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See detailIdentification of a pharmacologically tractable Fra-1/ADORA2B axis promoting breast cancer metastasis
Desmet, Christophe ULiege; Gallenne, Tristan; Prieur, Alexandre et al

in Proceedings of the National Academy of Sciences of the United States of America (2013)

Metastasis confronts clinicians with two major challenges: estimating the patient's risk of metastasis and identifying therapeutic targets. Because they are key signal integrators connecting cellular ... [more ▼]

Metastasis confronts clinicians with two major challenges: estimating the patient's risk of metastasis and identifying therapeutic targets. Because they are key signal integrators connecting cellular processes to clinical outcome, we aimed to identify transcriptional nodes regulating cancer cell metastasis. Using rodent xenograft models that we previously developed, we identified the transcription factor Fos-related antigen-1 (Fra-1) as a key coordinator of metastasis. Because Fra-1 often is overexpressed in human metastatic breast cancers and has been shown to control their invasive potential in vitro, we aimed to assess the implication and prognostic significance of the Fra-1-dependent genetic program in breast cancer metastasis and to identify potential Fra-1-dependent therapeutic targets. In several in vivo assays in mice, we demonstrate that stable RNAi depletion of Fra-1 from human breast cancer cells strongly suppresses their ability to metastasize. These results support a clinically important role for Fra-1 and the genetic program it controls. We show that a Fra-1-dependent gene-expression signature accurately predicts recurrence of breast cancer. Furthermore, a synthetic lethal drug screen revealed that antagonists of the adenosine receptor A2B (ADORA2B) are preferentially toxic to breast tumor cells expressing Fra-1. Both RNAi silencing and pharmacologic blockade of ADORA2B inhibited filopodia formation and invasive activity of breast cancer cells and correspondingly reduced tumor outgrowth in the lungs. These data show that Fra-1 activity is causally involved in and is a prognostic indicator of breast cancer metastasis. They suggest that Fra-1 activity predicts responsiveness to inhibition of pharmacologically tractable targets, such as ADORA2B, which may be used for clinical interference of metastatic breast cancer. [less ▲]

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See detailDeep sequencing reveals abundant non-canonical retroviral microRNAs in B-cell leukemia/lymphoma
Rosewick, Nicolas; Momont, Mélanie ULiege; Durkin, Keith ULiege et al

in Proceedings of the National Academy of Sciences of the United States of America (2013)

Viral tumor models have significantly contributed to our understanding of oncogenic mechanisms. How transforming delta-retroviruses induce malignancy however remains poorly understood, especially as viral ... [more ▼]

Viral tumor models have significantly contributed to our understanding of oncogenic mechanisms. How transforming delta-retroviruses induce malignancy however remains poorly understood, especially as viral mRNA/protein are tightly silenced in tumors. Here, using deep sequencing of broad windows of small RNA sizes in the Bovine Leukemia Virus ovine model of leukemia/lymphoma, we provide in vivo evidence of the production of non-canonical Pol IIItranscribed viral microRNAs in leukemic B-cells in the complete absence of Pol II 5’ LTR-driven transcriptional activity. Processed from a cluster of five independent self-sufficient transcriptional units located in a proviral region dispensable for in vivo infectivity, BLV microRNAs represent ~ 40 % of all microRNAs in both experimental and natural malignancy. They are subject to strong purifying selection and associate with Argonautes, consistent with a critical function in silencing of important cellular and/or viral targets. BLV microRNAs are strongly expressed in preleukemic and malignant cells in which structural and regulatory gene expression is repressed, suggesting a key role in tumor onset and progression. Understanding how Pol III-dependent microRNAs subvert cellular and viral pathways will contribute in deciphering the intricate perturbations that underlie malignant transformation. [less ▲]

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See detailGenetic basis of neurocognitive decline and reduced white-matter integrity in normal human brain aging.
Glahn, David C.; Kent, Jack W. Jr; Sprooten, Emma et al

in Proceedings of the National Academy of Sciences of the United States of America (2013), 110(47), 19006-11

Identification of genes associated with brain aging should markedly improve our understanding of the biological processes that govern normal age-related decline. However, challenges to identifying genes ... [more ▼]

