ON and OFF starburst amacrine cells are controlled by distinct cholinergic pathways.

Cholinergic signaling in the retina is mediated by acetylcholine (ACh) released from starburst amacrine cells (SACs), which are key neurons for motion detection. SACs comprise ON and OFF subtypes, which morphologically show mirror symmetry to each other. Although many physiological studies on SACs have targeted ON cells only, the synaptic computation of ON and OFF SACs is assumed to be similar.

Effects of Progesterone and Other Gonadal Hormones on Glutamatergic Circuits in the Retina.

Background: Gonadal hormones function in the retina; however, their targets have not yet been identified. Therefore, the present study examined the effects of progesterone and other gonadal hormones on glutamatergic circuits in the retina.

Methods: Extracellular glutamate concentrations, which correspond to the amount of glutamate released, were examined using an enzyme-linked fluorescent assay system.

Starburst amacrine cells form gap junctions in the early postnatal stage of the mouse retina.

Although gap junctional coupling in the developing retina is important for the maturation of neuronal networks, its role in the development of individual neurons remains unclear. Therefore, we herein investigated whether gap junctional coupling by starburst amacrine cells (SACs), a key neuron for the formation of direction selectivity, occurs during the developmental stage in the mouse retina. Neurobiotin-injected SACs coupled with many neighboring cells before eye-opening.

P2X receptors supply extracellular choline as a substrate for acetylcholine synthesis.

Acetylcholine (ACh), an excitatory neurotransmitter, is biosynthesized from choline in cholinergic neurons. Import from the extracellular space to the intracellular environment through the high-affinity choline transporter is currently regarded to be the only source of choline for ACh synthesis. We recently demonstrated that the P2X receptor, through which large cations permeate, functions as an alternative pathway for choline transport in the mouse retina.

Orai1 Channels Are Essential for Amplification of Glutamate-Evoked Ca Signals in Dendritic Spines to Regulate Working and Associative Memory.

Store-operated Orai1 calcium channels function as highly Ca-selective ion channels and are broadly expressed in many tissues including the central nervous system, but their contributions to cognitive processing are largely unknown. Here, we report that many measures of synaptic, cellular, and behavioral models of learning are markedly attenuated in mice lacking Orai1 in forebrain excitatory neurons. Results with focal glutamate uncaging in hippocampal neurons support an essential role of Orai1 channels in amplifying NMDA-receptor-induced dendritic Ca transients that drive activity-dependent spine morphogenesis and long-term potentiation at Schaffer collateral-CA1 synapses.

Interspike intervals within retinal spike bursts combinatorially encode multiple stimulus features.

Neurons in various regions of the brain generate spike bursts. While the number of spikes within a burst has been shown to carry information, information coding by interspike intervals (ISIs) is less well understood. In particular, a burst with k spikes has k-1 intraburst ISIs, and these k-1 ISIs could theoretically encode k-1 independent values.

Involvement of the C-terminal domain in cell surface localization and G-protein coupling of mGluR6.

Metabotropic glutamate receptor 6, mGluR6, interacts with scaffold proteins and Gβγ subunits via its intracellular C-terminal domain (CTD). The mGluR6 pathway is critically involved in the retinal processing of visual signals. We herein investigated whether the CTD (residues 840-871) was necessary for mGluR6 cell surface localization and G-protein coupling using mGluR6-CTD mutants with immunocytochemistry, surface biotinylation assays, and electrophysiological approaches.

Two Types of Cl Transporters Contribute to the Regulation of Intracellular Cl Concentrations in ON- and OFF-type Bipolar Cells in the Mouse Retina.

In the retina, ON- and OFF-type bipolar cells are classified by subtype-specific center responses, which are attributed to differences in glutamate receptor subtypes. However, the mechanisms by which ON- and OFF-type bipolar cells generate subtype-specific surround responses remain unclear. One hypothesis for surround responses is that intracellular Cl concentrations ([Cl-]) are set at different levels to achieve opposite polarities for GABA responses in ON- and OFF-type bipolar cells.

