Publications










IF du Neurocentre
IF1234567891011121314151617181920253035404550
Nombre00134448343018985796983314074601
%00267543221121221111011101


797 publications

* equal contribution
The indicated IF have been collected by the Web of Sciences in June 2020



12/2014 | Nat Neurosci   IF 15
Encoding of fear learning and memory in distributed neuronal circuits.
Herry C, Johansen JP

Abstract:
How sensory information is transformed by learning into adaptive behaviors is a fundamental question in neuroscience. Studies of auditory fear conditioning have revealed much about the formation and expression of emotional memories and have provided important insights into this question. Classical work focused on the amygdala as a central structure for fear conditioning. Recent advances, however, have identified new circuits and neural coding strategies mediating fear learning and the expression of fear behaviors. One area of research has identified key brain regions and neuronal coding mechanisms that regulate the formation, specificity and strength of fear memories. Other work has discovered critical circuits and neuronal dynamics by which fear memories are expressed through a medial prefrontal cortex pathway and coordinated activity across interconnected brain regions. Here we review these recent advances alongside prior work to provide a working model of the extended circuits and neuronal coding mechanisms mediating fear learning and memory.





10/11/2014 | Nat Neurosci   IF 15
Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1 mice.
Zhang Y*, Bonnan A*, Bony G*, Ferezou I, Pietropaolo S, Ginger M, Sans N, Rossier J, Oostra B, Lemasson G, Frick A

Abstract:
Hypersensitivity in response to sensory stimuli and neocortical hyperexcitability are prominent features of Fragile X Syndrome (FXS) and autism spectrum disorders, but little is known about the dendritic mechanisms underlying these phenomena. We found that the primary somatosensory neocortex (S1) was hyperexcited in response to tactile sensory stimulation in Fmr1-/y mice. This correlated with neuronal and dendritic hyperexcitability of S1 pyramidal neurons, which affect all major aspects of neuronal computation, from the integration of synaptic input to the generation of action potential output. Using dendritic electrophysiological recordings, calcium imaging, pharmacology, biochemistry and a computer model, we found that this defect was, at least in part, attributable to the reduction and dysfunction of dendritic h- and BKCa channels. We pharmacologically rescued several core hyperexcitability phenomena by targeting BKCa channels. Our results provide strong evidence pointing to the utility of BKCa channel openers for the treatment of the sensory hypersensitivity aspects of FXS.





01/11/2014 | Neuropharmacology   IF 4.8
Serotonin receptor stimulation inhibits cocaine-induced Fos expression and DARPP-32 phosphorylation in the rat striatum independently of dopamine outflow.
Devroye C, Cathala A, Maitre M, Piazza PV, Abrous DN, Revest JM, Spampinato U

Abstract:
The serotonin2C receptor (5-HT2CR) is known to control dopamine (DA) neuron function by modulating DA neuronal firing and DA exocytosis at terminals. Recent studies assessing the influence of 5-HT2CRs on cocaine-induced neurochemical and behavioral responses have shown that 5-HT2CRs can also modulate mesoaccumbens DA pathway activity at post-synaptic level, by controlling DA transmission in the nucleus accumbens (NAc), independently of DA release itself. A similar mechanism has been proposed to occur at the level of the nigrostriatal DA system. Here, using in vivo microdialysis in freely moving rats and molecular approaches, we assessed this hypothesis by studying the influence of the 5-HT2CR agonist Ro 60-0175 on cocaine-induced responses in the striatum. The intraperitoneal (i.p.) administration of 1 mg/kg Ro 60-0175 had no effect on the increase in striatal DA outflow induced by cocaine (15 mg/kg, i.p.). Conversely, Ro 60-0175 inhibited cocaine-induced Fos immunoreactivity and phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine 75 residue in the striatum. Finally, the suppressant effect of Ro 60-0175 on cocaine-induced DARPP-32 phosphorylation was reversed by the selective 5-HT2CR antagonist SB 242084 (0.5 mg/kg, i.p.). In keeping with the key role of DARPP-32 in DA neurotransmission, our results demonstrate that 5-HT2CRs are capable of modulating nigrostriatal DA pathway activity at post-synaptic level, by specifically controlling DA signaling in the striatum.





11/2014 | Med Sci (Paris)
[Prefrontal parvalbumin-expressing interneurons control fear behavior].
Courtin J, Dejean C, Herry C



11/2014 | Mol Cell Endocrinol   IF 4.2
Influence of mTOR in energy and metabolic homeostasis.
Haissaguerre M*, Saucisse N*, Cota D

Abstract:
The mechanistic (or mammalian) target of rapamycin couples a variety of different environmental signals, including nutrients and hormones, with the regulation of several energy-demanding cellular functions, spanning from protein and lipid synthesis to mitochondrial activity and cytoskeleton dynamics. mTOR forms two distinct protein complexes in cells, mTORC1 and mTORC2. This review focuses on recent advances made in understanding the roles played by these two complexes in the regulation of whole body metabolic homeostasis. Studies carried out in the past few years have shown that mTORC1 activity in the hypothalamus varies by cell and stimulus type, and that this complex is critically implicated in the regulation of food intake and body weight and in the central actions of both nutrients and hormones, such as leptin, ghrelin and triiodothyronine. As a regulator of cellular anabolic processes, mTORC1 activity in the periphery favors adipogenesis, lipogenesis, glucose uptake and beta-cell mass expansion. Much less is known about the function of mTORC2 in the hypothalamus, while in peripheral organs this second complex exerts roles strikingly similar to those described for mTORC1. Deregulation of mTORC1 and mTORC2 is associated with obesity, type 2 diabetes, cancer and neurodegenerative disorders. Insights on the exact relationship between mTORC1 and mTORC2 in the context of the regulation of metabolic homeostasis and on the specific molecular mechanisms engaged by these two complexes in such regulation may provide new avenues for therapy.





11/2014 | Med Sci (Paris)
[The multiple links between cilia and planar cell polarity].
Ezan J, Montcouquiol M

Abstract:
Since our seminal study in 2003, much has been written about core planar cell polarity (core PCP) signaling and the inner ear. In just a few years, and using the inner ear as a model system, our understanding of the molecular basis of this signaling pathway and how it can influence the development of tissues in mammals has increased considerably. Recently, a number of studies using various animal models of development have uncovered original relationships between the cilia and PCP, and the study of the hair cells of the inner ear has helped elucidating one of these links. In this review, we highlight the differences of PCP signaling between mammals and invertebrates. In the light of recent results, we sum up our current knowledge about PCP signaling in the mammalian cochlear epithelium and we discuss the impact of recent data in the field. We focus our attention on the interrelationship between asymmetric polarity complexes and the position of the cilium, which is essential for the establishment of the overall tissue polarity.





