Biology subjects

Carnicella, S.

Publications and source records attributed to Carnicella, S..

7 recordsLinked to original sources

bioRxiv2026

miR-10a-5p as a critical molecular regulator of dopaminergic impulsivity in the nucleus accumbens

Impulsive-compulsive disorders (ICDs), including pathological gambling, hypersexuality, and compulsive buying, are frequently precipitated by dopamine D2/3 receptor agonists such as pramipexole (PPX), yet the molecular mechanisms that confer individual vulnerability remain poorly understood. Impulsive choice, a core dimension of ICDs, is modulated by dopaminergic signaling within corticostriatal circuits, but the microRNAs (miRs) that potentially translate this signaling into persistent behavioral change have not been identified. Here, we combined a delay discounting task (DDT) with high-throughput miR sequencing in the dorsal striatum and nucleus accumbens (NAcc) of rats stratified by baseline impulsivity and subchronic PPX treatment. PPX increased impulsive choice selectively in low- and mid-impulsive rats, whereas high-impulsive rats remained unaffected, consistent with a ceiling effect. Among the differentially expressed miRs, miR-10a-5p emerged as the strongest candidate: it was constitutively elevated in high-impulsive rats and upregulated by PPX in low- and mid-impulsive animals in both regions, thereby paralleling the trait-dependent behavioral effect of the drug. In vivo viral-mediated overexpression of miR-10a-5p confirmed its predicted downregulation of the PI3K-AKT-mTOR and BDNF pathways in the striatum, and, critically, overexpression restricted to the NAcc, but not the dorsal striatum, was sufficient to increase impulsive choice, recapitulating the pro-impulsive effect of PPX. These findings identify miR-10a-5p as a critical molecular regulator of impulsivity through its activity in the NAcc, providing a mechanistic link between dopaminergic perturbation, trait vulnerability, and ICDs, and opening new avenues for the development of miR-directed therapeutic strategies for these disorders.

neuroscience↗

bioRxiv2023

Pramipexole restores behavioral inhibition in highly impulsive rats through a paradoxical modulation of frontostriatal networks

Impulse control disorders (ICDs), a wide spectrum of maladaptive behaviors which includes pathological gambling, hypersexuality and compulsive buying, have been recently suggested to be triggered or aggravated by treatments with dopamine D2/3 receptor agonists, such as pramipexole (PPX). Despite evidence showing that impulsivity is associated with functional alterations in corticostriatal networks, the neural basis of the exacerbation of impulsivity by PPX has not been elucidated. Here we used a hotspot analysis to assess the functional recruitment of several corticostriatal structures by PPX in male rats identified as highly (HI), moderately impulsive (MI) or with low levels of impulsivity (LI) in the 5-choice serial reaction time task (5-CSRTT). PPX dramatically reduced impulsivity in HI rats. Assessment of the expression pattern of the two immediate early genes C-fos and Zif268 by in situ hybridization subsequently revealed that PPX resulted in a decrease in Zif268 mRNA levels in different striatal regions of both LI and HI rats accompanied by a high impulsivity specific reduction of Zif268 mRNA levels in prelimbic and cingulate cortices. PPX also decreased C-fos mRNA levels in all striatal regions of LI rats, but only in the dorsolateral striatum and nucleus accumbens core (NAc Core) of HI rats. Structural equation modelling further suggested that the anti-impulsive effect of PPX was mainly attributable to the specific downregulation of Zif268 mRNA in the NAc Core. Altogether, our results show that PPX restores impulse control in highly impulsive rats by modulation of limbic frontostriatal circuits.

neuroscience↗

bioRxiv2022

Re-routing metabolism by the mitochondrial pyruvate carrier inhibitor MSDC-0160 attenuates neurodegeneration in a rat model of Parkinson's disease

BackgroundA growing body of evidence supports the idea that mitochondrial dysfunction might represent a key feature of Parkinsons disease (PD). Central regulators of energy production, mitochondria are also involved in several other essential functions such as cell death pathways and neuroinflammation which make them a potential therapeutic target for PD management. Interestingly, recent studies related to PD have reported a neuroprotective effect of targeting mitochondrial pyruvate carrier (MPC) by the insulin sensitizer MSDC-0160. As the sole point of entry of pyruvate into the mitochondrial matrix, MPC plays a crucial role in energetic metabolism which is impacted in PD. This study therefore aimed at providing insights into the mechanisms underlying the neuroprotective effect of MSDC-0160. MethodsWe investigated behavioral, cellular and metabolic impact of chronic MSDC-0160 treatment in unilateral 6-OHDA PD rats. We evaluated mitochondrial related processes through the expression of pivotal mitochondrial enzymes in dorsal striatal biopsies and the level of metabolites in serum samples using nuclear magnetic resonance spectroscopy (NMR)-based metabolomics. ResultsMSDC-0160 treatment in unilateral 6-OHDA rats improved motor behavior, decreased dopaminergic denervation and reduced mTOR activity and neuroinflammation. Concomitantly, MSDC-0160 administration strongly modified energy metabolism as revealed by increased ketogenesis, beta oxidation and glutamate oxidation to satisfy energy needs and maintain energy homeostasis. ConclusionMSDC-0160 exerts its neuroprotective effect through reorganization of multiple pathways connected to energy metabolism.

