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Morishima, M.

Publications and source records attributed to Morishima, M..

5 recordsLinked to original sources

Thalamocortical credit routing from the basal ganglia and cerebellum: anatomical constraints and circuit principles

Animals learn to select actions that maximize reward in complex environments. A central challenge in this process is credit routing: behavioral outcomes must be routed back to the neural populations that contributed to generating the relevant actions. One possible route is through thalamocortical pathways conveying learning signals from the basal ganglia and cerebellum, where plasticity is shaped by reward-prediction errors. However, how these pathways route such signals back to specific cortical circuits remains unclear. To address this question, we combined anatomical circuit mapping in mice with closed-loop circuit modeling. Anterograde transsynaptic tracing revealed that thalamic neurons receiving input from the substantia nigra pars reticulata or the lateral cerebellar nucleus were largely segregated, with partial overlap in the ventromedial thalamus. Nevertheless, their cortical axons shared a pronounced enrichment in layer 1a, most prominently in secondary motor cortex. In a brain- wide synergistic loop-circuit model, learning was enhanced when both pathways delivered additive and gain-modulating feedback aligned with the cortical action readout. Local activity- based calibration established this alignment, whereas dendritic-spike- and reward-prediction- error-dependent thalamocortical plasticity further refined behavioral output. Module-specific feedback was essential for a brain-machine interface task requiring the simultaneous conditioning of multiple target neurons. Together, these findings define a credit-routing architecture in which laminar convergence, plastic alignment, and modular feedback link parallel subcortical learning systems to cortical action representations.

neuroscience↗

Modeling interregional propagation of α-synuclein in human striatal-midbrain assembloids

Parkinsons disease is characterized by the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra that project to the striatum. Postmortem studies have found that -synuclein pathology spreads across brain regions in a prion-like manner. Human three-dimensional neural tissues provide experimentally tractable platforms for clarifying the molecular pathology of synucleinopathy that overcome the limitations of postmortem brain studies. In this study, we established a human striatal-midbrain assembloid model enabling spatially and temporally controlled -synuclein induction after formation of the nigrostriatal pathway within hStrMAs. Human induced pluripotent stem cells (hiPSCs) were differentiated into striatal spheroids and midbrain spheroids, which were fused to reconstruct the nigrostriatal pathway in vitro. Histological, electrophysiological, and single-cell RNA sequencing analyses confirmed the generation of region-specific neuronal populations, including striatal GABAergic neurons and midbrain DA neurons, and demonstrated that distinct forebrain and ventral midbrain identities were preserved within assembloids. To model synucleinopathy, we generated a doxycycline-inducible -synuclein hiPSC line, permitting selective induction of -synuclein expression in the striatal region after assembloid formation. Spatially restricted -synuclein induction resulted in the progressive accumulation of phosphorylated and fibrillar -synuclein in midbrain DA neurons, indicating interregional propagation through established neural circuits. Transcriptomic analysis of the midbrain region revealed significant downregulation of DA identity and synaptic function genes, suggesting functional impairment of DA neurons following -synuclein propagation. These findings demonstrate that the human neural circuit architecture contributes to the interregional propagation of -synuclein pathology. Our controllable human assembloid platform provides a powerful experimental framework for dissecting the mechanisms of pathological protein spread and developing therapeutic strategies targeting molecular pathology in neurodegenerative diseases. Significance statementOne pathological feature of Parkinsons disease is the progressive spread of -synuclein pathology across brain regions. However, the molecular mechanisms underlying this process remain poorly understood. In this study, we established a human striatal-midbrain assembloid model in which -synuclein expression can be spatially restricted and temporally induced after the nigrostriatal pathway is formed, thus enabling the experimental dissection of interregional -synuclein propagation across brain regions. We demonstrated that -synuclein pathology initiated in the striatal region propagated to midbrain dopaminergic neurons, leading to disease-relevant molecular and transcriptional alterations. These findings provide direct evidence that human neural circuits contribute to the spread of synucleinopathy and offer a controllable human model for studying disease progression and therapeutic strategies.

