Publications by authors named "Hervé Denis"

67 Publications

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

Eur J Neurosci 2021 Mar 7;53(5):1450-1472. Epub 2020 Dec 7.

Inserm UMR-S 1270, Paris, France.

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-CreER , which carries a transgene in which the promoter of the immediate early gene Egr1 drives the expression of the CreER recombinase that is only active in the presence of tamoxifen metabolite, 4-hydroxy-tamoxifen (4-OHT). Egr1-CreER 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 elicited 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.
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http://dx.doi.org/10.1111/ejn.15060DOI Listing
March 2021

Sedimentological and geochemical data in bed sediments from a tropical river-estuary system impacted by a developing megacity, Ho Chi Minh City - Vietnam.

Data Brief 2020 Aug 27;31:105938. Epub 2020 Jun 27.

CARE, Ho Chi Minh City University of Technology, VNU-HCM, Viet Nam.

Sedimentological and geochemical data were obtained for bed sediments from a tropical estuary environment in Vietnam in October 2014, January 2016, and November 2016. The data include grain-size distribution, percentage of clay, silt and sand, percentage of organic matter, concentration of total particulate phosphorus (TPP), concentration of particulate inorganic phosphorus (PIP), concentration of particulate organic phosphorus (POP), percentage of total nitrogen (TN), percentage of total carbon (TC), trace metals concentrations (V, Cr, Co, Ni, Cu, Zn, As, Mo, Cd, Pb) and major elements (Al, Fe, Mn). Geochemical indexes (Enrichment factor EF and Geo-accumulation Index I-geo) and sediment quality guideline (mean Effect Range Median quotients) were calculated.
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http://dx.doi.org/10.1016/j.dib.2020.105938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339034PMC
August 2020

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

Neuroimage 2020 10 23;220:117079. Epub 2020 Jun 23.

NeuroSpin, Commissariat à l'énergie Atomique et Aux énergies Alternatives, 91191, Gif-sur-Yvette, France; Human Informatics and Interaction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, 305-8568, Japan. Electronic address:

Abnormal structural and functional connectivity in the striatum during neurological disorders has been reported using functional magnetic resonance imaging (fMRI), although the effects of cell-type specific neuronal stimulation on fMRI and related behavioral alterations are not well understood. In this study, we combined DREADD technology with fMRI ("chemo-fMRI") to investigate alterations of spontaneous neuronal activity. These were induced by the unilateral activation of dopamine D1 receptor-expressing neurons (D1-neurons) in the mouse dorsal striatum (DS). After clozapine (CLZ) stimulation of the excitatory DREADD expressed in D1-neurons, the fractional amplitude of low frequency fluctuations (fALFF) increased bilaterally in the medial thalamus, nucleus accumbens and cortex. In addition, we found that the gamma-band of local field potentials was increased in the stimulated DS and cortex bilaterally. These results provide insights for better interpretation of cell type-specific activity changes in fMRI.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117079DOI Listing
October 2020

Astrocytic BDNF and TrkB regulate severity and neuronal activity in mouse models of temporal lobe epilepsy.

Cell Death Dis 2020 06 1;11(6):411. Epub 2020 Jun 1.

Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, 08036, Barcelona, Spain.

Astrocytes have emerged as crucial regulators of neuronal network activity, synapse formation, and underlying behavioral and cognitive processes. Despite some pathways have been identified, the communication between astrocytes and neurons remains to be completely elucidated. Unraveling this communication is crucial to design potential treatments for neurological disorders like temporal lobe epilepsy (TLE). The BDNF and TrkB molecules have emerged as very promising therapeutic targets. However, their modulation can be accompanied by several off-target effects such as excitotoxicity in case of uncontrolled upregulation or dementia, amnesia, and other memory disorders in case of downregulation. Here, we show that BDNF and TrkB from astrocytes modulate neuronal dysfunction in TLE models. First, conditional overexpression of BDNF from astrocytes worsened the phenotype in the lithium-pilocarpine mouse model. Our evidences pointed out to the astrocytic pro-BDNF isoform as a major player of this altered phenotype. Conversely, specific genetic deletion of BDNF in astrocytes prevented the increase in the number of firing neurons and the global firing rate in an in vitro model of TLE. Regarding to the TrkB, we generated mice with a genetic deletion of TrkB specifically in hippocampal neurons or astrocytes. Interestingly, both lines displayed neuroprotection in the lithium-pilocarpine model but only the mice with genetic deletion of TrkB in astrocytes showed significantly preserved spatial learning skills. These data identify the astrocytic BDNF and TrkB molecules as promising therapeutic targets for the treatment of TLE.
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http://dx.doi.org/10.1038/s41419-020-2615-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264221PMC
June 2020

Differential enhancement of ERK, PKA and Ca signaling in direct and indirect striatal neurons of Parkinsonian mice.

Neurobiol Dis 2019 10 17;130:104506. Epub 2019 Jun 17.

Inserm UMR-S 1270, Paris, France; Sorbonne Université, Science and Engineering Faculty, Paris, France; Institut du Fer à Moulin, Paris, France. Electronic address:

Parkinson's disease (PD) is characterized by severe locomotor deficits due to the disappearance of dopamine (DA) from the dorsal striatum. The development of PD symptoms and treatment-related complications such as dyskinesia have been proposed to result from complex alterations in intracellular signaling in both direct and indirect pathway striatal projection neurons (dSPNs and iSPNs, respectively) following loss of DA afferents. To identify cell-specific and dynamical modifications of signaling pathways associated with PD, we used a hemiparkinsonian mouse model with 6-hydroxydopamine (6-OHDA) lesion combined with two-photon fluorescence biosensors imaging in adult corticostriatal slices. After DA lesion, extracellular signal-regulated kinase (ERK) activation was increased in response to DA D1 receptor (D1R) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) stimulation. The cAMP-dependent protein kinase (PKA) pathway contributing to ERK activation displayed supersensitive responses to D1R stimulation after 6-OHDA lesion. This cAMP/PKA supersensitivity was specific of D1R-responding SPNs and resulted from Gα upregulation and deficient phosphodiesterase activity. In lesioned striatum, the number of D1R-SPNs with spontaneous Ca transients augmented while Ca response to AMPA receptor stimulation specifically increased in iSPNs. Our work reveals distinct cell type-specific signaling alterations in the striatum after DA denervation. It suggests that over-activation of ERK pathway, observed in PD striatum, known to contribute to dyskinesia, may be linked to the combined dysregulation of DA and glutamate signaling pathways in the two populations of SPNs. These findings bring new insights into the implication of these respective neuronal populations in PD motor symptoms and the occurrence of PD treatment complications.
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http://dx.doi.org/10.1016/j.nbd.2019.104506DOI Listing
October 2019

Cocaine conditioned place preference: unexpected suppression of preference due to testing combined with strong conditioning.

