Biology subjects

Herve, D.

Publications and source records attributed to Herve, D..

6 recordsLinked to original sources

bioRxiv2023

Operant training for highly palatable food alters translating mRNA in nucleus accumbens D2 neurons and reveals a modulatory role of Neurochondrin

BACKGROUNDHighly palatable food triggers behavioral alterations reminiscent of those induced by addictive drugs. These effects involve the reward system and dopamine neurons, which modulate neurons in the nucleus accumbens (NAc). The molecular mechanisms underlying the effects of highly palatable food on feeding behavior are poorly understood. METHODSWe studied the effects of 2-week operant conditioning of mice with standard or isocaloric highly palatable food. We investigated the behavioral effects and dendritic spine modifications in the NAc. We compared the translating mRNA in NAc neurons identified by the type of dopamine receptors they express, depending on the type of food and training. We tested the consequences of invalidation of an abundant downregulated gene, Ncdn (Neurochondrin). RESULTSOperant conditioning for highly palatable food increases motivation for food even in well-fed mice. In control mice, free access to regular or highly palatable food results in increased weight as compared to regular food only. Highly palatable food increases spine density in the NAc. In animals trained for highly palatable food, translating mRNAs are modified in NAc dopamine D2-receptor-expressing neurons, mostly corresponding to striatal projection neurons, but not in those expressing D1-receptors. Knock-out of Ncdn, an abundant down-regulated gene, opposes the conditioning-induced changes in satiety-sensitive feeding behavior and apparent motivation for highly palatable food, suggesting down-regulation may be a compensatory mechanism. CONCLUSIONSOur results emphasize the importance of mRNA alterations D2 striatal projection neurons in the NAc in the behavioral consequences of highly palatable food conditioning and suggest a modulatory contribution of Ncdn downregulation.

neuroscience↗

bioRxiv2020

Dopamine D1 receptor-expressing neurons activity is essential for locomotor and sensitizing effects of a single injection of cocaine

D1 dopamine receptors play an important role in the effects of cocaine. Here we investigated the role of neurons which express these receptors (D1-neurons) in the acute locomotor effects of cocaine and the locomotor sensitization observed after a second injection of this drug. We inhibited D1-neurons using double transgenic mice conditionally expressing the inhibitory Gi-coupled designer receptor exclusively activated by designer drugs (Gi-DREADD) in D1-neurons. Chemogenetic inhibition of D1-neurons by a low dose of clozapine (0.1 mg/kg) decreased the induction of Fos in striatal neurons. It diminished the basal locomotor activity and acute hyper-locomotion induced by cocaine (20 mg/kg). Clozapine 0.1 mg/kg had no effect by itself and did not alter cocaine effects in non-transgenic mice. Inhibition of D1-neurons during the first cocaine administration reduced the sensitization of the locomotor response in response to a second cocaine administration ten days later. At day 11, inhibition of D1-neurons by clozapine stimulation of Gi-DREADD, prevented the expression of the sensitized locomotor response, whereas at day 12, in the absence of clozapine and D1-neurons inhibition, all mice displayed a sensitized response to cocaine. These results show that chemogenetic inhibition of D1-neurons decreases spontaneous and cocaine-induced locomotor activity. It blunts the induction and prevents the expression of sensitization in a two-injection protocol of sensitization but does not alter established sensitization. Our study further supports the central role of D1-neurons in mediating the acute locomotor effects of cocaine and its sensitization.

neuroscience↗

bioRxiv2020

Long-lasting tagging of neurons activated by seizures or cocaine administration in Egr1-CreERT2 transgenic mice

Permanent tagging of neuronal ensembles activated in specific experimental situations is an important objective to study their properties and adaptations. In the context of learning and memory these neurons are referred to as engram neurons. Here we describe and characterize a novel mouse line, Egr1-CreERT2, which carries a transgene in which the promoter of the immediate early gene Egr1 drives the expression of the CreERT2 recombinase that is only active in the presence of tamoxifen metabolite, 4-hydroxy-tamoxifen (4-OHT). Egr1-CreERT2 mice were crossed with various reporter mice, Cre-dependently expressing a fluorescent protein. Without tamoxifen or 4-OHT, no or few tagged neurons were observed. Epileptic seizures induced by pilocarpine or pentylenetetrazol in the presence of tamoxifen or 4-OHT, induced the persistent tagging of many neurons and some astrocytes in the dentate gyrus of hippocampus, where Egr1 is transiently induced by seizures. One week after cocaine and 4-OHT administration, these mice displayed a higher number of tagged neurons in the dorsal striatum than saline/4-OHT controls, with differences between reporter lines. Cocaine-induced tagging required ERK activation and tagged neurons were more likely than others to exhibit ERK phosphorylation or Fos induction after a second injection. Interestingly neurons tagged in saline-treated mice also had an increased propensity to express Fos, suggesting the existence of highly responsive striatal neurons susceptible to be re-activated by cocaine repeated administration, which may contribute to the behavioral adaptations. Our report validates a novel transgenic mouse model for permanently tagging activated neurons and studying long term alterations of Egr1-expressing cells.

neuroscience↗

bioRxiv2020

Translational profiling of mouse dopaminoceptive neurons reveals a role of PGE2 in dorsal striatum

Forebrain dopaminoceptive neurons play a key role in movement, action selection, motivation, and working memory. Their activity is dysregulated in addiction, Parkinsons disease and other conditions. To characterize the diverse dopamine target neuronal populations, we compare translating mRNAs in neurons of dorsal striatum and nucleus accumbens expressing D1 or D2 dopamine receptor and prefrontal cortex expressing D1 receptor. We identify D1/D2 and striatal dorso-ventral differences in the translational and splicing landscapes, which establish the characteristics of dopaminoceptive neurons. Expression differences and network analyses identify novel transcription factors with presumptive roles in these differences. Prostaglandin E2 appears as a candidate upstream regulator in the dorsal striatum, a hypothesis supported by converging functional evidence indicating its role in enhancing D2 dopamine receptor action. Our study provides powerful resources for characterizing dopamine target neurons, new information about striatal gene expression patterns, and reveals the unforeseen role of prostaglandin E2 in the dorsal striatum.

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bioRxiv2020

Functional abnormalities in the cerebello-thalamic pathways in an animal model of dystonia

Dystonia is often associated with functional alterations in the cerebello-thalamic pathways, which have been proposed to contribute to the disorder by propagating pathological firing patterns to the forebrain. Here, we examined the function of the cerebello-thalamic pathways in a model of DYT25 dystonia, mice carrying a heterozygous invalidation of Gnal gene which notably disrupts striatal function, exhibiting dystonic movements and postures following systemic or striatal administration of oxotremorine. Theta-burst optogenetic stimulations of the cerebellar nuclei evoked a potentiation of the responses to cerebellar stimulations in the thalamus and motor cortex in WT mice, without evident motor function disruption. In contrast, theta burst stimulations evoked a depression of these responses only in dystonia-manifesting Gnal+/- mice after oxotremorine administration, decreased the disabling dystonia attacks, and increased normal active wake behaviour in Gnal+/- mice. The cerebellum could thus offer a gateway for a corrective treatment of motor impairments in dystonia including striatal dysfunction. One sentence summaryA mouse model of DYT25 dystonia, carrying a Gnal mutation disrupting striatal neurotransmission, exhibits anomalous cerebello-thalamic plasticity in the non-manifesting state, but theta-burst cerebellar stimulations during cholinergic-induced dystonia depress the cerebello-thalamic transmission and reduce the severity of the motor symptoms.

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bioRxiv2019

fMRI detects bilateral brain network activation following unilateral chemogenetic activation of direct striatal projection neurons

Although abnormal structural and functional connectivity in the striatum during neurological disorders has been reported using functional magnetic resonance imaging (fMRI), the effects of cell-type specific neuronal stimulation on fMRI and related behavioral alterations are not well understood. In this study, we successfully combined DREADD-technology with fMRI (chemo-fMRI) to investigate the alterations of spontaneous neuronal activity induced by the unilateral activation of dopamine D1 receptor-expressing neurons (D1-neurons) in the mouse dorsal striatum (DS). We compared the effects of two different DREADD ligands, clozapine (CLZ) and clozapine-N-oxide (CNO), on behavior and fMRI. We found that the effects of CLZ on behavior were more rapid than those of CNO. In fMRI, both systemic CLZ and CNO administrations, which evoked unilateral activations of D1-neurons in DS, increased the fractional amplitude of low frequency fluctuations (fALFF) in the thalamus and bilateral cortex. In addition, we found the increased gamma-band of local field potentials in DS and bilateral cortex after CLZ-evoked unilateral activation of D1-neuron in the striatum. These results provide bases for better interpretation of cell type-specific activity changes in fMRI.

neuroscience↗