Identification of genes associated with brain aging should markedly improve our understanding of the biological processes that govern normal age-related decline. However, challenges to identifying genes that facilitate successful brain aging are considerable, including a lack of established phenotypes and difficulties in modeling the effects of aging per se, rather than genes that influence the underlying trait. In a large cohort of randomly selected pedigrees (n = 1,129 subjects), we documented profound aging effects from young adulthood to old age (18-83 y) on neurocognitive ability and diffusion-based white-matter measures. Despite significant phenotypic correlation between white-matter integrity and tests of processing speed, working memory, declarative memory, and intelligence, no evidence for pleiotropy between these classes of phenotypes was observed. Applying an advanced quantitative gene-by-environment interaction analysis where age is treated as an environmental factor, we demonstrate a heritable basis for neurocognitive deterioration as a function of age. Furthermore, by decomposing gene-by-aging (G x A) interactions, we infer that different genes influence some neurocognitive traits as a function of age, whereas other neurocognitive traits are influenced by the same genes, but to differential levels, from young adulthood to old age. In contrast, increasing white-matter incoherence with age appears to be nongenetic. These results clearly demonstrate that traits sensitive to the genetic influences on brain aging can be identified, a critical first step in delineating the biological mechanisms of successful aging. [less ▲]

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See detailCTIP2 is a negative regulator of P-TEFb.
Cherrier, Thomas ULiege; Le Douce, Valentin; Eilebrecht, Sebastian et al

in Proceedings of the National Academy of Sciences of the United States of America (2013), 110(31), 12655-60

The positive transcription elongation factor b (P-TEFb) is involved in physiological and pathological events including inflammation, cancer, AIDS, and cardiac hypertrophy. The balance between its active ... [more ▼]

The positive transcription elongation factor b (P-TEFb) is involved in physiological and pathological events including inflammation, cancer, AIDS, and cardiac hypertrophy. The balance between its active and inactive form is tightly controlled to ensure cellular integrity. We report that the transcriptional repressor CTIP2 is a major modulator of P-TEFb activity. CTIP2 copurifies and interacts with an inactive P-TEFb complex containing the 7SK snRNA and HEXIM1. CTIP2 associates directly with HEXIM1 and, via the loop 2 of the 7SK snRNA, with P-TEFb. In this nucleoprotein complex, CTIP2 significantly represses the Cdk9 kinase activity of P-TEFb. Accordingly, we show that CTIP2 inhibits large sets of P-TEFb- and 7SK snRNA-sensitive genes. In hearts of hypertrophic cardiomyopathic mice, CTIP2 controls P-TEFb-sensitive pathways involved in the establishment of this pathology. Overexpression of the beta-myosin heavy chain protein contributes to the pathological cardiac wall thickening. The inactive P-TEFb complex associates with CTIP2 at the MYH7 gene promoter to repress its activity. Taken together, our results strongly suggest that CTIP2 controls P-TEFb function in physiological and pathological conditions. [less ▲]

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See detailDifferential effects of global versus local testosterone on singing behavior and its underlying neural substrate.
Alward, Beau A.; Balthazart, Jacques ULiege; Ball, Gregory F.

in Proceedings of the National Academy of Sciences of the United States of America (2013), 110(48), 19573-8

Steroid hormones regulate multiple but distinct aspects of social behaviors. Testosterone (T) has multiple effects on learned courtship song in that it regulates both the motivation to sing in a ... [more ▼]

Steroid hormones regulate multiple but distinct aspects of social behaviors. Testosterone (T) has multiple effects on learned courtship song in that it regulates both the motivation to sing in a particular social context as well as the quality of song produced. The neural substrate(s) where T acts to regulate the motivation to sing as opposed to other aspects of song has not been definitively characterized. We show here that T implants in the medial preoptic nucleus (POM) of castrated male canaries (Serinus canaria) increase song rate but do not enhance acoustic features such as song stereotypy compared with birds receiving peripheral T that can act globally throughout the brain. Strikingly, T action in the POM increased song control nuclei volume, consistent with the hypothesis that singing activity induces neuroplasticity in the song control system independent of T acting in these nuclei. When presented with a female canary, POM-T birds copulated at a rate comparable to birds receiving systemic T but produced fewer calls and songs in her presence. Thus, POM is a key site where T acts to activate copulation and increase song rate, an appetitive sexual behavior in songbirds, but T action in other areas of the brain or periphery (e.g., HVC, dopaminergic cell groups, or the syrinx) is required to enhance the quality of song (i.e., stereotypy) as well as regulate context-specific vocalizations. These results have broad implications for research concerning how steroids act at multiple brain loci to regulate distinct sociosexual behaviors and the associated neuroplasticity. [less ▲]