Auxiliary Proteins are the Predominant Determinants of Differential Efficacy of Clinical Candidates Acting as AMPA Receptor Positive Allosteric Modulators.

Positive allosteric modulators (PAMs) of AMPA receptors boost cognitive performance in preclinical and clinical studies. Their therapeutic window is narrow, however, and clinical application will likely only occur if greater discrimination in activity is achieved. Toward that end, we compared the modulatory activity of two PAMs recently considered as clinical candidates, LY451395 (mibampator) and PF-04958242/BIIB104, on recombinant and native AMPA receptors (AMPARs).

Dietary Supplementation with Lysine and Threonine Modulates the Performance and Plasma Metabolites of Broiler Chicken.

Here, we investigated whether the optimal threonine (Thr) to lysine (Lys) ratio in high Lys diet improves the growth performance of modern broiler chickens at finisher period and determined the possible mechanism underlying improvement in the growth performance of chickens fed with high Lys or Lys + Thr diet using metabolome analyses. Eighteen 21-day-old chickens housed in individual cages were randomly divided into three groups of six chickens fed with different diets as follows: control diet, high Lys diet (150% Lys content of National Research Council requirement), and high Lys + Thr diet (0.68 of Thr/Lys in high Lys diet).

Variation in the Phenotype of Photosensitive Cells Produced from Human Fibroblast Cell Lines.

Background: Photoreceptors differentiated from somatic cells are a useful tool for transplantation and drug screening. We previously showed that photosensitive cells are differentiated from human fibroblasts by direct reprogramming. In induced pluripotent stem (iPS) cells or embryonic stem (ES) cells, the properties of differentiated cells differ among the source of cell lines.

Peripherally derived T regulatory and γδ T cells have opposing roles in the pathogenesis of intractable pediatric epilepsy.

The pathophysiology of drug-resistant pediatric epilepsy is unknown. Flow cytometric analysis of inflammatory leukocytes in resected brain tissues from 29 pediatric patients with genetic (focal cortical dysplasia) or acquired (encephalomalacia) epilepsy demonstrated significant brain infiltration of blood-borne inflammatory myeloid cells and memory CD4 and CD8 T cells. Significantly, proinflammatory (IL-17- and GM-CSF-producing) γδ T cells were concentrated in epileptogenic lesions, and their numbers positively correlated with disease severity.

Excitatory Synaptic Input to Hilar Mossy Cells under Basal and Hyperexcitable Conditions.

Hilar mossy cells (HMCs) in the hippocampus receive glutamatergic input from dentate granule cells (DGCs) via mossy fibers (MFs) and back-projections from CA3 pyramidal neuron collateral axons. Many fundamental features of these excitatory synapses have not been characterized in detail despite their potential relevance to hippocampal cognitive processing and epilepsy-induced adaptations in circuit excitability. In this study, we compared pre- and postsynaptic parameters between MF and CA3 inputs to HMCs in young and adult mice of either sex and determined the relative contributions of the respective excitatory inputs during and models of hippocampal hyperexcitability.

Novel channel-mediated choline transport in cholinergic neurons of the mouse retina.

Choline uptake into the presynaptic terminal of cholinergic neurons is mediated by the high-affinity choline transporter and is essential for acetylcholine synthesis. In a previous study, we reported that P2X purinoceptors are selectively expressed in OFF-cholinergic amacrine cells of the mouse retina. Under specific conditions, P2X purinoceptors acquire permeability to large cations, such as -methyl-d-glucamine, and therefore potentially could act as a noncanonical pathway for choline entry into neurons.

Physiological contribution of P2X receptors in postreceptoral signal processing in the mouse retina.

ATP activates P2X receptors and acts as a neurotransmitter in the nervous system. We have previously reported that P2X receptors modulate the firing rate of retinal ganglion cells. Since many subtypes of P2X receptors are distributed in the mouse retina, it is likely that the modulatory effects of P2X receptor-mediated signaling can occur at multiple synaptic levels in the retina.