11/2014 | cancer epidemiol biomarkers prev   IF 4.3
Improved stool DNA integrity method for early colorectal cancer diagnosis.
Rengucci C, De Maio G, Menghi M, Scarpi E, Guglielmo S, Fusaroli P, Caletti G, Saragoni L, Casadei Gardini A, Zoli W, Falcini F, Amadori D, Calistri D

Abstract:
BACKGROUND: DNA integrity analysis could represent an alternative approach to the early detection of colorectal cancer. Previously, fluorescence long DNA (FL-DNA) in stools was extracted using a manual approach and analyzed by capillary electrophoresis assay (CE FL-DNA). We aimed to improve diagnostic accuracy using a simpler and more standardized method [Real Time PCR FL-DNA (RT FL-DNA)] for the detection of early malignant lesions in a population undergoing colorectal cancer screening. METHODS: From 241 stool samples, DNA was extracted using manual and semiautomatic extraction systems and analyzed using FL-DNA tests by CE and RT assays. The RT FL-DNA approach showed slightly higher sensitivity and specificity compared with the CE FL-DNA method. Furthermore, we compared the RT FL-DNA approach with the iFOBT report. RESULTS: Nonparametric ranking statistics were used to analyze the relationship between the median values of RT FL-DNA and the clinicohistopathologic characteristics. The median values of both variables were significantly higher in patients with cancer than in patients with noncancerous lesions. According to the Fagan nomogram results, the iFOBT and FL-DNA methods provided more accurate diagnostic information and were able to identify subgroups at varying risks of cancer. CONCLUSIONS: The combination of the semiautomatic extraction system and RT FL-DNA analysis improved the quality of DNA extracted from stool samples. IMPACT: RT FL-DNA shows great potential for colorectal cancer diagnosis as it is a reliable and relatively easy analysis to perform on routinely processed stool samples in combination with iFOBT.





23/10/2014 | Cell Rep   IF 7.2
Scribble1/AP2 complex coordinates NMDA receptor endocytic recycling.
Piguel NH, Fievre S, Blanc JM, Carta M, Moreau MM, Moutin E, Pinheiro VL, Medina C, Ezan J, Lasvaux L, Loll F, Durand CM, Chang K, Petralia RS, Wenthold RJ, Stephenson FA, Vuillard L, Darbon H, Perroy J, Mulle C, Montcouquiol M, Racca C, Sans N

Abstract:
The appropriate trafficking of glutamate receptors to synapses is crucial for basic synaptic function and synaptic plasticity. It is now accepted that NMDA receptors (NMDARs) internalize and are recycled at the plasma membrane but also exchange between synaptic and extrasynaptic pools; these NMDAR properties are also key to governing synaptic plasticity. Scribble1 is a large PDZ protein required for synaptogenesis and synaptic plasticity. Herein, we show that the level of Scribble1 is regulated in an activity-dependent manner and that Scribble1 controls the number of NMDARs at the plasma membrane. Notably, Scribble1 prevents GluN2A subunits from undergoing lysosomal trafficking and degradation by increasing their recycling to the plasma membrane following NMDAR activation. Finally, we show that a specific YxxR motif on Scribble1 controls these mechanisms through a direct interaction with AP2. Altogether, our findings define a molecular mechanism to control the levels of synaptic NMDARs via Scribble1 complex signaling.





19/10/2014 | Philos Trans R Soc Lond B Biol Sci
Organization, control and function of extrasynaptic NMDA receptors.
Papouin T, Oliet SH

Abstract:
N-methyl D-aspartate receptors (NMDARs) exist in different forms owing to multiple combinations of subunits that can assemble into a functional receptor. In addition, they are located not only at synapses but also at extrasynaptic sites. There has been intense speculation over the past decade about whether specific NMDAR subtypes and/or locations are responsible for inducing synaptic plasticity and excitotoxicity. Here, we review the latest findings on the organization, subunit composition and endogenous control of NMDARs at extrasynaptic sites and consider their putative functions. Because astrocytes are capable of controlling NMDARs through the release of gliotransmitters, we also discuss the role of the glial environment in regulating the activity of these receptors.





07/10/2014 | Genes Brain Behav   IF 3.5
Prefrontal neuronal circuits of contextual fear conditioning.
Rozeske RR, Valerio S, Chaudun F, Herry C

Abstract:
Over the past years, numerous studies have provided a clear understanding of the neuronal circuits and mechanisms involved in the formation, expression and extinction phases of conditioned cued fear memories. Yet, despite a strong clinical interest, a detailed understanding of these memory phases for contextual fear memories is still missing. Besides the well-known role of the hippocampus in encoding contextual fear behavior, growing evidence indicates that specific regions of the medial prefrontal cortex differentially regulate contextual fear acquisition and storage in both animals and humans that ultimately leads to expression of contextual fear memories. In this review, we provide a detailed description of the recent literature on the role of distinct prefrontal subregions in contextual fear behavior and provide a working model of the neuronal circuits involved in the acquisition, expression and generalization of contextual fear memories.







10/2014 | Mol Metab
CB1 cannabinoid receptor in SF1-expressing neurons of the ventromedial hypothalamus determines metabolic responses to diet and leptin.
Cardinal P, Andre C, Quarta C, Bellocchio L, Clark S, Elie M, Leste-Lasserre T, Maitre M, Gonzales D, Cannich A, Pagotto U, Marsicano G, Cota D

Abstract:
Metabolic flexibility allows rapid adaptation to dietary change, however, little is known about the CNS mechanisms regulating this process. Neurons in the hypothalamic ventromedial nucleus (VMN) participate in energy balance and are the target of the metabolically relevant hormone leptin. Cannabinoid type-1 (CB1) receptors are expressed in VMN neurons, but the specific contribution of endocannabinoid signaling in this neuronal population to energy balance regulation is unknown. Here we demonstrate that VMN CB1 receptors regulate metabolic flexibility and actions of leptin. In chow-fed mice, conditional deletion of CB1 in VMN neurons (expressing the steroidogenic factor 1, SF1) decreases adiposity by increasing sympathetic activity and lipolysis, and facilitates metabolic effects of leptin. Conversely, under high-fat diet, lack of CB1 in VMN neurons produces leptin resistance, blunts peripheral use of lipid substrates and increases adiposity. Thus, CB1 receptors in VMN neurons provide a molecular switch adapting the organism to dietary change.





26/09/2014 | Mol Cell Endocrinol   IF 4.2
New insights on food intake control by olfactory processes: The emerging role of the endocannabinoid system.
Soria-Gomez E, Bellocchio L, Marsicano G

Abstract:
The internal state of the organism is an important modulator of perception and behavior. The link between hunger, olfaction and feeding behavior is one of the clearest examples of these connections. At the neurobiological level, olfactory circuits are the targets of several signals (i.e. hormones and nutrients) involved in energy balance. Indicating that olfactory areas are potential sensors of the internal state of the organism. Thus, the aim of this manuscript is to review the literature showing the interplay between metabolic signals in olfactory circuits and its impact on food intake.





17/09/2014 | J Neurosci   IF 6.7
Enhanced endocannabinoid-mediated modulation of rostromedial tegmental nucleus drive onto dopamine neurons in Sardinian alcohol-preferring rats.
Melis M, Sagheddu C, De Felice M, Casti A, Madeddu C, Spiga S, Muntoni AL, Mackie K, Marsicano G, Colombo G, Castelli MP, Pistis M

Abstract:
The progressive predominance of rewarding effects of addictive drugs over their aversive properties likely contributes to the transition from drug use to drug dependence. By inhibiting the activity of DA neurons in the VTA, GABA projections from the rostromedial tegmental nucleus (RMTg) are well suited to shift the balance between drug-induced reward and aversion. Since cannabinoids suppress RMTg inputs to DA cells and CB1 receptors affect alcohol intake in rodents, we hypothesized that the endocannabinoid system, by modulating this pathway, might contribute to alcohol preference. Here we found that RMTg afferents onto VTA DA neurons express CB1 receptors and display a 2-arachidonoylglycerol (2-AG)-dependent form of short-term plasticity, that is, depolarization-induced suppression of inhibition (DSI). Next, we compared rodents with innate opposite alcohol preference, the Sardinian alcohol-preferring (sP) and alcohol-nonpreferring (sNP) rats. We found that DA cells from alcohol-naive sP rats displayed a decreased probability of GABA release and a larger DSI. This difference was due to the rate of 2-AG degradation. In vivo, we found a reduced RMTg-induced inhibition of putative DA neurons in sP rats that negatively correlated with an increased firing. Finally, alcohol failed to enhance RMTg spontaneous activity and to prolong RMTg-induced silencing of putative DA neurons in sP rats. Our results indicate functional modifications of RMTg projections to DA neurons that might impact the reward/aversion balance of alcohol attributes, which may contribute to the innate preference observed in sP rats and to their elevated alcohol intake.