Addict Biol 2019 05 10;24(3):364-375. Epub 2018 Jan 10.

Inserm UMR-S839, France.

Conditioned place preference (CPP) is widely used for evaluating the rewarding effects of drugs. Like other memories, CPP is proposed to undergo reconsolidation during which it is unstable and sensitive to pharmacological inhibition. Previous studies have shown that cocaine CPP can be apparently erased by extracellular signal-regulated kinase (ERK) pathway inhibition during cocaine reconditioning (re-exposure to the drug-paired environment in the presence of the drug). Here, we show that blockade of D1 receptors during reconditioning prevented ERK activation and induced a loss of CPP. However, we also unexpectedly observed a CPP disappearance in mice that underwent testing and reconditioning with cocaine alone, specifically in strong conditioning conditions. The loss was due to the intermediate test. CPP was not recovered with reconditioning or priming in the short term, but it spontaneously reappeared after a month. When we challenged the D1 antagonist-mediated erasure, we observed that both a high dose of cocaine and a first CPP test were required for this effect. Our results also suggest a balance between D1-dependent ERK pathway activation and an A2a-dependent mechanism in D2 striatal neurons in controlling CPP expression. Our data reveal that, paradoxically, a simple CPP test can induce a complete (but transient) loss of place preference following strong but not weak cocaine conditioning. This study emphasizes the complex nature of CPP memory and the importance of multiple parameters that must be taken into consideration when investigating reconsolidation.
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http://dx.doi.org/10.1111/adb.12600DOI Listing
May 2019

Serotonin 2B Receptors in Mesoaccumbens Dopamine Pathway Regulate Cocaine Responses.

J Neurosci 2017 10 21;37(43):10372-10388. Epub 2017 Sep 21.

Institut national de la santé et de la recherche médicale, Unité Mixte de Recherche-S839, F-75005 Paris, France,

Addiction is a maladaptive pattern of behavior following repeated use of reinforcing drugs in predisposed individuals, leading to lifelong changes. Common among these changes are alterations of neurons releasing dopamine in the ventral and dorsal territories of the striatum. The serotonin 5-HT receptor has been involved in various behaviors, including impulsivity, response to antidepressants, and response to psychostimulants, pointing toward putative interactions with the dopamine system. Despite these findings, it remains unknown whether 5-HT receptors directly modulate dopaminergic activity and the possible mechanisms involved. To answer these questions, we investigated the contribution of 5-HT receptors to cocaine-dependent behavioral responses. Male mice permanently lacking 5-HT receptors, even restricted to dopamine neurons, developed heightened cocaine-induced locomotor responses. Retrograde tracing combined with single-cell mRNA amplification indicated that 5-HT receptors are expressed by mesolimbic dopamine neurons. and electrophysiological recordings showed that 5-HT-receptor inactivation in dopamine neurons affects their neuronal activity and increases AMPA-mediated over NMDA-mediated excitatory synaptic currents. These changes are associated with lower ventral striatum dopamine activity and blunted cocaine self-administration. These data identify the 5-HT receptor as a pharmacological intermediate and provide mechanistic insight into attenuated dopamine tone following exposure to drugs of abuse. Here we report that mice lacking 5-HT receptors totally or exclusively in dopamine neurons exhibit heightened cocaine-induced locomotor responses. Despite the sensitized state of these mice, we found that associated changes include lower ventral striatum dopamine activity and lower cocaine operant self-administration. We described the selective expression of 5-HT receptors in a subpopulation of dopamine neurons sending axons to the ventral striatum. Increased bursting properties of these dopamine neurons and a concomitant increase in AMPA synaptic transmission to dopamine neurons were found in mice lacking 5-HT receptors. These data support the idea that the chronic 5-HT-receptor inhibition makes mice behave like animals already exposed to cocaine with higher cocaine-induced locomotion associated with changes in dopamine neuron reactivity.
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http://dx.doi.org/10.1523/JNEUROSCI.1354-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596631PMC
October 2017

The BEACH Protein LRBA Promotes the Localization of the Heterotrimeric G-protein G to Olfactory Cilia.

Sci Rep 2017 08 16;7(1):8409. Epub 2017 Aug 16.

Department of Neuroscience, Uppsala University, S-75124, Uppsala, Sweden.

BEACH domain proteins are involved in membrane protein traffic and human diseases, but their molecular mechanisms are not understood. The BEACH protein LRBA has been implicated in immune response and cell proliferation, and human LRBA mutations cause severe immune deficiency. Here, we report a first functional and molecular phenotype outside the immune system of LRBA-knockout mice: compromised olfaction, manifesting in reduced electro-olfactogram response amplitude, impaired food-finding efficiency, and smaller olfactory bulbs. LRBA is prominently expressed in olfactory and vomeronasal chemosensory neurons of wild-type mice. Olfactory impairment in the LRBA-KO is explained by markedly reduced concentrations (20-40% of wild-type levels) of all three subunits α, β and γ of the olfactory heterotrimeric G-protein, G, in the sensory cilia of olfactory neurons. In contrast, cilia morphology and the concentrations of many other proteins of olfactory cilia are not or only slightly affected. LRBA is also highly expressed in photoreceptor cells, another cell type with a specialized sensory cilium and heterotrimeric G-protein-based signalling; however, visual function appeared unimpaired by the LRBA-KO. To our knowledge, this is the first observation that a BEACH protein is required for the efficient subcellular localization of a lipid-anchored protein, and of a ciliary protein.
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http://dx.doi.org/10.1038/s41598-017-08543-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559528PMC
August 2017

Heterozygous Gnal Mice Are a Novel Animal Model with Which to Study Dystonia Pathophysiology.

J Neurosci 2017 06 25;37(26):6253-6267. Epub 2017 May 25.