neuroscience↗

bioRxiv2021

Hypodopaminergic state of the nigrostriatal pathway drives compulsive alcohol use

The neurobiological mechanisms underlying compulsive alcohol use, a cardinal feature of alcohol use disorder, remain elusive. The key modulator of motivational processes dopamine (DA) is suspected to play an important role in this pathology, but its exact implication remains to be determined. Here, we found that rats expressing compulsive alcohol-related behavior, operationalized as punishment-resistant self-administration, showed a decrease in DA levels restricted to the dorsolateral territories of the striatum, the main output structure of the nigrostriatal DA pathway. We then causally demonstrated that a chemogenetic-induced selective hypodopaminergia of this pathway results in compulsive alcohol self-administration in rats otherwise resilient, accompanied by the emergence of alcohol withdrawal-like motivational impairments. These results demonstrate a major implication of tonic nigrostriatal hypodopaminergic state in alcohol addiction and provide new insights into our understanding of the neurobiological mechanisms underlying compulsive alcohol use.

neuroscience↗

bioRxiv2021

Early diagnosis of Parkinson's disease: A cross-species biomarker

BackgroundCare management of Parkinsons disease (PD) patients currently remains symptomatic, especially because diagnosis relying on the expression of the cardinal motor symptoms is made too late. Detecting PD earlier therefore represents a key step for developing therapies able to delay or slow down its progression. MethodsWe investigated metabolic markers in three different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 2 cohorts of de novo PD patients (n = 95). Serum and brain tissue samples were analyzed by nuclear magnetic resonance spectroscopy and data submitted to advanced multivariate statistics. ResultsOur translational strategy reveals common metabolic dysregulations in serum of the different animal models and PD patients. Some of them were mirrored in the tissue samples, possibly reflecting pathophysiological mechanisms associated with PD development. Interestingly, some metabolic dysregulations appeared before motor symptom emergence, and could represent early biomarkers of PD. Finally, we built a composite biomarker with a combination of 6 metabolites. This biomarker discriminated animals mimicking PD from controls, even from the first, non-motor signs and very interestingly, also discriminated PD patients from healthy subjects. ConclusionFrom our translational study which included three animal models and two PD patient cohorts, we propose a promising composite biomarker exhibiting a high level of predictivity for PD diagnosis in its early phase, before motor symptoms appearance. FundingsANR, DOPALCOMP, Institut National de la Sante et de la Recherche Medicale, Grenoble Alpes University.

pathology↗

bioRxiv2020

Bilateral but not unilateral subthalamic stimulation promotes apathy: a translational study in rodents and Parkinson's disease patients

Apathy, depression, and anxiety represent the main neuropsychiatric symptoms of Parkinsons disease (PD). How subthalamic nucleus deep brain stimulation (STN-DBS) influences these symptoms, especially apathy, is a controversial topic. The present translational study investigates and compares the effect of bilateral or unilateral STN-DBS on this neuropsychiatric triad, combining a pre-clinical approach in rodents and a clinical follow-up of patients with PD. While depression and anxiety related behaviors remain unchanged, bilateral but not unilateral STN-DBS consistently induces apathy in patients and a reward seeking deficit in rodents. Together, these data substantiate the claim that STN-DBS may induce apathy by itself and suggest that bilateral but not the unilateral stimulation might be a critical factor.

neuroscience↗

bioRxiv2020

Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats.

Although Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) represent a technical revolution in integrative neuroscience, the first ligands used were not as selective as expected. Compound 21 (C21) was recently proposed as an alternative, but in vivo characterization of its properties is not sufficient yet. Here, we evaluated its potency to selectively modulate the activity of nigral dopaminergic (DA) neurons through the canonical DREADD receptor hM4Di using TH-Cre rats. In males, 1 mg.kg-1 of C21 strongly increased nigral neurons activity in control animals, indicative of a significant off-target effect. Reducing the dose to 0.5 mg.kg-1 circumvented this aspecific effect, while activated the inhibitory DREADDs and selectively reduced nigral neurons firing. In females, 0.5 mg.kg-1 of C21 induced a transient and residual off-target effect that may mitigated the inhibitory DREADDs-mediated effect. This study raises up the necessity to test selectivity and efficacy of chosen ligands for each new experimental condition.

neuroscience↗