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See detailSerial population extinctions in a small mammal indicate Late Pleistocene ecosystem instability
Brace, Selina; Palkopoulou, Eleftheria; Dalén, Love et al

in Proceedings of the National Academy of Sciences of the United States of America (2012), 109(50), 20532-20536

The Late Pleistocene global extinction of many terrestrial mammal species has been a subject of intensive scientific study for over a century, yet the relative contributions of environmental changes and ... [more ▼]

The Late Pleistocene global extinction of many terrestrial mammal species has been a subject of intensive scientific study for over a century, yet the relative contributions of environmental changes and the global expansion of humans remain unresolved. A defining component of these extinctions is a bias toward large species, with the majority of small-mammal taxa apparently surviving into the present. Here, we investigate the population-level history of a key tundra-specialist small mammal, the collared lemming (Dicrostonyx torquatus), to explore whether events during the Late Pleistocene had a discernible effect beyond the large mammal fauna. Using ancient DNA techniques to sample across three sites in North-West Europe, we observe a dramatic reduction in genetic diversity in this species over the last 50,000 y. We further identify a series of extinction-recolonization events, indicating a previously unrecognized instability in Late Pleistocene small-mammal populations, which we link with climatic fluctuations. Our results reveal climate-associated, repeated regional extinctions in a keystone prey species across the Late Pleistocene, a pattern likely to have had an impact on the wider steppe-tundra community, and one that is concordant with environmental change as a major force in structuring Late Pleistocene biodiversity. [less ▲]

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See detailA discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer.
Herfs, Michael ULiege; Yamamoto, Yusuke; Laury, Anna et al

in Proceedings of the National Academy of Sciences of the United States of America (2012), 109(26), 10516-21

Infection by carcinogenic human papillomaviruses (HPV) results in precancers [cervical intraepithelial neoplasia (CIN)] and cancers near the ectoendocervical squamocolumnar (SC) junction of the cervix ... [more ▼]

Infection by carcinogenic human papillomaviruses (HPV) results in precancers [cervical intraepithelial neoplasia (CIN)] and cancers near the ectoendocervical squamocolumnar (SC) junction of the cervix. However, the specific cells targeted by HPV have not been identified and the cellular origin of cervical cancer remains elusive. In this study, we uncovered a discrete population of SC junctional cells with unique morphology and gene-expression profile. We also demonstrated that the selected junctional biomarkers were expressed by a high percentage of high-grade CIN and cervical cancers associated with carcinogenic HPVs but rarely in ectocervical/transformation zone CINs or those associated with noncarcinogenic HPVs. That the original SC junction immunophenotype was not regenerated at new SC junctions following excision, not induced by expression of viral oncoproteins in foreskin keratinocytes, and not seen in HPV-related precursors of the vagina, vulva, and penis further support the notion that junctional cells are the source of cervical cancer. Taken together, our findings suggest that carcinogenic HPV-related CINs and cervical cancers are linked to a small, discrete cell population that localizes to the SC junction of the cervix, expresses a unique gene expression signature, and is not regenerated after excision. The findings in this study uncover a potential target for cervical cancer prevention, provide insight into the risk assessment of cervical lesions, and establish a model for elucidating the pathway to cervical cancer following carcinogenic HPV infection. [less ▲]

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See detailHigh-throughput genomic sequencing of cassava bacterial blight strains identifies conserved effectors to target for durable resistance.
Bart, Rebecca; Cohn, Megan; Kassen, Andrew et al

in Proceedings of the National Academy of Sciences of the United States of America (2012), 109(28), 1972-9

