to sociability dysfunctions.

neuroscience↗

bioRxiv2021

Oxytocin neurons mediates the effect of social isolation via the VTA circuits

Social interaction during adolescence strongly influences brain function and behaviour, and the recent pandemic has emphasized the devastating effect of social distancing on mental health. While accumulating evidences have shown the importance of the reward system in encoding specific aspects of social interaction, the consequences of social isolation on the reward system and the development of social skills later in adulthood are still largely unknown. Here, we found that one week of social isolation during adolescence in mice increased social interaction at the expense of social habituation and social novelty preference. Behavioural changes were accompanied by the acute hyperexcitability of dopamine (DA) neurons in the ventral segmental area (VTA) and long-lasting expression of GluA2-lacking AMPARs at excitatory inputs onto DA neurons that project to the prefrontal cortex (PFC). Social isolation-dependent behavioural deficits and changes in neural activity and synaptic plasticity were reversed by chemogenetic inhibition of oxytocin neurons in the paraventricular nucleus (PVN) of the hypothalamus. These results demonstrate that social isolation has acute and long-lasting effects on social interaction and suggest that these effects are mediated by homeostatic adaptations within the reward circuit.

neuroscience↗

bioRxiv2021

Optogenetic stimulation of BLA terminals in the BNST elicits long term synaptic plasticity and restores synaptic alterations induced by adolescent Shank3 downregulation

Anxiety disorders are the most prevalent co-morbidity factor associated with the core domains of Autism Spectrum Disorders (ASD). Investigations on potential common neuronal mechanisms that may explain the co-occurrence of ASD and anxiety disorders are still poorly unexplored. One of the key questions which remained unsolved is the role of Shank3 protein in anxiety behaviors. Here we used shRNA strategy to model Shank3 insufficiency in the bed nucleus of the stria terminalis (BNST). We found that Shank3 downregulation in the BNST induced anxiogenic effects. Associated with these behavioural defects, we showed alteration of glutamatergic synaptic functions in the BNST induced by Shank3 insufficiency during adolescence. In addition, we pointed that adolescence represents a crucial time window to interfere with BNST maturation, a key hub for anxiety control. Together, these results unravelled the crucial role of Shank3 expression in the BNST during adolescence. Our study provided a new insight in the neuronal mechanisms underlying anxiety disorders. We proposed to screen a novel molecular target essential for BNST integrity during adolescence. This result may further help for the diagnosis and the development of therapeutic strategy for anxiety disorders and anxiety disorders implicated in some forms of ASD.

neuroscience↗

bioRxiv2019

Gene editing preserves visual function in a mouse model of retinal degeneration

Inherited retinal dystrophies are a large and heterogeneous group of degenerative diseases caused by mutations in various genes. Given the favourable anatomical and immunological characteristics of the eye, gene therapy holds great potential for their treatment. We used a tailored CRISPR/Cas9-based gene editing system to prevent retinal photoreceptor death in the Rd10 mouse model of retinitis pigmentosa. We tested the gene editing tool in vitro and then used in vivo subretinal electroporation to deliver it to one of the retinas of mouse pups at different stages of photoreceptor differentiation. Three months after gene editing, the treated eye exhibited a higher visual acuity compared to the untreated eye. Moreover, we observed preservation of light-evoked responses both in explanted retinas and in the visual cortex of treated animals. Our study validates a CRISPR/Cas9-based therapy as a valuable new approach for the treatment of retinitis pigmentosa caused by autosomal recessive loss-of-function point mutations.

neuroscience↗

bioRxiv2018

SHANK3 downregulation in the VTA accelerates the extinction of contextual associations induced by non-familiar conspecific interaction

Conditioned place preference (CPP) paradigms, traditionally adopted to study the reinforcing properties of drugs of abuse, have been developed to investigate the neurobiological mechanisms underlying the reinforcing properties of social stimuli. These protocols are largely based on single-housing before and/or during the social stimulus-contextual cues acquisition phase. Here, based on previously established social interaction-induced CPP paradigms, we characterize a place preference task relying on the reinforcing properties of free interaction with a non-familiar (novel) conspecific. The formation of contextual associations induced by the interaction with a novel social stimulus does not require single-housing, necessitates dopamine (DA) receptor 2/3 (D2/3R) activation and undergoes extinction. Interestingly, while extinction of CPP responses is reduced by single-housing, it is accelerated by the downregulation of the autism spectrum disorder (ASD)-related protein SHANK3 in the ventral tegmental area (VTA). Thus, inspired by the literature on drug of abuse-induced contextual learning, we propose that acquisition and extinction of CPP might be used as behavioral assays to assess social-induced contextual association and \"social-seeking\" dysfunctions in animal models of psychiatric disorders.

neuroscience↗