15/09/2014 | Int J Obes (Lond)   IF 5.4
The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms.
Lu B, Diz-Chaves Y, Markovic D, Contarino A, Penicaud L, Fanelli F, Clark S, Lehnert H, Cota D, Grammatopoulos DK, Tabarin A

Abstract:
Objectives:The corticotrophin-releasing factor (CRF)/urocortin system is expressed in the adipose tissue of mammals, but its functional role in this tissue remains unknown.Methods:Pharmacological manipulation of the activity of CRF receptors, CRF1 and CRF2, was performed in 3T3L1 white pre-adipocytes and T37i brown pre-adipocytes during in vitro differentiation. The expression of genes of the CRF/urocortin system and of markers of white and brown adipocytes was evaluated along with mitochondrial biogenesis and cellular oxygen consumption. Metabolic evaluation of corticosterone-deficient or supplemented Crhr1-null (Crhr1-/-) mice and their wild-type controls was performed along with gene expression analysis carried out in white (WAT) and brown (BAT) adipose tissues.Results:Peptides of the CRF/urocortin system and their cognate receptors were expressed in both pre-adipocyte cell lines. In vitro pharmacological studies showed an inhibition of the expression of the CRF2 pathway by the constitutive activity of the CRF1 pathway. Pharmacological activation of CRF2 and, to a lesser extent, inhibition of CRF1 signaling induced molecular and functional changes indicating transdifferentiation of white pre-adipocytes and differentiation of brown pre-adipocytes. Crhr1-/- mice showed increased expression of CRF2 and its agonist Urocortin 2 in adipocytes that was associated to brown conversion of WAT and activation of BAT. Crhr1-/- mice were resistant to diet-induced obesity and glucose intolerance. Restoring physiological circulating corticosterone levels abrogated molecular changes in adipocytes and the favorable phenotype of Crhr1-/- mice.Conclusions:Our findings suggest the importance of the CRF2 pathway in the control of adipocyte plasticity. Increased CRF2 activity in adipocytes induces browning of WAT, differentiation of BAT and is associated with a favorable metabolic phenotype in mice lacking CRF1. Circulating corticosterone represses CRF2 activity in adipocytes and may thus regulate adipocyte physiology through the modulation of the local CRF/urocortin system. Targeting CRF receptor signaling specifically in the adipose tissue may represent a novel approach to tackle obesity.International Journal of Obesity advance online publication, 14 October 2014; doi:10.1038/ijo.2014.164.





09/2014 | Mol Psychiatry   IF 15.1
BDNF-TrkB signaling through Erk1/2 MAPK phosphorylation mediates the enhancement of fear memory induced by glucocorticoids.
Revest JM, Le Roux A, Roullot-Lacarriere V, Kaouane N, Vallee M, Kasanetz F, Rouge-Pont F, Tronche F, Desmedt A, Piazza PV

Abstract:
Activation of glucocorticoid receptors (GR) by glucocorticoid hormones (GC) enhances contextual fear memories through the activation of the Erk1/2(MAPK) signaling pathway. However, the molecular mechanism mediating this effect of GC remains unknown. Here we used complementary molecular and behavioral approaches in mice and rats and in genetically modified mice in which the GR was conditionally deleted (GR(NesCre)). We identified the tPA-BDNF-TrkB signaling pathway as the upstream molecular effectors of GR-mediated phosphorylation of Erk1/2(MAPK) responsible for the enhancement of contextual fear memory. These findings complete our knowledge of the molecular cascade through which GC enhance contextual fear memory and highlight the role of tPA-BDNF-TrkB-Erk1/2(MAPK) signaling pathways as one of the core effectors of stress-related effects of GC.





05/08/2014 | j exp clin cancer res   IF 3.3
Promoter methylation of tumor suppressor genes in pre-neoplastic lesions; potential marker of disease recurrence.
Rengucci C, De Maio G, Casadei Gardini A, Zucca M, Scarpi E, Zingaretti C, Foschi G, Tumedei MM, Molinari C, Saragoni L, Puccetti M, Amadori D, Zoli W, Calistri D

Abstract:
BACKGROUND: Epigenetic alterations of specific genes have been reported to be related to colorectal cancer (CRC) transformation and would also appear to be involved in the early stages of colorectal carcinogenesis. Little data are available on the role of these alterations in determining a different risk of colorectal lesion recurrence. The aim of the present study was to verify whether epigenetic alterations present in pre-neoplastic colorectal lesions detected by colonoscopy can predict disease recurrence. METHODS: A retrospective series of 78 adenomas were collected and classified as low (35) or high-risk (43) for recurrence according to National Comprehensive Cancer Network guidelines. Methylation alterations were analyzed by the methylation-specific multiplex ligation probe assay (MS-MLPA) which is capable of quantifying methylation levels simultaneously in 24 different gene promoters. MS-MLPA results were confirmed by pyrosequencing and immunohistochemistry. RESULTS: Higher levels of methylation were associated with disease recurrence. In particular, MLH1, ATM and FHIT gene promoters were found to be significantly hypermethylated in recurring adenomas. Unconditional logistic regression analysis used to evaluate the relative risk (RR) of recurrence showed that FHIT and MLH1 were independent variables with an RR of 35.30 (95% CI 4.15-300.06, P = 0.001) and 17.68 (95% CI 1.91-163.54, P = 0.011), respectively. CONCLUSIONS: Histopathological classification does not permit an accurate evaluation of the risk of recurrence of colorectal lesions. Conversely, results from our methylation analysis suggest that a classification based on molecular parameters could help to define the mechanisms involved in carcinogenesis and prove an effective method for identifying patients at high risk of recurrence.





29/07/2014 | Proc Natl Acad Sci U S A
A dual role for planar cell polarity genes in ciliated cells.
Boutin C, Labedan P, Dimidschstein J, Richard F, Cremer H, Andre P, Yang Y, Montcouquiol M, Goffinet AM, Tissir F

Abstract:
In the nervous system, cilia dysfunction perturbs the circulation of the cerebrospinal fluid, thus affecting neurogenesis and brain homeostasis. A role for planar cell polarity (PCP) signaling in the orientation of cilia (rotational polarity) and ciliogenesis is established. However, whether and how PCP regulates cilia positioning in the apical domain (translational polarity) in radial progenitors and ependymal cells remain unclear. By analysis of a large panel of mutant mice, we show that two PCP signals are operating in ciliated cells. The first signal, controlled by cadherin, EGF-like, laminin G-like, seven-pass, G-type receptor (Celsr) 2, Celsr3, Frizzled3 (Fzd3) and Van Gogh like2 (Vangl2) organizes multicilia in individual cells (single-cell polarity), whereas the second signal, governed by Celsr1, Fzd3, and Vangl2, coordinates polarity between cells in both radial progenitors and ependymal cells (tissue polarity). Loss of either of these signals is associated with specific defects in the cytoskeleton. Our data reveal unreported functions of PCP and provide an integrated view of planar polarization of the brain ciliated cells.