Cassava bacterial blight (CBB), incited by Xanthomonas axonopodis pv. manihotis (Xam), is the most important bacterial disease of cassava, a staple food source for millions of people in developing ... [more ▼]

Cassava bacterial blight (CBB), incited by Xanthomonas axonopodis pv. manihotis (Xam), is the most important bacterial disease of cassava, a staple food source for millions of people in developing countries. Here we present a widely applicable strategy for elucidating the virulence components of a pathogen population. We report Illumina-based draft genomes for 65 Xam strains and deduce the phylogenetic relatedness of Xam across the areas where cassava is grown. Using an extensive database of effector proteins from animal and plant pathogens, we identify the effector repertoire for each sequenced strain and use a comparative sequence analysis to deduce the least polymorphic of the conserved effectors. These highly conserved effectors have been maintained over 11 countries, three continents, and 70 y of evolution and as such represent ideal targets for developing resistance strategies. [less ▲]

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See detailOn a fundamental structure of gene networks in living cells
Kravchenko-Balasha, Nataly; Levitzki, Alexander; Goldstein, Andrew et al

in Proceedings of the National Academy of Sciences of the United States of America (2012), 109(12), 4702-4707

Computers are organized into hardware and software. Using a theoretical approach to identify patterns in gene expression in a variety of species, organs, and cell types, we found that biological systems ... [more ▼]

Computers are organized into hardware and software. Using a theoretical approach to identify patterns in gene expression in a variety of species, organs, and cell types, we found that biological systems similarly are comprised of a relatively unchanging hardware-like gene pattern. Orthogonal patterns of software-like transcripts vary greatly, even among tumors of the same type from different individuals. Two distinguishable classes could be identified within the hardware-like component: those transcripts that are highly expressed and stable and an adaptable subset with lower expression that respond to external stimuli. Importantly, we demonstrate that this structure is conserved across organisms. Deletions of transcripts from the highly stable core are predicted to result in cell mortality. The approach provides a conceptual thermodynamic-like framework for the analysis of gene-expression levels and networks and their variations in diseased cells. [less ▲]

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See detailHierarchical clustering of brain activity during human nonrapid eye movement sleep.
Boly, Mélanie ULiege; Perlbarg, V; Marrelec, G et al

in Proceedings of the National Academy of Sciences of the United States of America (2012)

Consciousness is reduced during nonrapid eye movement (NREM) sleep due to changes in brain function that are still poorly understood. Here, we tested the hypothesis that impaired consciousness during NREM ... [more ▼]

Consciousness is reduced during nonrapid eye movement (NREM) sleep due to changes in brain function that are still poorly understood. Here, we tested the hypothesis that impaired consciousness during NREM sleep is associated with an increased modularity of brain activity. Cerebral connectivity was quantified in resting-state functional magnetic resonance imaging times series acquired in 13 healthy volunteers during wakefulness and NREM sleep. The analysis revealed a modification of the hierarchical organization of large-scale networks into smaller independent modules during NREM sleep, independently from EEG markers of the slow oscillation. Such modifications in brain connectivity, possibly driven by sleep ultraslow oscillations, could hinder the brain's ability to integrate information and account for decreased consciousness during NREM sleep. [less ▲]

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See detailInterplay between spontaneous and induced brain activity during human non-rapid eye movement sleep.
Dang Vu, Thien Thanh ULiege; Bonjean, Maxime; Schabus, Manuel et al

in Proceedings of the National Academy of Sciences of the United States of America (2011), 108(37), 15438-43

Humans are less responsive to the surrounding environment during sleep. However, the extent to which the human brain responds to external stimuli during sleep is uncertain. We used simultaneous EEG and ... [more ▼]