Inserm Unité Mixte de Recherche Scientifique 839, F-75005 Paris, France,

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions and its pathophysiological mechanisms are still poorly understood. Dominant mutations of the gene are a cause of isolated dystonia (DYT25) in patients. Some mutations result in a complete loss of function of the encoded protein, Gα, an adenylyl-cyclase-stimulatory G-protein highly enriched in striatal projection neurons, where it mediates the actions of dopamine and adenosine. We used male and female heterozygous knock-out mice () to study how haplodeficiency is implicated in dystonia. In basal conditions, no overt dystonic movements or postures or change in locomotor activity were observed. However, Gnal haploinsufficiency altered self-grooming, motor coordination, and apparent motivation in operant conditioning, as well as spine morphology and phospho-CaMKIIβ in the striatum. After systemic administration of oxotremorine, an unselective cholinergic agonist, mice developed more abnormal postures and movements than WT mice. These effects were not caused by seizures as indicated by EEG recordings. They were prevented by the M1-preferring muscarinic antagonists, telenzepine, pirenzepine, and trihexyphenidyl, which alleviate dystonic symptoms in patients. The motor defects were worsened by mecamylamine, a selective nicotinic antagonist. These oxotremorine-induced abnormalities in mice were replicated by oxotremorine infusion into the striatum, but not into the cerebellum, indicating that defects in striatal neurons favor the appearance of dystonia-like movement alterations after oxotremorine. Untreated and oxotremorine-treated mice provide a model of presymptomic and symptomatic stages of DYT25-associated dystonia, respectively, and clues about the mechanisms underlying dystonia pathogenesis. Adult-onset dystonia DYT25 is caused by dominant loss-of-function mutations of GNAL, a gene encoding the stimulatory G-protein Gαolf, which is critical for activation of the cAMP pathway in the striatal projection neurons. Here, we demonstrate that -haplodeficient mice have a mild neurological phenotype and display vulnerability to developing dystonic movements after systemic or intrastriatal injection of the cholinergic agonist oxotremorine. Therefore, impairment of the cAMP pathway in association with an increased cholinergic tone creates alterations in striatal neuron functions that can promote the onset of dystonia. Our results also provide evidence that untreated and oxotremorine-treated -haplodeficient mice are powerful models with which to study presymptomic and symptomatic stages of DYT25-associated dystonia, respectively.
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http://dx.doi.org/10.1523/JNEUROSCI.1529-16.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705700PMC
June 2017

Spatial variation and risk assessment of trace metals in water and sediment of the Mekong Delta.

Chemosphere 2017 Jul 27;179:367-378. Epub 2017 Mar 27.

Faculty of Environment, HCMUT, Ho Chi Minh City, Viet Nam.

The Mekong Delta, is home to 17 million inhabitants and faces numerous challenges relating to climate change, environmental degradation and water issues. In this study, we assess trace metals concentrations (Al, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Mo, Cd, Hg, Pb) in the water, suspended particulate matter and surface sediments of the Tien River, the Northern branch of the Mekong Delta, during both dry and rainy seasons. Metal concentrations in the dissolved and suspended particle phases remain in the low concentration range of the main Asian Tropical River. During transportation in the riverine part, we evidenced that V, Cr, Co, As and Pb are dominant in the particulate phase while Mo, Ni and Cu dominate in the dissolved fraction. In the salinity gradient, dissolved U, V, Mo exhibit conservative behaviour while Ni, Cu, As, Co and Cd showed additive behaviour suggesting desorption processes. In the surface sediment, metal concentrations are controlled by the particle-size, POC contents and Fe, Al and Mn - oxy(hydr)oxides. Calculated Enrichment Factor and Geoaccumulation Index evidenced As enrichment while the calculated mean effect range median quotients evidenced a low to medium ecotoxicological potential effects range in the surface sediments.
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http://dx.doi.org/10.1016/j.chemosphere.2017.03.105DOI Listing
July 2017

Baseline seasonal investigation of nutrients and trace metals in surface waters and sediments along the Saigon River basin impacted by the megacity of Ho Chi Minh (Vietnam).

Environ Sci Pollut Res Int 2017 Feb 10;24(4):3226-3243. Epub 2016 Oct 10.

Faculty of Environment, HCMUT, Ho Chi Minh City, Vietnam.

The Saigon River, Southern Vietnam, crosses one of the most dynamic developing Megacity in Southeast Asia: Ho Chi Minh City (HCMC). The increased economic, industrial, and domestic developments may affect the environmental quality of water and halieutic resources. In this study, we evaluated the seasonal (dry and wet seasons) biogeochemical state of the Saigon River during two snapshot campaigns conducted along the river basin upstream from HCMC; the Saigon River was characterized by slightly acidic (pH 5.7-7.7) and oxygen-depleted water (dissolved oxygen (DO), 0.36-5.18 mg l). Nutrients (N-NH = 0.01-2.41, N-NO = 0.14-2.72, and P-PO = ~0-0.42 mg l), DOC (2.2-8.0 mg l), POC, and trace metal(oid) (As, Cd, Cr, Cu, Zn, and Hg) concentrations were low showing a good quality of the upstream river. In the urban center area, DO dropped to 0.03 mg l accompanied with a rise of nutrient concentrations (e.g., N-NH, up to 17.7 mg l) likely originating from wastewater discharges. Trace metal concentrations also rose sharply (e.g., Cr and Hg rose up to 10-fold higher) in both water and sediments but remained under the World Health Organization (WHO) and Vietnamese concentration guidelines. In the downstream estuarine area, the intrusion of marine waters diluted water flowing from HCMC, leading water quality to return close to the state observed upstream from HCMC. In general, levels of nutrient and metal contaminations along the Saigon River during both seasons appear moderate regarding to Vietnamese and WHO guidelines although the urban area is highlighted as the major contributor for metal(oid) emissions. Finally, we showed that apart from wastewater and industrial discharges that affect the river quality, metal(oid) partitioning between solid and solution is controlled by the change in water geochemistry along the continuum during both seasons, such as DO (e.g., for As and Cr) and pH (e.g., for Pb) which drives their sorption/dissolution dynamics.
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http://dx.doi.org/10.1007/s11356-016-7660-7DOI Listing
February 2017

Anatomical and molecular characterization of dopamine D1 receptor-expressing neurons of the mouse CA1 dorsal hippocampus.

Brain Struct Funct 2017 May 27;222(4):1897-1911. Epub 2016 Sep 27.

CNRS UMR 5203, Institut de Génomique Fonctionnelle, 141 rue de la Cardonille, 34094, Montpellier Cedex 05, France.

In the hippocampus, a functional role of dopamine D1 receptors (D1R) in synaptic plasticity and memory processes has been suggested by electrophysiological and pharmacological studies. However, comprehension of their function remains elusive due to the lack of knowledge on the precise localization of D1R expression among the diversity of interneuron populations. Using BAC transgenic mice expressing enhanced green fluorescent protein under the control of D1R promoter, we examined the molecular identity of D1R-containing neurons within the CA1 subfield of the dorsal hippocampus. In agreement with previous findings, our analysis revealed that these neurons are essentially GABAergic interneurons, which express several neurochemical markers, including calcium-binding proteins, neuropeptides, and receptors among others. Finally, by using different tools comprising cell type-specific isolation of mRNAs bound to tagged-ribosomes, we provide solid data indicating that D1R is present in a large proportion of interneurons expressing dopamine D2 receptors. Altogether, our study indicates that D1Rs are expressed by different classes of interneurons in all layers examined and not by pyramidal cells, suggesting that CA1 D1R mostly acts via modulation of GABAergic interneurons.
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http://dx.doi.org/10.1007/s00429-016-1314-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5406422PMC
May 2017

Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice.