07/2014 | Mol Metab
Cannabinoid control of brain bioenergetics: Exploring the subcellular localization of the CB1 receptor.
Hebert-Chatelain E, Reguero L, Puente N, Lutz B, Chaouloff F, Rossignol R, Piazza PV, Benard G, Grandes P, Marsicano G

Abstract:
Brain mitochondrial activity is centrally involved in the central control of energy balance. When studying mitochondrial functions in the brain, however, discrepant results might be obtained, depending on the experimental approaches. For instance, immunostaining experiments and biochemical isolation of organelles expose investigators to risks of false positive and/or false negative results. As an example, the functional presence of cannabinoid type 1 (CB1) receptors on brain mitochondrial membranes (mtCB1) was recently reported and rapidly challenged, claiming that the original observation was likely due to artifact results. Here, we addressed this issue by directly comparing the procedures used in the two studies. Our results show that the use of appropriate controls and quantifications allows detecting mtCB1 receptor with CB1 receptor antibodies, and that, if mitochondrial fractions are enriched and purified, CB1 receptor agonists reliably decrease respiration in brain mitochondria. These data further underline the importance of adapted experimental procedures to study brain mitochondrial functions.





07/2014 | Mol Metab
Studying mitochondrial CB1 receptors: Yes we can.
Hebert-Chatelain E, Reguero L, Puente N, Lutz B, Chaouloff F, Rossignol R, Piazza PV, Benard G, Grandes P, Marsicano G





22/05/2014 | Nature   IF 42.4
Amygdala interneuron subtypes control fear learning through disinhibition.
Wolff SB, Grundemann J, Tovote P, Krabbe S, Jacobson GA, Muller C, Herry C, Ehrlich I, Friedrich RW, Letzkus JJ, Luthi A

Abstract:
Learning is mediated by experience-dependent plasticity in neuronal circuits. Activity in neuronal circuits is tightly regulated by different subtypes of inhibitory interneurons, yet their role in learning is poorly understood. Using a combination of in vivo single-unit recordings and optogenetic manipulations, we show that in the mouse basolateral amygdala, interneurons expressing parvalbumin (PV) and somatostatin (SOM) bidirectionally control the acquisition of fear conditioning--a simple form of associative learning--through two distinct disinhibitory mechanisms. During an auditory cue, PV(+) interneurons are excited and indirectly disinhibit the dendrites of basolateral amygdala principal neurons via SOM(+) interneurons, thereby enhancing auditory responses and promoting cue-shock associations. During an aversive footshock, however, both PV(+) and SOM(+) interneurons are inhibited, which boosts postsynaptic footshock responses and gates learning. These results demonstrate that associative learning is dynamically regulated by the stimulus-specific activation of distinct disinhibitory microcircuits through precise interactions between different subtypes of local interneurons.





Abstract:
Dendritic spines are basic units of neuronal information processing and their structure is closely reflected in their function. Defects in synaptic development are common in neurodevelopmental disorders, making detailed knowledge of age-dependent changes in spine morphology essential for understanding disease mechanisms. However, little is known about the functionally important fine-morphological structures, such as spine necks, due to the limited spatial resolution of conventional light microscopy. Using stimulated emission depletion microscopy (STED), we examined spine morphology at the nanoscale during normal development in mice, and tested the hypothesis that it is impaired in a mouse model of fragile X syndrome (FXS). In contrast to common belief, we find that, in normal development, spine heads become smaller, while their necks become wider and shorter, indicating that synapse compartmentalization decreases substantially with age. In the mouse model of FXS, this developmental trajectory is largely intact, with only subtle differences that are dependent on age and brain region. Together, our findings challenge current dogmas of both normal spine development as well as spine dysgenesis in FXS, highlighting the importance of super-resolution imaging approaches for elucidating structure-function relationships of dendritic spines.





11/04/2014 | Brain Struct Funct   IF 4.6
An anterograde rabies virus vector for high-resolution large-scale reconstruction of 3D neuron morphology.
Haberl MG*, Viana da Silva S*, Guest JM, Ginger M, Ghanem A, Mulle C, Oberlaender M, Conzelmann KK, Frick A

Abstract:
Glycoprotein-deleted rabies virus (RABV G) is a powerful tool for the analysis of neural circuits. Here, we demonstrate the utility of an anterograde RABV G variant for novel neuroanatomical approaches involving either bulk or sparse neuronal populations. This technology exploits the unique features of RABV G vectors, namely autonomous, rapid high-level expression of transgenes, and limited cytotoxicity. Our vector permits the unambiguous long-range and fine-scale tracing of the entire axonal arbor of individual neurons throughout the brain. Notably, this level of labeling can be achieved following infection with a single viral particle. The vector is effective over a range of ages (>14 months) aiding the studies of neurodegenerative disorders or aging, and infects numerous cell types in all brain regions tested. Lastly, it can also be readily combined with retrograde RABV G variants. Together with other modern technologies, this tool provides new possibilities for the investigation of the anatomy and physiology of neural circuits.





28/03/2014 | Neuroscience   IF 3.3
Cannabinoid type-1 receptors in the paraventricular nucleus of the hypothalamus inhibit stimulated food intake.
Soria-Gomez E, Massa F, Bellocchio L, Rueda-Orozco PE, Ciofi P, Cota D, Oliet SH, Prospero-Garcia O, Marsicano G

Abstract:
Cannabinoid receptor type 1 (CB1)-dependent signaling in the brain is known to modulate food intake. Recent evidence has actually shown that CB1 can both inhibit and stimulate food intake in fasting/refeeding conditions, depending on the specific neuronal circuits involved. However, the exact brain sites where this bimodal control is exerted and the underlying neurobiological mechanisms are not fully understood yet. Using pharmacological and electrophysiological approaches, we show that local CB1 blockade in the paraventricular nucleus of the hypothalamus (PVN) increases fasting-induced hyperphagia in rats. Furthermore, local CB1 blockade in the PVN also increases the orexigenic effect of the gut hormone ghrelin in animals fed ad libitum. At the electrophysiological level, CB1 blockade in slices containing the PVN potentiates the decrease of the activity of PVN neurons induced by long-term application of ghrelin. Hence, the PVN is (one of) the site(s) where signals associated with the body's energy status determine the direction of the effects of endocannabinoid signaling on food intake.





Abstract:
In keeping with its ability to control the mesoaccumbens dopamine (DA) pathway, the serotonin2C receptor (5-HT2C R) plays a key role in mediating the behavioral and neurochemical effects of drugs of abuse. Studies assessing the influence of 5-HT2C R agonists on cocaine-induced responses have suggested that 5-HT2C Rs can modulate mesoaccumbens DA pathway activity independently of accumbal DA release, thereby controlling DA transmission in the nucleus accumbens (NAc). In the present study, we assessed this hypothesis by studying the influence of the 5-HT2C R agonist Ro 60-0175 on cocaine-induced behavioral, neurochemical and molecular responses. The i.p. administration of 1 mg/kg Ro 60-0175 inhibited hyperlocomotion induced by cocaine (15 mg/kg, i.p.), had no effect on cocaine-induced DA outflow in the shell, and increased it in the core subregion of the NAc. Furthermore, Ro 60-0175 inhibited the late-onset locomotion induced by the subcutaneous administration of the DA-D2 R agonist quinpirole (0.5 mg/kg), as well as cocaine-induced increase in c-Fos immunoreactivity in NAc subregions. Finally, Ro 60-0175 inhibited cocaine-induced phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine residues in the NAc core, this effect being reversed by the selective 5-HT2C R antagonist SB 242084 (0.5 mg/kg, i.p.). Altogether, these findings demonstrate that 5-HT2C Rs are capable of modulating mesoaccumbens DA pathway activity at post-synaptic level by specifically controlling DA signaling in the NAc core subregion. In keeping with the tight relationship between locomotor activity and NAc DA function, this interaction could participate in the inhibitory control of cocaine-induced locomotor activity.