Humans are less responsive to the surrounding environment during sleep. However, the extent to which the human brain responds to external stimuli during sleep is uncertain. We used simultaneous EEG and functional MRI to characterize brain responses to tones during wakefulness and non-rapid eye movement (NREM) sleep. Sounds during wakefulness elicited responses in the thalamus and primary auditory cortex. These responses persisted in NREM sleep, except throughout spindles, during which they became less consistent. When sounds induced a K complex, activity in the auditory cortex was enhanced and responses in distant frontal areas were elicited, similar to the stereotypical pattern associated with slow oscillations. These data show that sound processing during NREM sleep is constrained by fundamental brain oscillatory modes (slow oscillations and spindles), which result in a complex interplay between spontaneous and induced brain activity. The distortion of sensory information at the thalamic level, especially during spindles, functionally isolates the cortex from the environment and might provide unique conditions favorable for off-line memory processing. [less ▲]

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See detailOceanic islands are not sinks of biodiversity in spore-producing plants
Hutsemekers, Virginie ULiege; Shaw, A. J.; Szvovenyi, P. et al

in Proceedings of the National Academy of Sciences of the United States of America (2011), 108

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See detailFunctional specialization for auditory-spatial processing in the occipital cortex of congenitally blind humans
Collignon, Olivier; Vandewalle, Gilles ULiege; Voss, Patrice et al

in Proceedings of the National Academy of Sciences of the United States of America (2011), 108(11), 4435-40

The study of the congenitally blind (CB) represents a unique opportunity to explore experience-dependant plasticity in a sensory region deprived of its natural inputs since birth. Although several studies ... [more ▼]

The study of the congenitally blind (CB) represents a unique opportunity to explore experience-dependant plasticity in a sensory region deprived of its natural inputs since birth. Although several studies have shown occipital regions of CB to be involved in nonvisual processing, whether the functional organization of the visual cortex observed in sighted individuals (SI) is maintained in the rewired occipital regions of the blind has only been recently investigated. In the present functional MRI study, we compared the brain activity of CB and SI processing either the spatial or the pitch properties of sounds carrying information in both domains (i.e., the same sounds were used in both tasks), using an adaptive procedure specifically designed to adjust for performance level. In addition to showing a substantial recruitment of the occipital cortex for sound processing in CB, we also demonstrate that auditory-spatial processing mainly recruits the right cuneus and the right middle occipital gyrus, two regions of the dorsal occipital stream known to be involved in visuospatial/motion processing in SI. Moreover, functional connectivity analyses revealed that these reorganized occipital regions are part of an extensive brain network including regions known to underlie audiovisual spatial abilities (i.e., intraparietal sulcus, superior frontal gyrus). We conclude that some regions of the right dorsal occipital stream do not require visual experience to develop a specialization for the processing of spatial information and to be functionally integrated in a preexisting brain network dedicated to this ability. [less ▲]

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See detailIntegrated logic circuits using single-atom transistors
Mol, J.; Verduijn, J.; Levine, R. D. et al

in Proceedings of the National Academy of Sciences of the United States of America (2011), 108(34), 13969-13972

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See detailCrucial role of a shared extracellular loop in apamin sensitivity and maintenance of pore shape of small-conductance calcium-activated potassium (SK) channel
Weatherall, Kate; Seutin, Vincent ULiege; Liégeois, Jean-François ULiege et al

in Proceedings of the National Academy of Sciences of the United States of America (2011), 108(45), 18488-18493

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See detailOn the strong and selective isotope effect in the UV excitation of N2 with implications toward the nebula and Martian atmosphere
Muskatel, B. H.; Remacle, Françoise ULiege; Thiemens, Mark et al

in Proceedings of the National Academy of Sciences of the United States of America (2011), 108(15), 6020-6025

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See detailOptimal concentrations in nectar feeding
Kim, Wonjung; Gilet, Tristan ULiege; Bush, John W.M.

in Proceedings of the National Academy of Sciences of the United States of America (2011), 108(40), 16618

Nectar drinkers must feed quickly and efficiently due to the threat of predation. While the sweetest nectar offers the greatest ener- getic rewards, the sharp increase of viscosity with sugar concentra ... [more ▼]

