Multiscale and Extended Retrieval of Associative Memory Structures in a Cortical Model of Local-Global Inhibition Balance.

Inhibitory neurons take on many forms and functions. How this diversity contributes to memory function is not completely known. Previous formal studies indicate inhibition differentiated by local and global connectivity in associative memory networks functions to rescale the level of retrieval of excitatory assemblies.

Neural mechanisms for learning hierarchical structures of information.

Spatial and temporal information from the environment is often hierarchically organized, so is our knowledge formed about the environment. Identifying the meaningful segments embedded in hierarchically structured information is crucial for cognitive functions, including visual, auditory, motor, memory, and language processing. Segmentation enables the grasping of the links between isolated entities, offering the basis for reasoning and thinking.

Multiscale representations of community structures in attractor neural networks.

Our cognition relies on the ability of the brain to segment hierarchically structured events on multiple scales. Recent evidence suggests that the brain performs this event segmentation based on the structure of state-transition graphs behind sequential experiences. However, the underlying circuit mechanisms are poorly understood.

Extended Temporal Association Memory by Modulations of Inhibitory Circuits.

Hebbian learning of excitatory synapses plays a central role in storing activity patterns in associative memory models. Interstimulus Hebbian learning associates multiple items by converting temporal correlation to spatial correlation between attractors. Growing evidence suggests the importance of inhibitory plasticity in memory processing, but the consequence of such regulation in associative memory has not been understood.

Unsupervised Detection of Cell-Assembly Sequences by Similarity-Based Clustering.

Neurons which fire in a fixed temporal pattern (i.e., "cell assemblies") are hypothesized to be a fundamental unit of neural information processing.

Neuronal stability in medial frontal cortex sets individual variability in decision-making.

In the brain, decision making is instantiated in dedicated neural circuits. However, there is considerable individual variability in decision-making behavior, particularly under uncertainty. The origins of decision variability within these conserved neural circuits are not known.

Dendritic processing of spontaneous neuronal sequences for single-trial learning.

Spontaneous firing sequences are ubiquitous in cortical networks, but their roles in cellular and network-level computations remain unexplored. In the hippocampus, such sequences, conventionally called preplay, have been hypothesized to participate in learning and memory. Here, we present a computational model for encoding input sequence patterns into internal network states based on the propagation of preplay sequences in recurrent neuronal networks.

Recurrent network model for learning goal-directed sequences through reverse replay.

Reverse replay of hippocampal place cells occurs frequently at rewarded locations, suggesting its contribution to goal-directed path learning. Symmetric spike-timing dependent plasticity (STDP) in CA3 likely potentiates recurrent synapses for both forward (start to goal) and reverse (goal to start) replays during sequential activation of place cells. However, how reverse replay selectively strengthens forward synaptic pathway is unclear.

Correction to: Reproducibility and Validity of a Questionnaire Measuring Treatment Burden on Patients with Type 2 Diabetes: Diabetic Treatment Burden Questionnaire (DTBQ).

In the original publication, second author's name was incorrectly published as Hiroki Shin. The correct name should read as 'Koki Shin'.

Reproducibility and Validity of a Questionnaire Measuring Treatment Burden on Patients with Type 2 Diabetes: Diabetic Treatment Burden Questionnaire (DTBQ).

Introduction: To measure the burden of pharmacotherapy on patients with type 2 diabetes mellitus (T2DM), we developed the Diabetes Treatment Burden Questionnaire (DTBQ), a patient-administered questionnaire composed of 18 questions, and evaluated its reproducibility and validity.

Methods: We enrolled 240 patients with T2DM under pharmacotherapy over 20 years of age at seven institutes in Japan. Their physicians filled out report forms on patient backgrounds, and the patients answered both the DTBQ and the Diabetes Treatment Satisfaction Questionnaire (DTSQ).

Temporal relation between neural activity and neurite pruning on a numerical model and a microchannel device with micro electrode array.