In vitro transdifferentiation of human peripheral blood mononuclear cells to photoreceptor-like cells.

Direct reprogramming is a promising, simple and low-cost approach to generate target cells from somatic cells without using induced pluripotent stem cells. Recently, peripheral blood mononuclear cells (PBMCs) have attracted considerable attention as a somatic cell source for reprogramming. As a cell source, PBMCs have an advantage over dermal fibroblasts with respect to the ease of collecting tissues.

Crizotinib-Induced Abnormal Signal Processing in the Retina.

Molecular target therapy for cancer is characterized by unique adverse effects that are not usually observed with cytotoxic chemotherapy. For example, the anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor crizotinib causes characteristic visual disturbances, whereas such effects are rare when another ALK-tyrosine kinase inhibitor, alectinib, is used. To elucidate the mechanism responsible for these visual disturbances, the responses to light exhibited by retinal ganglion cells treated with these agents were evaluated using a C57BL6 mouse ex vivo model.

ON-pathway-dominant glycinergic regulation of cholinergic amacrine cells in the mouse retina.

Direction selectivity in the retina has been studied as a model of dendritic computation of neural circuits. Starburst amacrine cells (SACs) have been examined as a model system of dendritic computation as they play a pivotal role in the formation of direction selectivity. Because the difference of anatomical location inside the retina made ON-SACs an easier target to record, the biophysical properties of ON-SACs have been used to predict those of OFF-SACs.

Derivation of human differential photoreceptor cells from adult human dermal fibroblasts by defined combinations of CRX, RAX, OTX2 and NEUROD.

Redirecting differentiation of somatic cells by over-expression of transcription factors is a promising approach for regenerative medicine, elucidation of pathogenesis and development of new therapies. We have previously defined a transcription factor combination, that is, CRX, RAX and NEUROD, that can generate photosensitive photoreceptor cells from human iris cells. Here, we show that human dermal fibroblasts are differentiated to photoreceptor cells by the same transcription factor combination as human iris cells.

Distribution and development of P2Y1-purinoceptors in the mouse retina.

There is increasing evidence that ATP acts on purinergic receptors and mediates synaptic transmission in the retina. In a previous study, we raised the possibility that P2X-purinoceptors, presumably P2X(2)-purinoceptors in OFF-cholinergic amacrine cells, play a key role in the formation of OFF pathway-specific modulation. In this study, we examined whether the P2Y(1)-purinoceptors can function in cholinergic amacrine cells in the mouse retina since cholinergic amacrine cells in the rat retina express P2Y(1)-purinoceptors.

Mismatched decoding in the brain.

"How is information decoded in the brain?" is one of the most difficult and important questions in neuroscience. We have developed a general framework for investigating to what extent the decoding process in the brain can be simplified. First, we hierarchically constructed simplified probabilistic models of neural responses that ignore more than Kth-order correlations using the maximum entropy principle.

Evaluation of the usefulness of a simple touch-panel method for the screening of dementia.

In clinical settings, Hasegawa's dementia scale, revised (HDS-R), and the mini-mental state examination (MMSE) are widely employed as simple mental function tests useful for the diagnosis of dementia. In recent years, for the early diagnosis of dementia, a simple computerized touch panel-type screening test (touch panel-type screening test), called the "forgetfulness consultation program" (Nihon Kohden Corp.), has been developed.

Estimating receptive fields from responses to natural stimuli with asymmetric intensity distributions.

The reasons for using natural stimuli to study sensory function are quickly mounting, as recent studies have revealed important differences in neural responses to natural and artificial stimuli. However, natural stimuli typically contain strong correlations and are spherically asymmetric (i.e.

Pathway-dependent modulation by P2-purinoceptors in the mouse retina.

Adenosine trisphosphate (ATP) activates purinoceptors and acts as a neurotransmitter in the nervous system. In the retina, we previously reported that the immunohistochemical distribution of the subset of P2-purinoceptors differs between the ON and OFF pathways. Here, we investigated whether ATP activates P2-purinoceptors and modulates the physiological function of the mouse retina.