17/03/2014 | Neuropsychopharmacology   IF 7.8
Frequency of Cocaine Self-Administration Influences Drug Seeking in the Rat: Optogenetic Evidence for a Role of the Prelimbic Cortex.
Martin-Garcia E, Courtin J, Renault P, Fiancette JF, Wurtz H, Simonnet A, Levet F, Herry C, Deroche-Gamonet V

Abstract:
High-frequency intake and high drug-induced seeking are associated with cocaine addiction in both human and animals. However, their relationships and neurobiological underpinnings remain hypothetical. The medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and nucleus accumbens (NAc) have been shown to have a role in cocaine seeking. However, their involvement in regulating high-frequency intake and high cocaine-induced seeking is unclear. We manipulated frequency of cocaine self-administration and investigated whether it influenced cocaine seeking. The contribution of the aforementioned structures was evaluated using changes in expression of the immediate early gene c-Fos and targeted optogenetic manipulations. Rats that self-administered at High frequency (short inter-infusion intervals allowed by short time-out) showed higher cocaine-induced seeking than low frequency rats (long inter-infusions intervals imposed by long time-out), as measured with cocaine-induced reinstatement. c-Fos was enhanced in High frequency rats in the prelimbic (PL) and infralimbic (IL) areas of the mPFC, the BLA, and the NAc core and shell. Correlational analysis of c-Fos revealed that the PL was a critical node strongly correlated with both the IL and NAc core in High frequency rats. Targeted optogenetic inactivation of the PL decreased cocaine-induced reinstatement, but increased cocaine self-administration, in High frequency rats. In contrast, optogenetic activation of the PL had no effect on Low frequency rats. Thus, high-frequency intake promotes a PL-dependent control of cocaine seeking, with the PL exerting a facilitatory or inhibitory effect, depending on operant contingencies. Individual differences in cocaine-induced PL activation might be a source of vulnerability for poorly controlled cocaine-induced seeking and/or cocaine intake.Neuropsychopharmacology advance online publication, 16 April 2014; doi:10.1038/npp.2014.66.





03/2014 | Nat Neurosci   IF 15
The endocannabinoid system controls food intake via olfactory processes.
Soria-Gomez E, Bellocchio L, Reguero L, Lepousez G, Martin C, Bendahmane M, Ruehle S, Remmers F, Desprez T, Matias I, Wiesner T, Cannich A, Nissant A, Wadleigh A, Pape HC, Chiarlone AP, Quarta C, Verrier D, Vincent P, Massa F, Lutz B, Guzman M, Gurden H, Ferreira G, Lledo PM, Grandes P, Marsicano G

Abstract:
Hunger arouses sensory perception, eventually leading to an increase in food intake, but the underlying mechanisms remain poorly understood. We found that cannabinoid type-1 (CB1) receptors promote food intake in fasted mice by increasing odor detection. CB1 receptors were abundantly expressed on axon terminals of centrifugal cortical glutamatergic neurons that project to inhibitory granule cells of the main olfactory bulb (MOB). Local pharmacological and genetic manipulations revealed that endocannabinoids and exogenous cannabinoids increased odor detection and food intake in fasted mice by decreasing excitatory drive from olfactory cortex areas to the MOB. Consistently, cannabinoid agonists dampened in vivo optogenetically stimulated excitatory transmission in the same circuit. Our data indicate that cortical feedback projections to the MOB crucially regulate food intake via CB1 receptor signaling, linking the feeling of hunger to stronger odor processing. Thus, CB1 receptor-dependent control of cortical feedback projections in olfactory circuits couples internal states to perception and behavior.





19/02/2014 | Neuron   IF 16
Gliotransmitters travel in time and space.
Araque A, Carmignoto G, Haydon PG, Oliet SH, Robitaille R, Volterra A

Abstract:
The identification of the presence of active signaling between astrocytes and neurons in a process termed gliotransmission has caused a paradigm shift in our thinking about brain function. However, we are still in the early days of the conceptualization of how astrocytes influence synapses, neurons, networks, and ultimately behavior. In this Perspective, our goal is to identify emerging principles governing gliotransmission and consider the specific properties of this process that endow the astrocyte with unique functions in brain signal integration. We develop and present hypotheses aimed at reconciling confounding reports and define open questions to provide a conceptual framework for future studies. We propose that astrocytes mainly signal through high-affinity slowly desensitizing receptors to modulate neurons and perform integration in spatiotemporal domains complementary to those of neurons.





11/02/2014 | Nat Commun   IF 10.7
Neonatal testosterone suppresses a neuroendocrine pulse generator required for reproduction.
Israel JM, Cabelguen JM, Le Masson G, Oliet SH, Ciofi P

Abstract:
The pituitary gland releases hormones in a pulsatile fashion guaranteeing signalling efficiency. The determinants of pulsatility are poorly circumscribed. Here we show in magnocellular hypothalamo-neurohypophyseal oxytocin (OT) neurons that the bursting activity underlying the neurohormonal pulses necessary for parturition and the milk-ejection reflex is entirely driven by a female-specific central pattern generator (CPG). Surprisingly, this CPG is active in both male and female neonates, but is inactivated in males after the first week of life. CPG activity can be restored in males by orchidectomy or silenced in females by exogenous testosterone. This steroid effect is aromatase and caspase dependent, and is mediated via oestrogen receptor-alpha. This indicates the apoptosis of the CPG network during hypothalamic sexual differentiation, explaining why OT neurons do not burst in adult males. This supports the view that stereotypic neuroendocrine pulsatility is governed by CPGs, some of which are subjected to gender-specific perinatal programming.





09/02/2014 | Brain Struct Funct   IF 4.6
Influence of ontogenetic age on the role of dentate granule neurons.
Tronel S, Lemaire V, Charrier V, Montaron MF, Abrous DN

Abstract:
New neurons are continuously produced in the adult dentate gyrus of the hippocampus, a key structure in learning and memory. It has been shown that adult neurogenesis is crucial for normal memory processing. However, it is not known whether neurons born during the developmental period and during adulthood support the same functions. Here, we demonstrate that neurons born in neonates (first postnatal week) are activated in different memory processes when they are mature compared to neurons born in adults. By imaging the activation of these two different neuron generations in the same rat and using the IEG Zif268 and Fos, we show that these neurons are involved in discriminating dissimilar contexts and spatial problem solving, respectively. These findings demonstrate that the ontogenetic stage during which neurons are generated is crucial for their function within the memory network.