Synapse elimination and neurite pruning are essential processes for the formation of neuronal circuits. These regressive events depend on neural activity and occur in the early postnatal days known as the critical period, but what makes this temporal specificity is not well understood. One possibility is that the neural activities during the developmentally regulated shift of action of GABA inhibitory transmission lead to the critical period.

Molecular properties of the high-affinity choline transporter CHT1.

This article summarizes molecular properties of the high-affinity choline transporter (CHT1) with reference to the historical background focusing studies performed in laboratories of the author. CHT1 is present on the presynaptic terminal of cholinergic neurons, and takes up choline which is the precursor of acetylcholine. The Na(+)-dependent uptake of choline by CHT1 is the rate-limiting step for synthesis of acetylcholine.

Role of the third intracellular loop in the subtype-specific internalization and recycling of muscarinic M2 and M4 receptors.

Muscarinic M2, M4, and M2-M4 chimera receptors were transiently expressed in HEK-293 tsA201 cells, and agonist-dependent internalization of these receptors and recycling of internalized receptors were examined by measuring the amount of cell-surface receptors as [3H]N-methylscopolamine (NMS) binding activity. Coexpression of a dominant negative form of dynamin (DN-dynamin,dynamin K44A) greatly reduced the agonist-dependent internalization of M4 receptors but not of M2 receptors, as was reported by Vögler et al. (J Biol Chem 273, 12155-12160, 1998).

Interaction of the muscarinic acetylcholine receptor M₂ subtype with G protein Gα(i/o) isotypes and Gβγ subunits as studied with the maltose-binding protein-M₂-Gα(i/o) fusion proteins expressed in Escherichia coli.

We expressed the fusion proteins of the muscarinic acetylcholine receptor M2 subtype (M2 receptor) with a maltose-binding protein (MBP) and various G protein α subunits (Gα(i1-i3/o)) at its N- and C-terminals, respectively (MBP-M2-Gα(i/o)), in Escherichia coli, and examined the effect of G protein βγ subunits (Gβγ) on the receptor-Gα interaction as assessed by agonist- and GDP-dependent [(35)S]GTPγS binding of the fusion proteins. We found that (i) Gβγ promoted both the agonist-dependent and -independent [(35)S]GTPγS binding with little effect on the guanine nucleotide-sensitive high-affinity agonist binding, (ii) the specific [(35)S]GTPγS binding activity was much greater for MBP-M2-Gα(oA) than for MBP-M2-Gα(i1-i3) in the absence of Gβγ, whereas Gβγ preferentially promoted the agonist-dependent decrease in the affinity for GDP of MBP-M2-Gα(i1-i3) rather than of MBP-M2-Gα(oA), and (iii) the proportion of agonist-dependent [(35)S]GTPγS binding was roughly 50% irrespective of species of Gα and the presence or absence of Gβγ. These results demonstrate that receptor-Gα fusion proteins expressed in E.

Chemokine receptor CCR8 is required for lipopolysaccharide-triggered cytokine production in mouse peritoneal macrophages.

Chemokine (C-C motif) receptor 8 (CCR8), the chemokine receptor for chemokine (C-C motif) ligand 1 (CCL1), is expressed in T-helper type-2 lymphocytes and peritoneal macrophages (PMφ) and is involved in various pathological conditions, including peritoneal adhesions. However, the role of CCR8 in inflammatory responses is not fully elucidated. To investigate the function of CCR8 in macrophages, we compared cytokine secretion from mouse PMφ or bone marrow-derived macrophages (BMMφ) stimulated with various Toll-like receptor (TLR) ligands in CCR8 deficient (CCR8-/-) and wild-type (WT) mice.

Estimation of templates and timings of spikes in extracellular voltage signals containing overlaps of the arbitrary number of spikes.

Development of methods to detect and classify neural spikes in extracellular voltage signals (e.g. commonly referred to as spike sorting) have been one of important subjects in neuroscience and neural engineering.