Nat Med 2016 Mar 25;22(3):254-61. Epub 2016 Jan 25.

Institut du Fer à Moulin, Paris, France.

The lateral habenula (LHb) encodes aversive signals, and its aberrant activity contributes to depression-like symptoms. However, a limited understanding of the cellular mechanisms underlying LHb hyperactivity has precluded the development of pharmacological strategies to ameliorate depression-like phenotypes. Here we report that an aversive experience in mice, such as foot-shock exposure (FsE), induces LHb neuronal hyperactivity and depression-like symptoms. This occurs along with increased protein phosphatase 2A (PP2A) activity, a known regulator of GABAB receptor (GABABR) and G protein-gated inwardly rectifying potassium (GIRK) channel surface expression. Accordingly, FsE triggers GABAB1 and GIRK2 internalization, leading to rapid and persistent weakening of GABAB-activated GIRK-mediated (GABAB-GIRK) currents. Pharmacological inhibition of PP2A restores both GABAB-GIRK function and neuronal excitability. As a consequence, PP2A inhibition ameliorates depression-like symptoms after FsE and in a learned-helplessness model of depression. Thus, GABAB-GIRK plasticity in the LHb represents a cellular substrate for aversive experience. Furthermore, its reversal by PP2A inhibition may provide a novel therapeutic approach to alleviate symptoms of depression in disorders that are characterized by LHb hyperactivity.
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http://dx.doi.org/10.1038/nm.4037DOI Listing
March 2016

DARPP-32 interaction with adducin may mediate rapid environmental effects on striatal neurons.

Nat Commun 2015 Dec 7;6:10099. Epub 2015 Dec 7.

Inserm UMR-S 839, Paris 75005, France.

Environmental enrichment has multiple effects on behaviour, including modification of responses to psychostimulant drugs mediated by striatal neurons. However, the underlying molecular and cellular mechanisms are not known. Here we show that DARPP-32, a hub signalling protein in striatal neurons, interacts with adducins, which are cytoskeletal proteins that cap actin filaments' fast-growing ends and regulate synaptic stability. DARPP-32 binds to adducin MARCKS domain and this interaction is modulated by DARPP-32 Ser97 phosphorylation. Phospho-Thr75-DARPP-32 facilitates β-adducin Ser713 phosphorylation through inhibition of a cAMP-dependent protein kinase/phosphatase-2A cascade. Caffeine or 24-h exposure to a novel enriched environment increases adducin phosphorylation in WT, but not T75A mutant mice. This cascade is implicated in the effects of brief exposure to novel enriched environment on dendritic spines in nucleus accumbens and cocaine locomotor response. Our results suggest a molecular pathway by which environmental changes may rapidly alter responsiveness of striatal neurons involved in the reward system.
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http://dx.doi.org/10.1038/ncomms10099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675091PMC
December 2015

Selective Effects of PDE10A Inhibitors on Striatopallidal Neurons Require Phosphatase Inhibition by DARPP-32

eNeuro 2015 Jul-Aug;2(4). Epub 2015 Aug 31.

CNRS, UMR8256 "Biological Adaptation and Ageing", Institut de Biologie Paris-Seine (IBPS) , F-75005 Paris, France ; Université Pierre et Marie Curie (UPMC, Paris 6), Sorbonne Universités , Paris, F-75005, France.

Type 10A phosphodiesterase (PDE10A) is highly expressed in the striatum, in striatonigral and striatopallidal medium-sized spiny neurons (MSNs), which express D1 and D2 dopamine receptors, respectively. PDE10A inhibitors have pharmacological and behavioral effects suggesting an antipsychotic profile, but the cellular bases of these effects are unclear. We analyzed the effects of PDE10A inhibition in vivo by immunohistochemistry, and imaged cAMP, cAMP-dependent protein kinase A (PKA), and cGMP signals with biosensors in mouse brain slices. PDE10A inhibition in mouse striatal slices produced a steady-state increase in intracellular cAMP concentration in D1 and D2 MSNs, demonstrating that PDE10A regulates basal cAMP levels. Surprisingly, the PKA-dependent AKAR3 phosphorylation signal was strong in D2 MSNs, whereas D1 MSNs remained unresponsive. This effect was also observed in adult mice in vivo since PDE10A inhibition increased phospho-histone H3 immunoreactivity selectively in D2 MSNs in the dorsomedial striatum. The PKA-dependent effects in D2 MSNs were prevented in brain slices and in vivo by mutation of the PKA-regulated phosphorylation site of 32 kDa dopamine- and cAMP-regulated phosphoprotein (DARPP-32), which is required for protein phosphatase-1 inhibition. These data highlight differences in the integration of the cAMP signal in D1 and D2 MSNs, resulting from stronger inhibition of protein phosphatase-1 by DARPP-32 in D2 MSNs than in D1 MSNs. This study shows that PDE10A inhibitors share with antipsychotic medications the property of activating preferentially PKA-dependent signaling in D2 MSNs.
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http://dx.doi.org/10.1523/ENEURO.0060-15.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596023PMC
October 2015

Unilateral Lesion of Dopamine Neurons Induces Grooming Asymmetry in the Mouse.

PLoS One 2015 23;10(9):e0137185. Epub 2015 Sep 23.

Inserm UMR-S 839, 75005, Paris, France; Institut du Fer à Moulin, 75005, Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (UPMC, Paris-6), Paris, France.

Grooming behaviour is the most common innate behaviour in animals. In rodents, it consists of sequences of movements organized in four phases, executed symmetrically on both sides of the animal and creating a syntactic chain of behavioural events. The grooming syntax can be altered by stress and novelty, as well as by several mutations and brain lesions. Grooming behaviour is known to be affected by alterations of the dopamine system, including dopamine receptor modulation, dopamine alteration in genetically modified animals, and after brain lesion. While a lot is known about the initiation and syntactic modifications of this refined sequence of movements, effects of unilateral lesion of dopamine neurons are unclear particularly regarding the symmetry of syntactic chains. In the present work we studied grooming in mice unilaterally lesioned in the medial forebrain bundle by 6-hydroxydopamine. We found a reduction in completion of grooming bouts, associated with reduction in number of transitions between grooming phases. The data also revealed the development of asymmetry in grooming behaviour, with reduced tendency to groom the contralateral side to the lesion. Symmetry was recovered following treatment with L-DOPA. Thus, the present work shows that unilateral lesion of dopamine neurons reduces self-grooming behaviour by affecting duration and numbers of events. It produces premature discontinuation of grooming chains but the sequence syntax remains correct. This deficient grooming could be considered as an intrinsic symptom of Parkinson's disease in animal models and could present some similarities with abnormalities of motor movement sequencing seen in patients. Our study also suggests grooming analysis as an additional method to screen parkinsonism in animal models.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137185PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580614PMC
May 2016

PKA-dependent phosphorylation of ribosomal protein S6 does not correlate with translation efficiency in striatonigral and striatopallidal medium-sized spiny neurons.

J Neurosci 2015 Mar;35(10):4113-30

Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5203, Institut de Génomique Fonctionnelle, Montpellier, F-34094, France, INSERM, U1191, Montpellier, F-34094, France; Université de Montpellier, Montpellier, F-34094, France,

Ribosomal protein S6 (rpS6), a component of the 40S ribosomal subunit, is phosphorylated on several residues in response to numerous stimuli. Although commonly used as a marker for neuronal activity, its upstream mechanisms of regulation are poorly studied and its role in protein synthesis remains largely debated. Here, we demonstrate that the psychostimulant d-amphetamine (d-amph) markedly increases rpS6 phosphorylation at Ser235/236 sites in both crude and synaptoneurosomal preparations of the mouse striatum. This effect occurs selectively in D1R-expressing medium-sized spiny neurons (MSNs) and requires the cAMP/PKA/DARPP-32/PP-1 cascade, whereas it is independent of mTORC1/p70S6K, PKC, and ERK signaling. By developing a novel assay to label nascent peptidic chains, we show that the rpS6 phosphorylation induced in striatonigral MSNs by d-amph, as well as in striatopallidal MSNs by the antipsychotic haloperidol or in both subtypes by papaverine, is not correlated with the translation of global or 5' terminal oligopyrimidine tract mRNAs. Together, these results provide novel mechanistic insights into the in vivo regulation of the post-translational modification of rpS6 in the striatum and point out the lack of a relationship between PKA-dependent rpS6 phosphorylation and translation efficiency.
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http://dx.doi.org/10.1523/JNEUROSCI.3288-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605295PMC
March 2015

Gene expression analyses identify Narp contribution in the development of L-DOPA-induced dyskinesia.

J Neurosci 2015 Jan;35(1):96-111

Sorbonne Universités, UPMC Univ Paris 06, Paris, France, Inserm, UMR-S 1127, ICM, Pitié-Salpêtrière Hospital, 75013 Paris, France, CNRS, UMR 7225, 75013 Paris, France, Assistance Publique Hôpitaux de Paris, Inserm, Clinical Investigation Center, CIC-1422, Pitié-Salpêtrière Hospital, 75013 Paris, France

In Parkinson's disease, long-term dopamine replacement therapy is complicated by the appearance of L-DOPA-induced dyskinesia (LID). One major hypothesis is that LID results from an aberrant transcriptional program in striatal neurons induced by L-DOPA and triggered by the activation of ERK. To identify these genes, we performed transcriptome analyses in the striatum in 6-hydroxydopamine-lesioned mice. A time course analysis (0-6 h after treatment with L-DOPA) identified an acute signature of 709 genes, among which genes involved in protein phosphatase activity were overrepresented, suggesting a negative feedback on ERK activation by l-DOPA. l-DOPA-dependent deregulation of 28 genes was blocked by pretreatment with SL327, an inhibitor of ERK activation, and 26 genes were found differentially expressed between highly and weakly dyskinetic animals after treatment with L-DOPA. The intersection list identified five genes: FosB, Th, Nptx2, Nedd4l, and Ccrn4l. Nptx2 encodes neuronal pentraxin II (or neuronal activity-regulated pentraxin, Narp), which is involved in the clustering of glutamate receptors. We confirmed increased Nptx2 expression after L-DOPA and its blockade by SL327 using quantitative RT-PCR in independent experiments. Using an escalating L-DOPA dose protocol, LID severity was decreased in Narp knock-out mice compared with their wild-type littermates or after overexpression of a dominant-negative form of Narp in the striatum. In conclusion, we have identified a molecular signature induced by L-DOPA in the dopamine-denervated striatum that is dependent on ERK and associated with LID. Here, we demonstrate the implication of one of these genes, Nptx2, in the development of LID.
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http://dx.doi.org/10.1523/JNEUROSCI.5231-13.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605247PMC
January 2015

Mitogen- and stress-activated protein kinase 1 is required for specific signaling responses in dopamine-denervated mouse striatum, but is not necessary for L-DOPA-induced dyskinesia.

Neurosci Lett 2014 Nov 16;583:76-80. Epub 2014 Sep 16.

Inserm UMR-S 839, Paris, France; Université Pierre et Marie Curie (UPMC), Sorbonne Universités, Paris, France; Institut du Fer à Moulin, Paris, France. Electronic address:

In advanced Parkinson's disease, l-DOPA treatment causes the appearance of abnormal involuntary movements or l-DOPA-induced dyskinesia (LID). LID results in part from l-DOPA-induced activation of extracellular signal-regulated kinase (ERK) in the dopamine-denervated striatum. Activated ERK triggers nuclear responses, including phosphorylation of mitogen- and stress-activated protein kinase 1 (MSK1) and histone H3, and transcription of genes such as FosB. To determine the role of MSK1, wild type and MSK1 knockout mice with unilateral 6-hydroxydopamine lesion in the dorsolateral striatum were chronically treated with l-DOPA. The absence of MSK1 had no effect on the lesion or l-DOPA-induced ERK activation, but reduced l-DOPA-induced phosphorylation of histone H3 and FosB accumulation in the dopamine-denervated striatum. MSK1 deficiency also prevented the increase in Gαolf, the stimulatory α subunit of G protein coupling striatal dopamine D1 receptor to adenylyl cyclase. However, the intensity of LID was similar in MSK1-deficient and wild type mice. In conclusion, l-DOPA-induced activation of MSK1 contributes to histone H3 phosphorylation, induction of FosB, and Gαolf up-regulation but appears not to be necessary for the development of LID.
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http://dx.doi.org/10.1016/j.neulet.2014.09.018DOI Listing
November 2014

Fluorescence-activated sorting of fixed nuclei: a general method for studying nuclei from specific cell populations that preserves post-translational modifications.

