Biology subjects

Dufourd, T.

Publications and source records attributed to Dufourd, T..

3 recordsLinked to original sources

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↗

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↗