ASPM-associated stem cell proliferation is involved in malignant progression of gliomas and constitutes an attractive therapeutic target

<p>Abstract</p> <p>Background</p> <p>ASPM (<it>Abnormal Spindle-like Microcephaly associated</it>) over-expression was recently implicated in the development of malignant gliomas.</p> <p>Results</p> <p>To better characterize the involvement of ASPM in gliomas, we investigated the mRNA expression in 175 samples, including 8 WHO Grade II, 75 WHO Grade III and 92 WHO Grade IV tumors. <it>Aspm </it>expression was strongly correlated with tumor grade and increased at recurrence when compared to the initial lesion, whatever the initial grade of the primary tumor. ASPM expression also increased over serial passages in gliomaspheres <it>in vitro </it>and in mouse xenografts <it>in vivo</it>. Lentivirus-mediated shRNA silencing of ASPM resulted in dramatic proliferation arrest and cell death in two different gliomasphere models.</p> <p>Conclusion</p> <p>These data suggest that ASPM is involved in the malignant progression of gliomas, possibly through expansion of a cancer stem cell compartment, and is an attractive therapeutic target in glioblastoma multiforme.</p

Insular and Ventrolateral Orbitofrontal Cortices Differentially Contribute to Goal-Directed Behavior in Rodents

The medial prefrontal cortex (mPFC) has long been considered a critical site in action control. However, recent evidence indicates that the contribution of cortical areas to goal-directed behavior likely extends beyond mPFC. Here, we examine the function of both insular (IC) and ventrolateral orbitofrontal (vlOFC) cortices in action-dependent learning. We used chemogenetics to study the consequences of IC or vlOFC inhibition on acquisition and performance of instrumental actions using the outcome devaluation task. Rats first learned to associate actions with desirable outcomes. Then, one of these outcomes was devalued and we assessed the rats' choice between the 2 actions. Typically, rats will bias their selection towards the action that delivers the still valued outcome. We show that chemogenetic-induced inhibition of IC during choice abolishes goal-directed control whereas inhibition during instrumental acquisition is without effect. IC is therefore necessary for action selection based on current outcome value. By contrast, vlOFC inhibition during acquisition or the choice test impaired goal-directed behavior but only following a shift in the instrumental contingencies. Our results provide clear evidence that vlOFC plays a critical role in action-dependent learning, which challenges the popular idea that this region of OFC is exclusively involved in stimulus-dependent behaviors.Bases neuronales du comportement dirigé vers un but chez le RatInternational Mobility Programme to Strengthen Skills and Excellence in Research for Agricultur

Multisensory control of multimodal behavior: do the legs know what the tongue is doing?

Understanding of adaptive behavior requires the precisely controlled presentation of multisensory stimuli combined with simultaneous measurement of multiple behavioral modalities. Hence, we developed a virtual reality apparatus that allows for simultaneous measurement of reward checking, a commonly used measure in associative learning paradigms, and navigational behavior, along with precisely controlled presentation of visual, auditory and reward stimuli. Rats performed a virtual spatial navigation task analogous to the Morris maze where only distal visual or auditory cues provided spatial information. Spatial navigation and reward checking maps showed experience-dependent learning and were in register for distal visual cues. However, they showed a dissociation, whereby distal auditory cues failed to support spatial navigation but did support spatially localized reward checking. These findings indicate that rats can navigate in virtual space with only distal visual cues, without significant vestibular or other sensory inputs. Furthermore, they reveal the simultaneous dissociation between two reward-driven behaviors

Major impairments of glutamatergic transmission and long term synaptic plasticity in the hippocampus of mice lacking the melanin-concentrating hormone receptor-1

The hypothalamic neuropeptide melanin-concentrating hormone (MCH) plays important roles in energy homeostasis, anxiety, and sleep regulation. Since the MCH receptor-1 (MCH-R1), the only functional receptor that mediates MCH functions in rodents, facilitates behavioral performance in hippocampus-dependent learning tasks, we investigated whether glutamatergic transmission in CA1 pyramidal cells could be modulated in mice lacking the MCH-R1 gene (MCH-R1(-/-)). We found that both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptor-mediated transmissions were diminished in the mutant mice compared with their controls. This deficit was explained, at least in part, by a postsynaptic down-regulation of these receptors since the amplitude of miniature excitatory postsynaptic currents and the NMDA/AMPA ratio were decreased. Long-term synaptic potentiation (LTP) was also impaired in MCH-R1(-/-) mice. This was due to an altered induction, rather than an impaired, expression because repeating the induction stimulus restored LTP to a normal magnitude. In addition, long-term synaptic depression was strongly diminished in MCH-R1(-/-) mice. These results suggest that MCH exerts a facilitatory effect on CA1 glutamatergic synaptic transmission and long-term synaptic plasticity. Recently, it has been shown that MCH neurons fire exclusively during sleep and mainly during rapid eye movement sleep. Thus these findings provide a mechanism by which sleep might facilitate memory consolidation

Localization of the brainstem GABAergic neurons controlling paradoxical (REM) sleep

Paradoxical sleep (PS) is a state characterized by cortical activation, rapid eye movements and muscle atonia. Fifty years after its discovery, the neuronal network responsible for the genesis of PS has been only partially identified. We recently proposed that GABAergic neurons would have a pivotal role in that network. To localize these GABAergic neurons, we combined immunohistochemical detection of Fos with non-radioactive in situ hybridization of GAD67 mRNA (GABA synthesis enzyme) in control rats, rats deprived of PS for 72 h and rats allowed to recover after such deprivation. Here we show that GABAergic neurons gating PS (PS-off neurons) are principally located in the ventrolateral periaqueductal gray (vlPAG) and the dorsal part of the deep mesencephalic reticular nucleus immediately ventral to it (dDpMe). Furthermore, iontophoretic application of muscimol for 20 min in this area in head-restrained rats induced a strong and significant increase in PS quantities compared to saline. In addition, we found a large number of GABAergic PS-on neurons in the vlPAG/dDPMe region and the medullary reticular nuclei known to generate muscle atonia during PS. Finally, we showed that PS-on neurons triggering PS localized in the SLD are not GABAergic. Altogether, our results indicate that multiple populations of PS-on GABAergic neurons are distributed in the brainstem while only one population of PS-off GABAergic neurons localized in the vlPAG/dDpMe region exist. From these results, we propose a revised model for PS control in whic

Multisensory Control of Multimodal Behavior: Do the Legs Know What the Tongue Is Doing?

<div><p>Understanding of adaptive behavior requires the precisely controlled presentation of multisensory stimuli combined with simultaneous measurement of multiple behavioral modalities. Hence, we developed a virtual reality apparatus that allows for simultaneous measurement of reward checking, a commonly used measure in associative learning paradigms, and navigational behavior, along with precisely controlled presentation of visual, auditory and reward stimuli. Rats performed a virtual spatial navigation task analogous to the Morris maze where only distal visual or auditory cues provided spatial information. Spatial navigation and reward checking maps showed experience-dependent learning and were in register for distal visual cues. However, they showed a dissociation, whereby distal auditory cues failed to support spatial navigation but did support spatially localized reward checking. These findings indicate that rats can navigate in virtual space with only distal visual cues, without significant vestibular or other sensory inputs. Furthermore, they reveal the simultaneous dissociation between two reward-driven behaviors.</p></div

Navigational performance in the virtual audiovisual spatial navigation task.

<p>(A) Schematic of the virtual environment indicating distal auditory and visual cues and a hidden reward zone and the four start locations. (B) Example paths from a single rat from the 1^st session. The color of each path indicates start location, color coded from the arrows in A. (C) Example paths from the same rat from the 6^th session. (D) Acquisition curve of latency to reward across sessions. F(5,35)  = 4.266, p = 0.0061, Session 1 vs. Session 3: p<0.05, N =  6. (E) Acquisition curve of the distance traveled to reward across sessions. F(5,35)  = 3.00, p = 0.0296, Session 1 vs. Session 5: p<0.05. (F) 2-D histogram of mean occupancy averaged across final four task sessions of asymptotic performance with the smaller reward zone. (G) Example of a probe trial path. (H) Percentage quadrant measures for occupancy time during the final four task sessions performance and during the probe trial. Effect of quadrant: F(3,23)  = 10.15, p = 0.007, F(3,23)  = 10.9, p = 0.0005, respectively.</p

Multisensory contribution to virtual spatial navigation and reward checking.

<p>(A) Schematic of the Audiovisual (AV), Visual (V) only and Auditory (A) virtual spatial mazes. Symbols as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080465#pone-0080465-g001" target="_blank">Figure 1</a>. (B) Example paths for the three trial types from a single rat. The color of each path indicates start location, color coded from the arrows in A. (C) Median latency and distance to reward for each trial type. Effect of trial type, F(2,17)  = 7.555, p = 0.01, F(2,17)  = 8.911, p = 0.006, respectively. A vs. AV and V: p<0.05 for both measures, N = 6. (D) Percentage occupancy in the target quadrant for the three trial types. Effect of trial type: F(2,17)  = 13.19, p = 0.0064. A vs. AV: p = 0.013, A and V: p = 0.018.</p