Oscillatory rhythms in different frequency ranges mark different behavioral states and are thought to provide distinct temporal windows that coherently bind cooperating neuronal assemblies. However, the rhythms in different bands can also interact with each other, suggesting the possibility of higher-order representations of brain states by such rhythmic activity. To explore this possibility, we analyzed local field potential oscillations recorded simultaneously from the striatum and the hippocampus. As rats performed a task requiring active navigation and decision making, the amplitudes of multiple high-frequency oscillations were dynamically modulated in task-dependent patterns by the phase of cooccurring theta-band oscillations both within and across these structures, particularly during decision-making behavioral epochs. Moreover, the modulation patterns uncovered distinctions among both high-and low-frequency subbands. Cross-frequency coupling of multiple neuronal rhythms could be a general mechanism used by the brain to perform networklevel dynamical computations underlying voluntary behavior.amplitude modulation ͉ gamma ͉ theta O scillations in neural population voltage activity are universal phenomena (1). Among brain rhythms, theta oscillations in local field potentials (LFPs) recorded in the hippocampus are prominent during active behaviors (2-5), and these have long been intensively analyzed in the rodent in relation to spatial navigation (6), memory (7), and sleep (8). Theta-band rhythms (4-12 Hz) are now known to occur in other cortical (9-12) and subcortical (12-15) regions, however, including the striatum (14-17), studied here. Gamma oscillations (30-100 Hz) have also received special attention because of their proposed role in functions such as sensory binding (18), selective attention (19-21), transient neuronal assembly formation (22), and information transmission and storage (23-25). The existence of physiologically meaningful neocortical oscillations at even higher frequencies, above the traditional gamma range, has been reported as well (10,(26)(27)(28). In rodents, for example, brief sharp-wave associated ripples (120-200 Hz) appear in the hippocampal formation during slow wave sleep, immobility and consummatory behavior, characteristically in the absence of theta waves (2, 29).The oscillatory activities conventionally assigned to different frequency bands are not completely independent (2-4, 9, 10, 30). In one type of interaction, the phase of low-frequency rhythms modulates the amplitude of higher-frequency oscillations (9, 10, 30). For example, theta phase is known to modulate gamma power in rodent hippocampal and cortical circuits (2-4, 31), and the phase of theta rhythms recorded in the human neocortex can modulate wide-band (60-200 Hz) high-frequency oscillations (10). Such theta-gamma nesting is thought to play a role in sequential memory organization and maintenance of working memory, and more generally in ''phase coding' ' (25, 31). Based on evidence suggesting that theta rhythms i...

Abstract. We have defined a signal responsible for the morphological differentiation of human umbilical vein and human dermal microvascular endothelial cells in vitro. We find that human umbilical vein endothelial cells deprived of growth factors undergo morphological differentiation with tube formation after 6-12 wk, and that human dermal microvascular endothelial cells differentiate after 1 wk of growth factor deprivation. Here, we report that morphological differentiation of both types of endothelial cells is markedly accelerated by culture on a reconstituted gel composed of basement membrane proteins. Under these conditions, tube formation begins in 1-2 h and is complete by 24 h. The tubes are maintained for >2 wk. Little or no proliferation occurs under these conditions, although the cells, when trypsinized and replated on fibronectin-coated tissue culture dishes, resume division. U1-trastructurally, the tubes possess a lumen surrounded by endothelial cells attached to one another by junctional complexes. The cells possess Weibel-Palade bodies and factor VIII-related antigens, and take up acetylated low density lipoproteins. Tubule formation does not occur on tissue culture plastic coated with laminin or collagen IV, either alone or in combination, or on an agarose or a collagen I gel. However, endothelial cells cultured on a collagen I gel supplemented with laminin form tubules, while supplementation with collagen IV induces a lesser degree of tubule formation. Preincubation of endothelial cells with antibodies to laminin prevented tubule formation while antibodies to collagen IV were less inhibitory. Preincubation of endotheial cells with synthetic peptides derived from the laminin B1 chain that bind to the laminin cell surface receptor or incorporation of these peptides into the gel matrix blocked tubule formation, whereas control peptides did not. These observations indicate that endothelial cells can rapidly differentiate on a basement membrane-like matrix and that laminin is the principal factor in inducing this change.