Efficient sequential Bayesian inference method for real-time detection and sorting of overlapped neural spikes.

Overlapping of extracellularly recorded neural spike waveforms causes the original spike waveforms to become hidden and merged, confounding the real-time detection and sorting of these spikes. Methods proposed for solving this problem include using a multi-trode or placing a restriction on the complexity of overlaps. In this paper, we propose a rapid sequential method for the robust detection and sorting of arbitrarily overlapped spikes recorded with arbitrary types of electrodes.

Molecular properties of muscarinic acetylcholine receptors.

Muscarinic acetylcholine receptors, which comprise five subtypes (M1-M5 receptors), are expressed in both the CNS and PNS (particularly the target organs of parasympathetic neurons). M1-M5 receptors are integral membrane proteins with seven transmembrane segments, bind with acetylcholine (ACh) in the extracellular phase, and thereafter interact with and activate GTP-binding regulatory proteins (G proteins) in the intracellular phase: M1, M3, and M5 receptors interact with Gq-type G proteins, and M2 and M4 receptors with Gi/Go-type G proteins. Activated G proteins initiate a number of intracellular signal transduction systems.

Transmembrane topology and oligomeric structure of the high-affinity choline transporter.

The high-affinity choline transporter CHT1 mediates choline uptake essential for acetylcholine synthesis in cholinergic nerve terminals. CHT1 belongs to the Na(+)/glucose cotransporter family (SLC5), which is postulated to have a common 13-transmembrane domain core; however, no direct experimental evidence for CHT1 transmembrane topology has yet been reported. We examined the transmembrane topology of human CHT1 using cysteine-scanning analysis.

Identification of physiologically active substances as novel ligands for MRGPRD.

Mas-related G-protein coupled receptor member D (MRGPRD) is a G protein-coupled receptor (GPCR) which belongs to the Mas-related GPCRs expressed in the dorsal root ganglia (DRG). In this study, we investigated two novel ligands in addition to beta-alanine: (1) beta-aminoisobutyric acid, a physiologically active substance, with which possible relation to tumors has been seen together with beta-alanine; (2) diethylstilbestrol, a synthetic estrogen hormone. In addition to the novel ligands, we found that transfection of MRGPRD leads fibroblast cells to form spheroids, which would be related to oncogenicity.

Platform for the rapid construction and evaluation of GPCRs for crystallography in Saccharomyces cerevisiae.

Background: Recent successes in the determination of G-protein coupled receptor (GPCR) structures have relied on the ability of receptor variants to overcome difficulties in expression and purification. Therefore, the quick screening of functionally expressed stable receptor variants is vital.

Results: We developed a platform using Saccharomyces cerevisiae for the rapid construction and evaluation of functional GPCR variants for structural studies.

Formation of one-way-structured cultured neuronal networks in microfluidic devices combining with micropatterning techniques.

We present a simple method to regulate the direction of axon development in cultured neurons using microfabrication and microfluidics techniques. We fabricate a PDMS-based device and place it onto a chemically micropatterned glass substrate. We confirm that cultured neurons extend neurites along the medium flow direction and the micropatterned regions.

The high-affinity choline transporter CHT1 is regulated by the ubiquitin ligase Nedd4-2.

The high-affinity choline transporter (CHT1), which is specifically expressed in cholinergic neurons, constitutes a rate-limiting step for acetylcholine synthesis. We have found that the exogenous ubiquitin ligase Nedd4-2 interacts with CHT1 expressed in HEK293 cells decreasing the amount of cell surface CHT1 by approximately 40%, and that small interfering RNA for endogenous Nedd4-2 enhances the choline uptake activity by CHT1 in HEK293 cells. These results indicate that Nedd4-2-mediated ubiquitination regulates the cell surface expression of CHT1 in cultured cells and suggest a possibility that treatments or drugs which inhibit the interaction between CHT1 and Nedd4-2 might be useful for diseases involving decrease in acetylcholine level such as Alzheimer's disease.

Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist.

The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases.