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7 publication(s) depuis Novembre 2007:

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23/05/2012 | J Neurosci   IF 6.1
Bimodal control of fear-coping strategies by CB(1) cannabinoid receptors.
Metna-Laurent M, Soria-Gomez E, Verrier D, Conforzi M, Jego P, Lafenetre P, Marsicano G

To maximize their chances of survival, animals need to rapidly and efficiently respond to aversive situations. These responses can be classified as active or passive and depend on the specific nature of threats, but also on individual fear coping styles. In this study, we show that the control of excitatory and inhibitory brain neurons by type-1 cannabinoid (CB(1)) receptors is a key determinant of fear coping strategies in mice. In classical fear conditioning, a switch between initially predominant passive fear responses (freezing) and active behaviors (escape attempts and risk assessment) develops over time. Constitutive genetic deletion of CB(1) receptors in CB(1)(-)/(-) mice disrupted this pattern by favoring passive responses. This phenotype can be ascribed to endocannabinoid control of excitatory neurons, because it was reproduced in conditional mutant mice lacking CB(1) receptors from cortical glutamatergic neurons. CB(1) receptor deletion from GABAergic brain neurons led to the opposite phenotype, characterized by the predominance of active coping. The CB(1) receptor agonist Delta(9)-tetrahydrocannabinol exerted a biphasic control of fear coping strategies, with lower and higher doses favoring active and passive responses, respectively. Finally, viral re-expression of CB(1) receptors in the amygdala of CB(1)(-)/(-) mice restored the normal switch between the two coping strategies. These data strongly suggest that CB(1) receptor signaling bimodally controls the spontaneous adoption of active or passive coping strategies in individuals. This primary function of the endocannabinoid system in shaping individual behavioral traits should be considered when studying the mechanisms of physiological and pathological fear.

03/2010 | Nat Neurosci   IF 21.1
Bimodal control of stimulated food intake by the endocannabinoid system
Bellocchio L*, Lafenetre P*, Cannich A, Cota D, Puente N, Grandes P, Chaouloff F, Piazza PV*, Marsicano G*


12/2009 | Neuropharmacology   IF 4.4
Bidirectional regulation of novelty-induced behavioral inhibition by the endocannabinoid system.
Lafenetre P, Chaouloff F, Marsicano G

The balance between novelty seeking and safety assessment is a key feature of adaptive behavior, and alterations in this equilibrium can lead to neuropsychiatric disorders. Excessive novelty seeking is a main form of pathological impulsivity, which is among the symptoms that define attention deficit hyperactivity disorder (ADHD). There is growing evidence that the endocannabinoid system (ECS) plays an important role in the control of this balance, but little is known about the underlying neuronal mechanisms. In this study, we aimed at dissecting the neurocircuits under the control of the ECS in novelty-induced behavioral inhibition. To reach this goal, we combined pharmacological, genetic and behavioral tools. Mice were repeatedly exposed to novel palatable food or a novel object and their responses to these stimuli were analyzed over several days. The results confirmed that systemic blockade of cannabinoid type-1 (CB(1)) receptors strongly decreases palatable food intake, but its impact onto the response to novelty is less pronounced. Using conditional mutant mice lacking the CB(1) receptor either in cortical glutamatergic or in GABAergic neurons, we found that the ECS exerts opposite functions on the balance between novelty seeking and behavioral inhibition. Whereas CB(1) receptors expressed in cortical glutamatergic neurons favors novelty seeking, CB(1)-dependent control of inhibitory GABAergic neurons promotes behavioral inhibition. These data show a tightly regulated influence of the ECS on impulsive behaviors and suggest the involvement of endocannabinoid signaling in the pathophysiological modulation of ADHD and related disorders.

13/01/2009 | Exp Brain Res   IF 1.9
Interneuronal growth and expression of interneuronal markers in visual cortex of mice with transgenic activation of Ras
Patz S, Colovic C, Wawro S, Lafenetre P, Leske O, Heumann R, Schonfelder S, Tomaschewski J, Rak A, Wahle P

The synRas transgenic mice express constitutively activated Valin12-Harvey Ras in postnatal neocortical pyramidal neurons. This leads to somatodendritic hypertrophy, higher densities of spines and synapses, and an enhancement of synaptic long-term potentiation associated with an increased glutamate receptor-mediated activity. It was less clear how the interneurons respond to these alterations, and this prompted the quantitative assessment of interneuron neurochemistry. Interneurons rarely expressed the transgene, however, several interneuron types displayed a transient somatic hypertrophy. Furthermore, NPY mRNA expression was persistently increased as were the laminar percentages of labeled neurons. The expression of parvalbumin and voltage-gated potassium channels Kv3.1b/3.2 was unchanged. A significant decline of GAD-67, but not GAD-65, mRNA expressing neurons was observed in layer VI in animals older than P60. This suggested that subtle deficits in inhibition and enhanced excitation evoke the interneuronal changes in the synRas-transgenic mouse cortex.

2009 | Curr Top Behav Neurosci   IF 2.7
Roles of the endocannabinoid system in learning and memory.
Marsicano G, Lafenetre P

The endocannabinoid system (ECS) plays a central role in the regulation of learning and memory processes. The fine-tuned regulation of neural transmission by the system is likely to be the mechanism underlying this important function. In this chapter, we review the data in the literature showing the direct involvement of the physiological activation of cannabinoid receptors in the modulation of different forms of learning and memory. When possible, we also address the likely mechanisms of this involvement. Finally, given the apparent special role of the ECS in the extinction of fear, we propose a reasonable model to assess how neuronal networks could be influenced by the endocannabinoids in these processes. Overall, the data reviewed indicate that, despite the enormous progress of recent years, much is still to be done to fully elucidate the mechanisms of the ECS influence on learning and memory processes.

01/2008 | J Neuro-oncol   IF 3.1
Intracellular application of TNF-alpha impairs cell to cell communication via gap junctions in glioma cells
Haghikia A, Ladage K, Lafenetre P, Haghikia A, Hinkerohe D, Smikalla D, Haase C G, Dermietzel R, Faustmann P M

Human gliomas are the most common class of brain neoplasm. In order to better characterize their response to inflammation, we evaluated the influence of tumor necrosis factor alpha (TNF-alpha) on the coupling behaviour and the membrane resting potential (MRP) of glioma cells (F98 glioma cell line) compared to primary astrocytes. In contrast to cultured primary astrocytes which exhibited a profound inhibition of gap junction mediated intercellular communication (GJIC), extracellular exposure of TNF-alpha to F98 glioma cells gained no effect on the functional coupling. Whereas, intracellular application of TNF-alpha into the glioma cells elicited similar effects as those found in primary astrocytes indicating a compromised accessibility of the TNF-alpha receptor in F98 cells. Western blotting, immunocytochemical staining and real time RT PCR analysis revealed a differential expression and distribution of TNF-alpha receptor 1 (TNFR1) in the glioma cells. Connexin 43 (Cx43) is the major astrocytic gap junction protein which when phosphorylated has been shown to reveal altered gating properties. Here we show that TNF-alpha increases the level of phosphorylated Cx43 in primary astrocytes but not in the F98 glioma cells. Our observations could account for the decreased regulatory effects of TNF-alpha on GJIC of F98 glioma cells.

The endocannabinoid system recently emerged as an important modulator of many neuronal functions. Among them, the control of anxiety and acquired fear represents nowadays one of the most interesting fields of research. Despite contrasting results obtained by the use of cannabinoid receptor agonists in experimental animals, there is growing evidence that the physiological activation of the endocannabinoid system plays a central role in the control of basal anxiety levels and in the modulation of fear responses. This review will summarise recent data on the role of the endocannabinoid system in most commonly used tests of anxiety and in the processing of acquired fear, with particular attention to its involvement in fear extinction. Finally, a neurobiological model possibly able to implement the role of the endocannabinoid system in these processes will be proposed.