Nectar drinkers must feed quickly and efficiently due to the threat of predation. While the sweetest nectar offers the greatest ener- getic rewards, the sharp increase of viscosity with sugar concentra- tion makes it the most difficult to transport. We here demonstrate that the sugar concentration that optimizes energy transport depends exclusively on the drinking technique employed. We iden- tify three nectar drinking techniques: active suction, capillary suction, and viscous dipping. For each, we deduce the dependence of the volume intake rate on the nectar viscosity and thus infer an optimal sugar concentration consistent with laboratory mea- surements. Our results provide the first rationale for why suction feeders typically pollinate flowers with lower sugar concentration nectar than their counterparts that use viscous dipping. [less ▲]

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See detailGenetic control over the resting brain.
Glahn, D. C.; Winkler, Anderson ULiege; Kochunov, P. et al

in Proceedings of the National Academy of Sciences of the United States of America (2010), 107(3), 1223-8

The default-mode network, a coherent resting-state brain network, is thought to characterize basal neural activity. Aberrant default-mode connectivity has been reported in a host of neurological and ... [more ▼]

The default-mode network, a coherent resting-state brain network, is thought to characterize basal neural activity. Aberrant default-mode connectivity has been reported in a host of neurological and psychiatric illnesses and in persons at genetic risk for such illnesses. Whereas the neurophysiologic mechanisms that regulate default-mode connectivity are unclear, there is growing evidence that genetic factors play a role. In this report, we estimate the importance of genetic effects on the default-mode network by examining covariation patterns in functional connectivity among 333 individuals from 29 randomly selected extended pedigrees. Heritability for default-mode functional connectivity was 0.424 +/- 0.17 (P = 0.0046). Although neuroanatomic variation in this network was also heritable, the genetic factors that influence default-mode functional connectivity and gray-matter density seem to be distinct, suggesting that unique genes influence the structure and function of the network. In contrast, significant genetic correlations between regions within the network provide evidence that the same genetic factors contribute to variation in functional connectivity throughout the default mode. Specifically, the left parahippocampal region was genetically correlated with all other network regions. In addition, the posterior cingulate/precuneus region, medial prefrontal cortex, and right cerebellum seem to form a subnetwork. Default-mode functional connectivity is influenced by genetic factors that cannot be attributed to anatomic variation or a single region within the network. By establishing the heritability of default-mode functional connectivity, this experiment provides the obligatory evidence required before these measures can be considered as endophenotypes for psychiatric or neurological illnesses or to identify genes influencing intrinsic brain function. [less ▲]

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See detailImpact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and Rural Africa
De Filippo, C.; Cavalieri, D.; Di Paola, M. et al

in Proceedings of the National Academy of Sciences of the United States of America (2010), 107(33), 14691-14696

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See detailBrain plasticity related to the consolidation of motor sequence learning and motor adaptation
Debas, K.; Carrier, J.; Orban, Patricia ULiege et al

in Proceedings of the National Academy of Sciences of the United States of America (2010), 107(41), 17839-44

This study aimed to investigate, through functional MRI (fMRI), the neuronal substrates associated with the consolidation process of two motor skills: motor sequence learning (MSL) and motor adaptation ... [more ▼]

This study aimed to investigate, through functional MRI (fMRI), the neuronal substrates associated with the consolidation process of two motor skills: motor sequence learning (MSL) and motor adaptation (MA). Four groups of young healthy individuals were assigned to either (i) a night/sleep condition, in which they were scanned while practicing a finger sequence learning task or an eight-target adaptation pointing task in the evening (test) and were scanned again 12 h later in the morning (retest) or (ii) a day/awake condition, in which they were scanned on the MSL or the MA tasks in the morning and were rescanned 12 h later in the evening. As expected and consistent with the behavioral results, the functional data revealed increased test-retest changes of activity in the striatum for the night/sleep group compared with the day/awake group in the MSL task. By contrast, the results of the MA task did not show any difference in test-retest activity between the night/sleep and day/awake groups. When the two MA task groups were combined, however, increased test-retest activity was found in lobule VI of the cerebellar cortex. Together, these findings highlight the presence of both functional and structural dissociations reflecting the off-line consolidation processes of MSL and MA. They suggest that MSL consolidation is sleep dependent and reflected by a differential increase of neural activity within the corticostriatal system, whereas MA consolidation necessitates either a period of daytime or sleep and is associated with increased neuronal activity within the corticocerebellar system. [less ▲]

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