Eur J Neurosci 2014 Apr;39(7):1234-44

Inserm UMR-S 839, Paris, France; Université Pierre & Marie Curie, Sorbonne Universités, Paris, France; Institut du Fer à Moulin, Paris, France.

Long-lasting brain alterations that underlie learning and memory are triggered by synaptic activity. How activity can exert long-lasting effects on neurons is a major question in neuroscience. Signalling pathways from cytoplasm to nucleus and the resulting changes in transcription and epigenetic modifications are particularly relevant in this context. However, a major difficulty in their study comes from the cellular heterogeneity of brain tissue. A promising approach is to directly purify identified nuclei. Using mouse striatum we have developed a rapid and efficient method for isolating cell type-specific nuclei from fixed adult brain (fluorescence-activated sorting of fixed nuclei; FAST-FIN). Animals are quickly perfused with a formaldehyde fixative that stops enzymatic reactions and maintains the tissue in the state it was at the time of death, including nuclear localisation of soluble proteins such as GFP and differences in nuclear size between cell types. Tissue is subsequently dissociated with a Dounce homogeniser and nuclei prepared by centrifugation in an iodixanol density gradient. The purified fixed nuclei can then be immunostained with specific antibodies and analysed or sorted by flow cytometry. Simple criteria allow distinction of neurons and non-neuronal cells. Immunolabelling and transgenic mice that express fluorescent proteins can be used to identify specific cell populations, and the nuclei from these populations can be efficiently isolated, even rare cell types such as parvalbumin-expressing interneurons. FAST-FIN allows the preservation and study of dynamic and labile post-translational protein modifications. It should be applicable to other tissues and species, and allow study of DNA and its modifications.
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http://dx.doi.org/10.1111/ejn.12506DOI Listing
April 2014

Role of the plasticity-associated transcription factor zif268 in the early phase of instrumental learning.

PLoS One 2014 23;9(1):e81868. Epub 2014 Jan 23.

Inserm UMR-S 839, Paris, France ; Université Pierre et Marie Curie, Paris, France ; Institut du Fer à Moulin, Paris, France.

Gene transcription is essential for learning, but the precise role of transcription factors that control expression of many other genes in specific learning paradigms is yet poorly understood. Zif268 (Krox24/Egr-1) is a transcription factor and an immediate-early gene associated with memory consolidation and reconsolidation, and induced in the striatum after addictive drugs exposure. In contrast, very little is known about its physiological role at early stages of operant learning. We investigated the role of Zif268 in operant conditioning for food. Zif268 expression was increased in all regions of the dorsal striatum and nucleus accumbens in mice subjected to the first session of operant conditioning. In contrast, Zif268 increase in the dorsomedial caudate-putamen and nucleus accumbens core was not detected in yoked mice passively receiving the food reward. This indicates that Zif268 induction in these structures is linked to experiencing or learning contingency, but not to reward delivery. When the task was learned (5 sessions), Zif268 induction disappeared in the nucleus accumbens and decreased in the medial caudate-putamen, whereas it remained high in the lateral caudate-putamen, previously implicated in habit formation. In transgenic mice expressing green fluorescent protein (GFP) in the striatonigral neurons, Zif268 induction occured after the first training session in both GFP-positive and negative neurons indicating an enhanced Zif268 expression in both striatonigral and striatopallidal neurons. Mutant mice lacking Zif268 expression obtained less rewards, but displayed a normal discrimination between reinforced and non-reinforced targets, and an unaltered approach to food delivery box. In addition, their motivation to obtain food rewards, evaluated in a progressive ratio schedule, was blunted. In conclusion, Zif268 participates in the processes underlying performance and motivation to execute food-conditioned instrumental task.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081868PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3900405PMC
November 2014

Haloperidol-induced Nur77 expression in striatopallidal neurons is under the control of protein phosphatase 1 regulation by DARPP-32.

Neuropharmacology 2014 Apr 15;79:559-66. Epub 2014 Jan 15.

Inserm, UMR-S 839, Paris, France; Université Pierre et Marie Curie (UPMC), Paris, France; Institut du Fer à Moulin, Paris, France. Electronic address:

Impaired dopaminergic signaling in the striatum is involved in diseases as diverse as Parkinson's disease, addiction, and schizophrenia. An important pathophysiological aspect is the loss of balance between striatopallidal and striatonigral pathways. Nur77 is an orphan nuclear receptor and dopamine-regulated immediate-early gene. Classical antipsychotic drugs widely used in the treatment of schizophrenia, such as haloperidol, increase Nur77 mRNA expression in the striatum. However, little is known about the intracellular signaling pathways involved in Nur77 induction. Here, using pharmacological approaches and transgenic mutant mice, we investigated the mechanisms underlying the up-regulation of Nur77 protein expression in the dorsal striatum after haloperidol injection. In drd1a::EGFP transgenic mice that express GFP in D1 neurons, Nur77 up-regulation induced by haloperidol occurred predominantly in GFP-negative neurons. In Gαolf heterozygous mutant mice, in which cAMP production in response to A2A stimulation is impaired in the striatum, haloperidol effect was not altered. In contrast, in DARPP-32 knock-in mutant mice bearing a T34A point mutation of the site responsible for cAMP-dependent phosphatase 1 inhibition, Nur77 up-regulation by haloperidol was prevented. Haloperidol also induced Nur77 protein in D2 neurons of the nucleus accumbens core of wild type but not T34A knock-in mice. Thus, our results show that expression of Nur77 is induced by haloperidol in D2 receptors-expressing medium-sized spiny neurons, through cAMP-dependent regulation of protein phosphatase 1, which is likely to modulate the effects of other protein kinases. Our results clarify the mechanisms of Nur77 induction by antipsychotic and its possible contribution to extrapyramidal effects.
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http://dx.doi.org/10.1016/j.neuropharm.2014.01.008DOI Listing
April 2014

Spatial distribution of D1R- and D2R-expressing medium-sized spiny neurons differs along the rostro-caudal axis of the mouse dorsal striatum.

Front Neural Circuits 2013 29;7:124. Epub 2013 Jul 29.

CNRS, UMR 5203, Institut de Génomique Fonctionnelle Montpellier, France ; INSERM, U661 Montpellier, France ; Universités de Montpellier 1 & 2, UMR 5203 Montpellier, France.