neuroscience↗

Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils

Microglia, the primary immune cells of the central nervous system, play a crucial role in maintaining brain homeostasis through phagocytosis of various substrates, including amyloid-{beta} (A{beta}) fibrils, a hallmark of Alzheimer disease (AD) pathology. However, the molecular mechanisms regulating microglial A{beta} uptake remain poorly understood. Here, we identified GPR34, a Gi/o-coupled receptor highly expressed in microglia, as a novel regulator of fibrillar A{beta} phagocytosis. Treatment with a selective GPR34 agonist, M1, specifically enhanced uptake of A{beta} fibrils, but not its monomer or oligomer, in both mouse and human microglia. Mechanistically, M1 reduced intracellular cAMP levels, which inversely correlated with A{beta} uptake activity. Importantly, a single intrahippocampal injection of M1 in an AD mouse model significantly increased microglial A{beta} uptake in vivo. Furthermore, single-nucleus RNA-sequencing analysis of Japanese AD patient samples revealed a significant reduction of GPR34 expression in microglia from AD patients compared to controls. We also observed an age-dependent decline in microglial GPR34 expression in both human and mouse datasets, suggesting a potential contribution of GPR34 downregulation to age-related A{beta} accumulation and AD risk. Collectively, our findings identify GPR34 as a promising target for modulating microglial A{beta} clearance and highlight the therapeutic potential of GPR34 agonists in AD. Significance statementAlzheimer disease (AD) is characterized by amyloid-{beta} (A{beta}) accumulation in the brain. Microglia, the brains immune cells, play a crucial role in the metabolism of A{beta}. We discovered that activating the microglial receptor GPR34 with a selective agonist enhances the phagocytosis of A{beta} fibrils, a key pathogenic form of A{beta}. Importantly, GPR34 expression decreases with aging and AD progression, potentially contributing to impaired A{beta} clearance. Our findings highlight GPR34 as a promising therapeutic target for AD, as boosting its activity could promote A{beta} clearance and slow disease progression. This study provides valuable insights into microglial function in AD and offers a novel strategy for developing disease-modifying therapies.

neuroscience↗

Proteomic profile of nuclei containing p62-positive inclusions in neuronal intranuclear inclusion disease

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the neurons, glial cells, and other somatic cells. Although CGG repeat expansions in NOTCH2NLC have been identified in most East Asian patients with NIID, the pathophysiology of NIID remains unclear. Intranuclear inclusions are the pathological hallmark of NIID. Previously, immunohistochemistry has revealed that intranuclear inclusions are ubiquitin-, p62-, and SUMO-1-positive, suggesting the possible alteration of the ubiquitin-proteasomal protein degradation system in the nuclei with inclusions. However, the molecular mechanisms within these nuclei remain unclear. Herein, we analyzed the proteomic profile of nuclei with p62-positive inclusions in NIID with CGG repeat expansion in NOTCH2NLC to discover the proteins involved in the NIID pathophysiology. We used fluorescence-activated cell sorting and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify each protein identified in the nuclei with p62-positive inclusions. The distribution of increased proteins in the autopsy brain samples from three NIID patients was confirmed via immunofluorescence. Overall, 526 proteins were identified, of which 243 were consistently quantified using MS. A 1.4-fold increase was consistently observed for 20 proteins in nuclei with p62-positive inclusions compared to those without. Fifteen proteins identified with medium or high confidence in the LC-MS/MS analysis were further evaluated. Gene ontology enrichment analysis showed enrichment of several terms, including poly(A) RNA binding, nucleosomal DNA binding, and protein binding. Immunofluorescence studies confirmed that the fluorescent intensities of increased RNA-binding proteins identified by proteomic analysis, namely hnRNP A3, hnRNP A2/B1, and hnRNP C1/C2, were higher in the nuclei with p62-positive inclusions than those without; however, they were not confined to the intranuclear inclusions. We identified several increased proteins in nuclei with p62-positive inclusions. These data can form the basis for understanding the pathophysiology of NIID.

biochemistry↗

Conformational change in the monomeric alpha-synuclein imparts fibril polymorphs

-Synuclein (Syn) inclusions are a pathological hallmark of several neurodegenerative disorders. While cryo-electron microscopy studies have revealed distinct fibril polymorphs across different synucleinopathies, the molecular switches controlling polymorphism remained unveiled. In this study, we found that fibril morphology is associated with the conformational state of monomeric Syn. Through systematic manipulation of the ionic strength and temperature, we pinpoint two distinct polymorphs: a twisted morphology at low ionic strength and temperature, and a rod-like morphology at higher ionic strength and temperature. Most strikingly, we found that a specific conformational change in the C-terminal domain of the monomeric Syn serves as the master switch for the formation of polymorphs. Interestingly, this conformational change can be triggered by calcium binding to the C-terminus, connecting environmental factors to specific fibril architectures. Our results unmask the C-terminal domain as a key player for orchestrating Syn fibril morphology, providing significant insights into the fibrogenesis of Syn. Significance StatementThe Syn C-terminus domain acts as the master switch programming its fibril polymorphism.

biophysics↗