02/2014 | Mol Neurobiol   IF 5.3
Glycogen synthase kinase-3beta is involved in electroacupuncture pretreatment via the cannabinoid CB1 receptor in ischemic stroke.
Wei H, Yao X, Yang L, Wang S, Guo F, Zhou H, Marsicano G, Wang Q, Xiong L

Abstract:
We have previously shown that electroacupuncture (EA) pretreatment produces neuroprotective effects, which were mediated through an endocannabinoid signal transduction mechanism. Herein, we have studied the possible contribution of the phosphorylated form of glycogen synthase kinase-3beta (GSK-3beta) in EA pretreatment-induced neuroprotection via the cannabinoid CB1 receptor (CB1R). Focal transient cerebral ischemia was induced by middle cerebral artery occlusion in rats. Phosphorylation of GSK-3beta at Ser-9 [p-GSK-3beta (Ser-9)] was evaluated in the penumbra tissue following reperfusion. Infarct size and neurological score were assessed in the presence of either PI3K inhibitors or a GSK-3beta inhibitor 72 h after reperfusion. Cellular apoptosis was evidenced by TUNEL staining and determination of the Bax/Bcl-2 ratio 24 h after reperfusion. The present study showed that EA pretreatment increased p-GSK-3beta(Ser-9) 2 h after reperfusion in the ipsilateral penumbra. Augmented phosphorylation of GSK-3beta induced similar neuroprotective effects as did EA pretreatment. By contrast, inhibition of PI3K dampened the levels of p-GSK-3beta(Ser-9), and reversed not only the neuroprotective effect but also the anti-apoptotic effect following EA pretreatment. Regulation of GSK-3beta by EA pretreatment was abolished following treatment with a CB1R antagonist and CB1R knockdown, whereas two CB1R agonists enhanced the phosphorylation of GSK-3beta. Therefore we conclude that EA pretreatment protects against cerebral ischemia/reperfusion injury through CB1R-mediated phosphorylation of GSK-3beta.





28/01/2014 | world j gastroenterol   IF 2.4
Circulating and stool nucleic acid analysis for colorectal cancer diagnosis.
De Maio G, Rengucci C, Zoli W, Calistri D

Abstract:
In recent years, the need to identify molecular markers characterized by high sensitivity and specificity in detecting and monitoring early and colorectal cancer lesions has increased. Up to now, none of the markers or panels of markers analyzed have met the rigorous standards required of a screening program. The important discovery of circulating nucleic acids in biological fluids has aroused intense scientific interest because of their usefulness in malignant and non malignant diseases. Over time, their yield and stability have been identified and compared with other 'standard' biomarkers. The analysis of circulating DNA from blood and stool is a relatively simple and non-invasive procedure, representing a very attractive marker to detect genetic and epigenetic mutations and to monitor disease progression. A correlation between blood and stool biomarkers could also help to enhance currently available diagnostic approaches. However, various processing and analytic problems need to be resolved before such an approach can be applied in clinical practice.





22/01/2014 | Neuron   IF 16
Long-range connectivity defines behavioral specificity of amygdala neurons.
Senn V, Wolff SB, Herry C, Grenier F, Ehrlich I, Grundemann J, Fadok JP, Muller C, Letzkus JJ, Luthi A

Abstract:
Memories are acquired and encoded within large-scale neuronal networks spanning different brain areas. The anatomical and functional specificity of such long-range interactions and their role in learning is poorly understood. The amygdala and the medial prefrontal cortex (mPFC) are interconnected brain structures involved in the extinction of conditioned fear. Here, we show that a defined subpopulation of basal amygdala (BA) projection neurons targeting the prelimbic (PL) subdivision of mPFC is active during states of high fear, whereas BA neurons targeting the infralimbic (IL) subdivision are recruited, and exhibit cell-type-specific plasticity, during fear extinction. Pathway-specific optogenetic manipulations demonstrate that the activity balance between pathways is causally involved in fear extinction. Together, our findings demonstrate that, although intermingled locally, long-range connectivity defines distinct subpopulations of amygdala projection neurons and indicate that the formation of long-term extinction memories depends on the balance of activity between two defined amygdala-prefrontal pathways.





03/01/2014 | Science   IF 31.5
Pregnenolone can protect the brain from cannabis intoxication.
Vallee M, Vitiello S, Bellocchio L, Hebert-Chatelain E, Monlezun S, Martin-Garcia E, Kasanetz F, Baillie GL, Panin F, Cathala A, Roullot-Lacarriere V, Fabre S, Hurst DP, Lynch DL, Shore DM, Deroche-Gamonet V, Spampinato U, Revest JM, Maldonado R, Reggio PH, Ross RA, Marsicano G, Piazza PV

Abstract:
Pregnenolone is considered the inactive precursor of all steroid hormones, and its potential functional effects have been largely uninvestigated. The administration of the main active principle of Cannabis sativa (marijuana), Delta(9)-tetrahydrocannabinol (THC), substantially increases the synthesis of pregnenolone in the brain via activation of the type-1 cannabinoid (CB1) receptor. Pregnenolone then, acting as a signaling-specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals a previously unknown paracrine/autocrine loop protecting the brain from CB1 receptor overactivation that could open an unforeseen approach for the treatment of cannabis intoxication and addiction.





02/01/2014 | Nature   IF 42.4
Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression.
Courtin J, Chaudun F, Rozeske RR, Karalis N, Gonzalez-Campo C, Wurtz H, Abdi A, Baufreton J, Bienvenu TC, Herry C

Abstract:
Synchronization of spiking activity in neuronal networks is a fundamental process that enables the precise transmission of information to drive behavioural responses. In cortical areas, synchronization of principal-neuron spiking activity is an effective mechanism for information coding that is regulated by GABA (gamma-aminobutyric acid)-ergic interneurons through the generation of neuronal oscillations. Although neuronal synchrony has been demonstrated to be crucial for sensory, motor and cognitive processing, it has not been investigated at the level of defined circuits involved in the control of emotional behaviour. Converging evidence indicates that fear behaviour is regulated by the dorsomedial prefrontal cortex (dmPFC). This control over fear behaviour relies on the activation of specific prefrontal projections to the basolateral complex of the amygdala (BLA), a structure that encodes associative fear memories. However, it remains to be established how the precise temporal control of fear behaviour is achieved at the level of prefrontal circuits. Here we use single-unit recordings and optogenetic manipulations in behaving mice to show that fear expression is causally related to the phasic inhibition of prefrontal parvalbumin interneurons (PVINs). Inhibition of PVIN activity disinhibits prefrontal projection neurons and synchronizes their firing by resetting local theta oscillations, leading to fear expression. Our results identify two complementary neuronal mechanisms mediated by PVINs that precisely coordinate and enhance the neuronal activity of prefrontal projection neurons to drive fear expression.





Abstract:
Transition to addiction is the shift from controlled to uncontrolled drug use that occurs after prolonged drug intake in a limited number of drug users. A major challenge of addiction research in recent years has been to develop models for studying this pathological transition. Toward this goal, a DSM-IV/5-based multi-symptomatic model of cocaine addiction has been developed in the rat. It is based on an operational translation of the main features of the disease. 1. Addiction is not just taking drug; it is a non-adaptive drug use: The procedure models addiction in relation to its clinical definition. 2. All drug users do not face the same individual risk of developing addiction: The model includes an individual-based approach. 3. Addiction develops after protracted periods of controlled drug use: This procedure allows for the study of the long-term shift from controlled drug use to addiction. We describe this model in detail and show how it can contribute to our understanding of the pathophysiology of cocaine addiction. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.





01/2014 | Faseb J   IF 5.5
Control of spasticity in a multiple sclerosis model using central nervous system-excluded CB1 cannabinoid receptor agonists.
Pryce G, Visintin C, Ramagopalan SV, Al-Izki S, De Faveri LE, Nuamah RA, Mein CA, Montpetit A, Hardcastle AJ, Kooij G, de Vries HE, Amor S, Thomas SA, Ledent C, Marsicano G, Lutz B, Thompson AJ, Selwood DL, Giovannoni G, Baker D

Abstract:
The purpose of this study was the generation of central nervous system (CNS)-excluded cannabinoid receptor agonists to test the hypothesis that inhibition of spasticity, due to CNS autoimmunity, could be controlled by affecting neurotransmission within the periphery. Procedures included identification of chemicals and modeling to predict the mode of exclusion; induction and control of spasticity in the ABH mouse model of multiple sclerosis; conditional deletion of CB1 receptor in peripheral nerves; side-effect profiling to demonstrate the mechanism of CNS-exclusion via drug pumps; genome-wide association study in N2(129xABH) backcross to map polymorphic cannabinoid drug pump; and sequencing and detection of cannabinoid drug-pump activity in human brain endothelial cell lines. Three drugs (CT3, SAB378 and SAD448) were identified that control spasticity via action on the peripheral nerve CB1 receptor. These were peripherally restricted via drug pumps that limit the CNS side effects (hypothermia) of cannabinoids to increase the therapeutic window. A cannabinoid drug pump is polymorphic and functionally lacking in many laboratory (C57BL/6, 129, CD-1) mice used for transgenesis, pharmacology, and toxicology studies. This phenotype was mapped and controlled by 1-3 genetic loci. ABCC1 within a cluster showing linkage is a cannabinoid CNS-drug pump. Global and conditional CB1 receptor-knockout mice were used as controls. In summary, CNS-excluded CB1 receptor agonists are a novel class of therapeutic agent for spasticity.





2014 | Pain   IF 5.8
Cancer pain is not necessarily correlated with spinal overexpression of reactive
glia markers

Ducourneau V*, Dolique T*, Hachem-Delaunay S, Miraucourt L, Amadio A, Blaszczyk L, Jacquot F, Ly J, Devoize L, Oliet SH, Dallel R, Mothet JP, Nagy F, Fenelon V*, Voisin D*

Abstract:
Bone cancer pain is a common and disruptive symptom in cancer patients. In cancer pain animal models, massive reactive astrogliosis in the dorsal horn of the spinal cord has been reported. Because astrocytes may behave as driving partners for pathological pain, we investigated the temporal development of pain behavior and reactive astrogliosis in a rat bone cancer pain model induced by injecting MRMT-1 rat mammary gland carcinoma cells into the tibia. Along with the development of bone lesions, a gradual mechanical and thermal allodynia and hyperalgesia as well as a reduced use of the affected limb developed in bone cancer-bearing animals, but not in sham-treated animals. Dorsal horn Fos expression after nonpainful palpation of the injected limb was also increased in bone cancer-bearing animals. However, at any time during the evolution of tumor, there was no increase in glial fibrillary acidic protein (GFAP) immunoreactivity in the dorsal horn. Further analysis at 21days after injection of the tumor showed no increase in GFAP and interleukin (IL) 1beta transcripts, number of superficial dorsal horn S100beta protein immunoreactive astrocytes, or immunoreactivity for microglial markers (OX-42 and Iba-1). In contrast, all these parameters were increased in the dorsal horn of rats 2weeks after sciatic nerve ligation. This suggests that in some cases, bone cancer pain may not be correlated with spinal overexpression of reactive glia markers, whereas neuropathic pain is. Glia may thus play different roles in the development and maintenance of chronic pain in these 2 situations.





2014 | J Physiol   IF 4.5
Extracellular signal-regulated kinase phosphorylation in forebrain neurones
contributes to osmoregulatory mechanisms

Dine J, Ducourneau V, Fenelon V, Fossat P, Amadio A, Eder M, Israel JM, Oliet SH, Voisin D



Abstract:
Dendritic spines are basic units of neuronal information processing and their structure is closely reflected in their function. Defects in synaptic development are common in neurodevelopmental disorders, making detailed knowledge of age-dependent changes in spine morphology essential for understanding disease mechanisms. However, little is known about the functionally important fine- morphological structures, such as spine necks, due to the limited spatial resolution of conventional light microscopy. Using stimulated emission depletion microscopy (STED), we examined spine morphology at the nanoscale during normal development in mice, and tested the hypothesis that it is impaired in a mouse model of fragile X syndrome (FXS). In contrast to common belief, we find that, in normal development, spine heads become smaller, while their necks become wider and shorter, indicating that synapse compartmentalization decreases substantially with age. In the mouse model of FXS, this developmental trajectory is largely intact, with only subtle differences that are dependent on age and brain region. Together, our findings challenge current dogmas of both normal spine development as well as spine dysgenesis in FXS, highlighting the importance of super-resolution imaging approaches for elucidating structure–function relationships of dendritic spines.





2014 | Front Cell Neurosci   IF 4.2
Novel cell separation method for molecular analysis of neuron-astrocyte co-cultures.
Goudriaan A, Camargo N, Carney KE, Oliet SH, Smit AB, Verheijen MH

Abstract:
Over the last decade, the importance of astrocyte-neuron communication in neuronal development and synaptic plasticity has become increasingly clear. Since neuron-astrocyte interactions represent highly dynamic and reciprocal processes, we hypothesized that many astrocyte genes may be regulated as a consequence of their interactions with maturing neurons. In order to identify such neuron-responsive astrocyte genes in vitro, we sought to establish an expedited technique for separation of neurons from co-cultured astrocytes. Our newly established method makes use of cold jet, which exploits different adhesion characteristics of subpopulations of cells (Jirsova etal., 1997), and is rapid, performed under ice-cold conditions and avoids protease-mediated isolation of astrocytes or time-consuming centrifugation, yielding intact astrocyte mRNA with approximately 90% of neuronal RNA removed. Using this purification method, we executed genome-wide profiling in which RNA derived from astrocyte-only cultures was compared with astrocyte RNA derived from differentiating neuron-astrocyte co-cultures. Data analysis determined that many astrocytic mRNAs and biological processes are regulated by neuronal interaction. Our results validate the cold jet as an efficient method to separate astrocytes from neurons in co-culture, and reveals that neurons induce robust gene-expression changes in co-cultured astrocytes.





2014 | Front Cell Neurosci   IF 4.2
ER to synapse trafficking of NMDA receptors.
Horak M, Petralia RS, Kaniakova M, Sans N

Abstract:
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. There are three distinct subtypes of ionotropic glutamate receptors (GluRs) that have been identified including 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptors (AMPARs), N-methyl-D-aspartate receptors (NMDARs) and kainate receptors. The most common GluRs in mature synapses are AMPARs that mediate the fast excitatory neurotransmission and NMDARs that mediate the slow excitatory neurotransmission. There have been large numbers of recent reports studying how a single neuron regulates synaptic numbers and types of AMPARs and NMDARs. Our current research is centered primarily on NMDARs and, therefore, we will focus in this review on recent knowledge of molecular mechanisms occurring (1) early in the biosynthetic pathway of NMDARs, (2) in the transport of NMDARs after their release from the endoplasmic reticulum (ER); and (3) at the plasma membrane including excitatory synapses. Because a growing body of evidence also indicates that abnormalities in NMDAR functioning are associated with a number of human psychiatric and neurological diseases, this review together with other chapters in this issue may help to enhance research and to gain further knowledge of normal synaptic physiology as well as of the etiology of many human brain diseases.