The striatum projection neurons are striatonigral and striatopallidal medium-sized spiny neurons (MSNs) that preferentially express D1 (D1R) and D2 (D2R) dopamine receptors, respectively. It is generally assumed that these neurons are physically intermingled, without cytoarchitectural organization although this has not been tested. To address this question we used BAC transgenic mice expressing enhanced green fluorescence (EGFP) under the control of Drd1a or Drd2 promoter and spatial point pattern statistics. We demonstrate that D1R- and D2R-expressing MSNs are randomly distributed in most of the dorsal striatum, whereas a specific region in the caudal striatum, adjacent to the GPe, lacks neurons expressing markers for indirect pathway neurons. This area comprises almost exclusively D1R-expressing MSNs. These neurons receive excitatory inputs from the primary auditory cortex and the medial geniculate thalamic nucleus and a rich dopamine innervation. This area contains cholinergic and GABAergic interneurons but apparently no D2R/A2aR modulation because no fluorescence was detected in the neuropil of Drd2-EGFP or Drd2-Cre, and Adora-Cre BAC transgenic mice crossed with reporter mice. This striatal area that expresses calbindin D28k, VGluT1 and 2, is poor in μ opiate receptors and preproenkephalin. Altogether, the differences observed in D1R-MSNs, D2R-MSNs, and interneurons densities, as well as the anatomical segregation of D1R- and D2R/A2aR-expressing MSNs suggest that there are regional differences in the organization of the striatum.
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http://dx.doi.org/10.3389/fncir.2013.00124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725430PMC
May 2014

Juvenile ethanol exposure increases rewarding properties of cocaine and morphine in adult DBA/2J mice.

Eur Neuropsychopharmacol 2013 Dec 22;23(12):1816-25. Epub 2013 Apr 22.

UMR-S 894, Inserm, Centre de Psychiatrie et Neuroscience, F-75013 Paris, France; Université Pierre et Marie Curie, F-75005 Paris, France.

Convergent data showed that ethanol exposure during adolescence can alter durably ethanol-related behaviour at adulthood. However, the consequences of juvenile ethanol exposure on the reinforcing effects of other drugs of abuse remain unclear. In the present work, we evaluated in adult male DBA/2J mice the effects of early ethanol exposure on the sensitivity to the incentive effects of cocaine and morphine, and on extracellular signal-regulated kinase (ERK) activation in response to cocaine. Juvenile male mice received intragastric administration of ethanol (2×2.5g/kg/day) or water for 5 days starting on postnatal day 28. When reaching adult age (10 week-old), animals were subjected to an unbiased procedure to assess conditioned place preference (CPP) to cocaine or morphine. In addition, activation of ERK in response to an acute injection of cocaine was investigated using immunoblotting in the striatum and the nucleus accumbens. Mice that have been subjected to early ethanol exposure developed CPP to doses of cocaine (5mg/kg) or morphine (10mg/kg) below the threshold doses to induce CPP in water pre-exposed mice. In addition, early ethanol administration significantly increased striatal ERK phosphorylation normally induced by acute cocaine (10 and 20mg/kg) in adult mice. These results show that, in DBA/2J mice, early exposure to ethanol enhanced the perception of the incentive effects of cocaine and morphine. Ethanol pre-exposure also induced a positive modulation of striatal ERK signalling, in line with the inference that juvenile ethanol intake may contribute to the development of addictive behaviour at adult age.
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http://dx.doi.org/10.1016/j.euroneuro.2013.03.010DOI Listing
December 2013

Striatal neurones have a specific ability to respond to phasic dopamine release.

J Physiol 2013 Jul 3;591(13):3197-214. Epub 2013 Apr 3.

Neurobiologie des Processus Adaptatifs UMR7102 CNRS UPMC, F-75005 Paris, France.

  The cAMP/protein kinase A (PKA) signalling cascade is ubiquitous, and each step in this cascade involves enzymes that are expressed in multiple isoforms. We investigated the effects of this diversity on the integration of the pathway in the target cell by comparing prefrontal cortical neurones with striatal neurones which express a very specific set of signalling proteins. The prefrontal cortex and striatum both receive dopaminergic inputs and we analysed the dynamics of the cAMP/PKA signal triggered by dopamine D1 receptors in these two brain structures. Biosensor imaging in mouse brain slice preparations showed profound differences in the D1 response between pyramidal cortical neurones and striatal medium spiny neurones: the cAMP/PKA response was much stronger, faster and longer lasting in striatal neurones than in pyramidal cortical neurones. We identified three molecular determinants underlying these differences: different activities of phosphodiesterases, particularly those of type 4, which strongly damp the cAMP signal in the cortex but not in the striatum; stronger adenylyl cyclase activity in the striatum, generating responses with a faster onset than in the cortex; and DARPP-32, a phosphatase inhibitor which prolongs PKA action in the striatum. Striatal neurones were also highly responsive in terms of gene expression since a single sub-second dopamine stimulation is sufficient to trigger c-Fos expression in the striatum, but not in the cortex. Our data show how specific molecular elements of the cAMP/PKA signalling cascade selectively enable the principal striatal neurones to respond to brief dopamine stimuli, a critical process in incentive learning.
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http://dx.doi.org/10.1113/jphysiol.2013.252197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3717223PMC
July 2013

Role of macropore flow in the transport of Escherichia coli cells in undisturbed cores of a brown leached soil.

Environ Sci Process Impacts 2013 Feb 23;15(2):347-56. Epub 2012 Nov 23.

Laboratoire d'Etudes des Transferts en Hydrologie et Environnement (LTHE, UMR 5564), CNRS-INSU/Univ. Grenoble I/INPG/IRD, Domaine Universitaire, BP53-38041, Grenoble Cedex 9, France.

The objective of this work was to evaluate the transport of Escherichia coli cells in undisturbed cores of a brown leached soil collected at La Côte St André (France). Two undisturbed soil cores subjected to repeated injections of bacterial cells and/or bromide tracer were used to investigate the effect of soil hydrodynamics and ionic strength on cell mobility. Under the tested experimental conditions, E. coli cells were shown to be transported at the water velocity (retardation factor close to 1) and their retention appeared almost insensitive to water flow and ionic strength variations, both factors being known to control bacterial transport in model saturated porous media. In contrast, E. coli breakthrough curves evolved significantly along with the repetition of the cell injections in each soil core, with a progressive acceleration of their transport. The evolution of E. coli cells BTCs was shown to be due to the evolution of the structure of soil hydraulic pathways caused by the repeated water infiltrations and drainage as may occur in the field. This evolution was demonstrated through mercury intrusion porosimetry (MIP) performed on soil aggregates before and after the repeated infiltrations of bacteria. MIP revealed a progressive and important reduction of the soil aggregate porosity, n, that decreased from approximately 0.5 to 0.3, along with a decrease of the soil percolating step from 27 to 2 μm. From this result a clear compaction of soil aggregates was evidenced that concerned preferentially the pores larger than 2 μm equivalent diameter, i.e. those allowing bacterial cell passage. Since no significant reduction of the global soil volume was observed at the core scale, this aggregate compaction was accompanied by macropore formation that became progressively the preferential hydraulic pathway in the soil cores, leading to transiently bi-modal bacterial BTCs. The evolution of the soil pore structure induced a modification of the main hydrodynamic processes, evolving from a matrix-dominant transfer of water and bacteria to a macropore-dominant transfer. This work points out the importance of using undisturbed natural soils to evaluate the mobility of bacteria in the field, since the evolving hydrodynamic properties of soils appeared to dominate most physicochemical factors.
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http://dx.doi.org/10.1039/c2em30586kDOI Listing
February 2013

Distribution and compartmental organization of GABAergic medium-sized spiny neurons in the mouse nucleus accumbens.

Front Neural Circuits 2013 19;7:22. Epub 2013 Feb 19.

CNRS, UMR-5203, Institut de Génomique Fonctionnelle Montpellier, France ; Inserm, U661 Montpellier, France ; Universités de Montpellier 1 & 2, UMR-5203 Montpellier, France.

The nucleus accumbens (NAc) is a critical brain region involved in many reward-related behaviors. The NAc comprises major compartments the core and the shell, which encompass several subterritories. GABAergic medium-sized spiny neurons (MSNs) constitute the output neurons of the NAc core and shell. While the functional organization of the NAc core outputs resembles the one described for the dorsal striatum, a simple classification of the NAc shell neurons has been difficult to define due to the complexity of the compartmental segregation of cells. We used a variety of BAC transgenic mice expressing enhanced green fluorescence (EGFP) or the Cre-recombinase (Cre) under the control of the promoter of dopamine D1, D2, and D3 receptors and of adenosine A2a receptor to dissect the microanatomy of the NAc. Moreover, using various immunological markers we characterized in detail the distribution of MSNs in the mouse NAc. In addition, cell-type specific extracellular signal-regulated kinase (ERK) phosphorylation in the NAc subterritories was analyzed following acute administration of SKF81297 (a D1R-like agonist), quinpirole (a D2 receptors (D2R)-like agonist), apomorphine (a non-selective DA receptor agonist), raclopride (a D2R-like antagonist), and psychostimulant drugs, including cocaine and d-amphetamine. Each drug generated a unique topography and cell-type specific activation of ERK in the NAc. Our results show the existence of marked differences in the receptor expression pattern and functional activation of MSNs within the shell subterritories. This study emphasizes the anatomical and functional heterogeneity of the NAc, which will have to be considered in its further study.
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http://dx.doi.org/10.3389/fncir.2013.00022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575607PMC
May 2014

Transient and rapid activation of Akt/GSK-3β and mTORC1 signaling by D3 dopamine receptor stimulation in dorsal striatum and nucleus accumbens.

J Neurochem 2013 May 11;125(4):532-44. Epub 2013 Mar 11.

Institut National de la Santé et de la Recherche Médicale-Inserm, Paris, France.

D2/D3 dopamine receptors (D2R/D3R) agonists regulate Akt, but their effects display a complex time-course. In addition, the respective roles of D2R and D3R are not defined and downstream targets remain poorly characterized, especially in vivo. These issues were addressed here for D3R. Systemic administration of quinelorane, a D2R/D3R agonist, transiently increased phosphorylation of Akt and GSK-3β in rat nucleus accumbens and dorsal striatum with maximal effects 10 min after injection. Akt activation was associated with phosphorylation of several effectors of the mammalian target of rapamycin complex 1 (mTORC1): p70S6 kinase, ribosomal protein-S6 (Ser240/244), and eukaryotic initiation factor-4E binding protein-1. The action of quinelorane was antagonized by a D2/D3R antagonist, raclopride, and the selective D3R antagonist S33084, inactive by themselves. Furthermore, no effect of quinerolane was seen in knock-out mice lacking D3R. In drd1a-EGFP transgenic mice, quinelorane activated Akt/GSK-3β in both neurons expressing and lacking D1 receptor. Thus, the stimulation of D3R transiently activates the Akt/GSK-3β pathway in the two populations of medium-size spiny neurons of the nucleus accumbens and dorsal striatum. This effect may contribute to the influence of D3R ligands on reward, cognition, and processes disrupted in schizophrenia, drug abuse, and Parkinson's disease.
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http://dx.doi.org/10.1111/jnc.12206DOI Listing
May 2013

Mutations in GNAL cause primary torsion dystonia.

Nat Genet 2013 Jan 9;45(1):88-92. Epub 2012 Dec 9.

Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA.

Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures. Its molecular pathophysiology is poorly understood, in part owing to limited knowledge of the genetic basis of the disorder. Only three genes for primary torsion dystonia (PTD), TOR1A (DYT1), THAP1 (DYT6) and CIZ1 (ref. 5), have been identified. Using exome sequencing in two families with PTD, we identified a new causative gene, GNAL, with a nonsense mutation encoding p.Ser293* resulting in a premature stop codon in one family and a missense mutation encoding p.Val137Met in the other. Screening of GNAL in 39 families with PTD identified 6 additional new mutations in this gene. Impaired function of several of the mutants was shown by bioluminescence resonance energy transfer (BRET) assays.
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http://dx.doi.org/10.1038/ng.2496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530620PMC
January 2013

5-HT(6) receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia.

EMBO Mol Med 2012 Oct;4(10):1043-56

CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.

Cognitive deficits in schizophrenia severely compromise quality of life and are poorly controlled by current antipsychotics. While 5-HT(6) receptor blockade holds special promise, molecular substrates underlying their control of cognition remain unclear. Using a proteomic strategy, we show that 5-HT(6) receptors physically interact with several proteins of the mammalian target of rapamycin (mTOR) pathway, including mTOR. Further, 5-HT(6) receptor activation increased mTOR signalling in rodent prefrontal cortex (PFC). Linking this signalling event to cognitive impairment, the mTOR inhibitor rapamycin prevented deficits in social cognition and novel object discrimination induced by 5-HT(6) agonists. In two developmental models of schizophrenia, specifically neonatal phencyclidine treatment and post-weaning isolation rearing, the activity of mTOR was enhanced in the PFC, and rapamycin, like 5-HT(6) antagonists, reversed these cognitive deficits. These observations suggest that recruitment of mTOR by prefrontal 5-HT(6) receptors contributes to the perturbed cognition in schizophrenia, offering new vistas for its therapeutic control.
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http://dx.doi.org/10.1002/emmm.201201410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491835PMC
October 2012