Learning to perform a behavioural procedure as a well-ingrained habit requires extensive repetition of the behavioural sequence, and learning not to perform such behaviours is notoriously difficult. Yet regaining a habit can occur quickly, with even one or a few exposures to cues previously triggering the behaviour. To identify neural mechanisms that might underlie such learning dynamics, we made long-term recordings from multiple neurons in the sensorimotor striatum, a basal ganglia structure implicated in habit formation, in rats successively trained on a reward-based procedural task, given extinction training and then given reacquisition training. The spike activity of striatal output neurons, nodal points in cortico-basal ganglia circuits, changed markedly across multiple dimensions during each of these phases of learning. First, new patterns of task-related ensemble firing successively formed, reversed and then re-emerged. Second, task-irrelevant firing was suppressed, then rebounded, and then was suppressed again. These changing spike activity patterns were highly correlated with changes in behavioural performance. We propose that these changes in task representation in cortico-basal ganglia circuits represent neural equivalents of the explore-exploit behaviour characteristic of habit learning.

Memories for habits and skills ("implicit or procedural memory") and memories for facts ("explicit or episodic memory") are built up in different brain systems and are vulnerable to different neurodegenerative disorders in humans. So that the striatum-based mechanisms underlying habit formation could be studied, chronic recordings from ensembles of striatal neurons were made with multiple tetrodes as rats learned a T-maze procedural task. Large and widely distributed changes in the neuronal activity patterns occurred in the sensorimotor striatum during behavioral acquisition, culminating in task-related activity emphasizing the beginning and end of the automatized procedure. The new ensemble patterns remained stable during weeks of subsequent performance of the same task. These results suggest that the encoding of action in the sensorimotor striatum undergoes dynamic reorganization as habit learning proceeds.

Understanding how an animal's ability to learn relates to neural activity or is altered by lesions, different attentional states, pharmacological interventions, or genetic manipulations are central questions in neuroscience. Although learning is a dynamic process, current analyses do not use dynamic estimation methods, require many trials across many animals to establish the occurrence of learning, and provide no consensus as how best to identify when learning has occurred. We develop a state-space model paradigm to characterize learning as the probability of a correct response as a function of trial number (learning curve). We compute the learning curve and its confidence intervals using a state-space smoothing algorithm and define the learning trial as the first trial on which there is reasonable certainty (Ͼ0.95) that a subject performs better than chance for the balance of the experiment. For a range of simulated learning experiments, the smoothing algorithm estimated learning curves with smaller mean integrated squared error and identified the learning trials with greater reliability than commonly used methods. The smoothing algorithm tracked easily the rapid learning of a monkey during a single session of an association learning experiment and identified learning 2 to 4 d earlier than accepted criteria for a rat in a 47 d procedural learning experiment. Our state-space paradigm estimates learning curves for single animals, gives a precise definition of learning, and suggests a coherent statistical framework for the design and analysis of learning experiments that could reduce the number of animals and trials per animal that these studies require.

Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with MEF2D fusions, TCF3–PBX1 fusions, ETV6–RUNX1–positive/ETV6–RUNX1–like, DUX4 fusions, ZNF384 fusions, BCR–ABL1/Ph–like, high hyperdiploidy, and KMT2A fusions), we defined six additional gene expression subgroups: G9 was associated with both PAX5 and CRLF2 fusions; G10 and G11 with mutations in PAX5 (p.P80R) and IKZF1 (p.N159Y), respectively; G12 with IGH–CEBPE fusion and mutations in ZEB2 (p.H1038R); and G13 and G14 with TCF3/4–HLF and NUTM1 fusions, respectively. In pediatric BCP ALL, subgroups G2 to G5 and G7 (51 to 65/67 chromosomes) were associated with low-risk, G7 (with ≤50 chromosomes) and G9 were intermediate-risk, whereas G1, G6, and G8 were defined as high-risk subgroups. In adult BCP ALL, G1, G2, G6, and G8 were associated with high risk, while G4, G5, and G7 had relatively favorable outcomes. This large-scale transcriptome sequence analysis of BCP ALL revealed distinct molecular subgroups that reflect discrete pathways of BCP ALL, informing disease classification and prognostic stratification. The combined results strongly advocate that RNA sequencing be introduced into the clinical diagnostic workup of BCP ALL.

Glabridin is the main ingredient in hydrophobic fraction of licorice extract affecting on skins. In this study, we investigated inhibitory effects of glabridin on melanogenesis and inflammation using cultured B16 murine melanoma cells and guinea pig skins. The results indicated that glabridin inhibits tyrosinase activity of these cells at concentrations of 0.1 to 1.0 microg/ml and had no detectable effect on their DNA synthesis. Combined analysis of SDS-polyacrylamide gel electrophoresis and DOPA staining on the large granule fraction of these cells disclosed that glabridin decreased specifically the activities of T1 and T3 tyrosinase isozymes. It was also shown that UVB-induced pigmentation and erythema in the skins of guinea pigs were inhibited by topical applications of 0.5% glabridin. Anti-inflammatory effects of glabridin in vitro were also shown by its inhibition of superoxide anion productions and cyclooxygenase activities. These data indicated that glabridin is a unique compound possessing more than one function; not only the inhibition of melanogenesis but also the inhibition of inflammation in the skins. By replacing each of hydroxyl groups of glabridin with others, it was revealed that the inhibitory effect of 2'-O-ethyl glabridin was significantly stronger than that of 4'-O-ethyl-glabridin on melanin synthesis in cultured B16 cells at the concentration of 1.0 mg/ml. With replacement of both of two hydroxyl groups, the inhibitory effect was totally lost. Based on these data, we concluded that two hydroxyl groups of glabridin are important for the inhibition of melanin synthesis and that the hydroxyl group at the 4' position of this compound is more closely related to melanin synthesis.

The striatum and hippocampus are conventionally viewed as complementary learning and memory systems, with the hippocampus specialized for fact-based episodic memory and the striatum for procedural learning and memory. Here we directly tested whether these two systems exhibit independent or coordinated activity patterns during procedural learning. We trained rats on a conditional T-maze task requiring navigational and cue-based associative learning. We recorded local field potential (LFP) activity with tetrodes chronically implanted in the caudoputamen and the CA1 field of the dorsal hippocampus during 6 -25 days of training. We show that simultaneously recorded striatal and hippocampal theta rhythms are modulated differently as the rats learned to perform the T-maze task but nevertheless become highly coherent during the choice period of the maze runs in rats that successfully learned the task. Moreover, in the rats that acquired the task, the phase of the striatal-hippocampal theta coherence was modified toward a consistent antiphase relationship, and these changes occurred in proportion to the levels of learning achieved. We suggest that rhythmic oscillations, including theta-band activity, could influence not only neural processing in cortico-basal ganglia circuits but also dynamic interactions between basal ganglia-based and hippocampus-based forebrain circuits during the acquisition and performance of learned behaviors. Experience-dependent changes in coordination of oscillatory activity across brain structures thus may parallel the well known plasticity of spike activity that occurs as a function of experience.basal ganglia ͉ hippocampus ͉ local field potential ͉ oscillations ͉ striatum T he striatum and the hippocampus are both forebrain structures implicated in the learning and memory of behavioral sequences, but behavioral sequences of different sorts. The striatum, as part of basal ganglia circuitry, is associated with learning sequences of actions that make up goal-directed procedures and habits (1-4). The hippocampus and adjoining cortical structures are recognized as critical for encoding and storing sequences on the basis of episodic, context-cued events (5-8). Lesion studies have dissociated striatum-dependent and hippocampus-dependent forms of learning and memory (9-11), supporting the view that these systems work independently or even competitively. In humans, there is evidence that one system can substitute for another (12). Other evidence, however, suggests that ''hippocampal'' deficits can follow damage in regions of the dorsal striatum interconnected with hippocampal/limbic circuits (13,14). Furthermore, part of the ventral striatum receives direct projections from the hippocampus.Rhythmic activity in the theta range (Ϸ7-14 Hz in the rodent) has been proposed to be crucial for mnemonic coding in the hippocampus and related limbic structures. Pathways interconnecting the hippocampus and neocortex are thought to use these rhythms for transferring and coordinating neural representations in cort...