2014 | Transl Psychiatry   IF 4.4
Nutritional omega-3 modulates neuronal morphology in the prefrontal cortex along with depression-related behaviour through corticosterone secretion.
Larrieu T, Hilal ML, Fourrier C, De Smedt-Peyrusse V, Sans N, Capuron L, Laye S

Abstract:
Understanding how malnutrition contributes to depression is building momentum. In the present study we unravel molecular and cellular mechanisms by which nutritional disturbances lead to impaired emotional behaviour in mice. Here we report that nutritional n-3 polyunsaturated fatty acids (PUFA) deficiency induces a chronic stress state reflected by disrupted glucocorticoid receptor (GR)-mediated signalling pathway along with hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. This hyperactivity in turn resulted in neuronal atrophy in the dorsolateral (dl)- and dorsomedial (dm)- prefrontal cortex (PFC) and subsequent mood-related behaviour alterations, similarly to chronic social defeat stress. Supplementation of n-3 PUFA prevented detrimental chronic social defeat stress-induced emotional and neuronal impairments by impeding HPA axis hyperactivity. These results indicate a role for dietary n-3 PUFA in the prevention of HPA axis dysfunction associated with the development of some neuropsychiatric disorders including depression.





2014 | Front Aging Neurosci   IF 2.8
Astrocytosis in parkinsonism: considering tripartite striatal synapses in physiopathology?
Charron G, Doudnikoff E, Canron MH, Li Q, Vega C, Marais S, Baufreton J, Vital A, Oliet SH, Bezard E

Abstract:
The current concept of basal ganglia organization and function in physiological and pathophysiological conditions excludes the most numerous cells in the brain, i.e., the astrocytes, present with a ratio of 10:1 neuron. Their role in neurodegenerative condition such as Parkinson's disease (PD) remains to be elucidated. Before embarking into physiological investigations of the yet-to-be-identified 'tripartite' synapses in the basal ganglia in general and the striatum in particular, we therefore characterized anatomically the PD-related modifications in astrocytic morphology, the changes in astrocytic network connections and the consequences on the spatial relationship between astrocytic processes and asymmetric synapses in normal and PD-like conditions in experimental and human PD. Our results unravel a dramatic regulation of striatal astrocytosis supporting the hypothesis of a key role in (dys) regulating corticostriatal transmission. Astrocytes and their various properties might thus represent a therapeutic target in PD.





2014 | prog mol biol transl sci   IF 0
Deciphering memory function with optogenetics.
Beyeler A, Eckhardt CA, Tye KM

Abstract:
Optogenetics has accelerated the field of neuroscience by overcoming many of the spatial, genetic, and temporal limitations of previous techniques to control neural activity. The study of learning and memory has profoundly benefited from these tools mainly from their use in rodents. New insights have been made regarding the involvement of specific cell types or populations of synapses in the acquisition, consolidation, and retrieval of memories. The cellular specificity and temporal precision of optogenetic manipulations have also shown to be useful to study synaptic mechanisms supporting learning and memory including long-term synaptic plasticity. Recently, new light-sensitive molecules have been developed to control intracellular pathways or gene expression, which promise to enhance our understanding of the molecular mechanism of memory function.





11/12/2013 | J Neurosci   IF 6.9
Stress switches cannabinoid type-1 (CB1) receptor-dependent plasticity from LTD to LTP in the bed nucleus of the stria terminalis.
Glangetas C, Girard D, Groc L, Marsicano G, Chaouloff F, Georges F

Abstract:
The bed nucleus of the stria terminalis (BNST) exerts a coordinated modulation of the psychoneuroendocrine responses to stress. However, how acute stress impacts on BNST in vivo plasticity is a crucial question that still remains unanswered. Here, neurons from the anterior portion of the BNST (aBNST) were recorded in vivo during and after stimulation of their medial prefrontal cortical (mPFC) afferents. In C57BL/6N mice, a 1 h restraint stress induced a switch from long-term depression (LTD) to long-term potentiation (LTP) in the aBNST after a 10 Hz mPFC stimulation. This switch was independent from glucocorticoid receptor stimulation. Because the endocannabinoid system regulates aBNST activity, we next examined the role of cannabinoid type-1 receptors (CB1-Rs) in these changes. Mutant mice lacking CB1-Rs (CB1(-/-) mice) displayed a marked deficit in the ability to develop plasticity under control and stress conditions, compared with their wild-type littermates (CB1(+/+) mice). This difference was not accounted for by genetic differences in stress sensitivity, as revealed by Fos immunohistochemistry analyses. Local blockade of CB1-Rs in the aBNST and the use of mutant mice bearing a selective deletion of CB1-Rs in cortical glutamatergic neurons indicated that stress-elicited LTP involved CB1-Rs located on aBNST excitatory terminals. These results show that acute stress reverts LTD into LTP in the aBNST and that the endocannabinoid system plays a key role therein.





Abstract:
The neuroimaging literature has shown consistent decreases in functional magnetic resonance imaging (fMRI) activity in the hippocampus of healthy older adults engaged in a navigation task. However, navigation in a virtual maze relies on spatial or response strategies known to depend on the hippocampus and caudate nucleus, respectively. Therefore, since the proportion of people using spatial strategies decreases with normal aging, we hypothesized that it was responsible for the observed decreases in fMRI activity in the hippocampus reported in the literature. The aim of this study was to examine the effects of aging on the hippocampus and caudate nucleus during navigation while taking into account individual navigational strategies. Young (N = 23) and older adults (N = 29) were tested using fMRI on the Concurrent Spatial Discrimination Learning Task, a radial task that dissociates between spatial and response strategies (in Stage 2) after participants reached criteria (in Stage 1). Success on Stage 2 requires that participants have encoded the spatial relationship between the target object and environmental landmarks, that is, the spatial strategy. While older adults required more trials, all participants reached criterion. fMRI results showed that, as a group, young adults had significant activity in the hippocampus as opposed to older adults who instead had significant activity in the caudate nucleus. Importantly, individual differences showed that the older participants who used a spatial strategy to solve the task had significant activity in the hippocampus. These findings suggest that the aging process involves a shift from using the hippocampus toward the caudate nucleus during navigation but that activity in the hippocampus is sustained in a subset of healthy older adults engaged in spatial strategies.





11/10/2013 | Pain   IF 5.6
Cancer pain is not necessarily correlated with spinal overexpression of reactive glia markers.
Ducourneau VR, Dolique T, Hachem-Delaunay S, Miraucourt LS, Amadio A, Blaszczyk L, Jacquot F, Ly J, Devoize L, Oliet SH, Dallel R, Mothet JP, Nagy F, Fenelon VS, Voisin DL

Abstract:
Bone cancer pain is a common and disruptive symptom in cancer patients. In cancer pain animal models, massive reactive astrogliosis in the dorsal horn of the spinal cord has been reported. Because astrocytes may behave as driving partners for pathological pain, we investigated the temporal development of pain behavior and reactive astrogliosis in a rat bone cancer pain model induced by injecting MRMT-1 rat mammary gland carcinoma cells into the tibia. Along with the development of bone lesions, a gradual mechanical and thermal allodynia and hyperalgesia as well as a reduced use of the affected limb developed in bone cancer-bearing animals, but not in sham-treated animals. Dorsal horn Fos expression after nonpainful palpation of the injected limb was also increased in bone cancer-bearing animals. However, at any time during the evolution of tumor, there was no increase in glial fibrillary acidic protein (GFAP) immunoreactivity in the dorsal horn. Further analysis at 21days after injection of the tumor showed no increase in GFAP and interleukin (IL) 1beta transcripts, number of superficial dorsal horn S100beta protein immunoreactive astrocytes, or immunoreactivity for microglial markers (OX-42 and Iba-1). In contrast, all these parameters were increased in the dorsal horn of rats 2weeks after sciatic nerve ligation. This suggests that in some cases, bone cancer pain may not be correlated with spinal overexpression of reactive glia markers, whereas neuropathic pain is. Glia may thus play different roles in the development and maintenance of chronic pain in these 2 situations.