Hidetoshi Urakubo

ABSTRACT The basal ganglia (BG) are central to action selection and reinforcement learning, yet how the topological organization of the BG circuit with dopamine (DA) D1- and D2-receptors shape learning remains unclear. We present a topologically organized spiking model of macaque BG with cortico-striatal inputs organized into competing channels, D1/D2 medium spiny neurons (MSNs), three-factor DA-modulated STDP for cortical synapses, asymmetric intra-striatal collaterals, and partially overlapping direct/indirect pathways. We validate resting activity and action selection, then study conditioning and generalization–discrimination learning using DA bursts (CS+) and dips (CS). Two structural determinants emerged. First, pathway overlap ( λ ) trades off selection efficiency and learning speed: higher overlap degrades GPi-based selection efficiency during conditioning, yet accelerates convergence during discrimination by strengthening D2 influence on GPi. Second, lateral inhibition from MSN-D2 to MSNs ( κ ) helps constrain competing actions but is not sufficient alone; robust discrimination requires DA-dip–dependent up-modulation of D2 collateral efficacy ( η ), which speeds and, at low overlap, enables convergence. Simulations under Parkinsonian and schizophrenia-like settings showed different deficits. A hypodopaminergic “Parkinsonian” STDP regime (D1 LTP loss, D2 LTD loss) impaired conditioning and failed to enhance discrimination. In contrast, attenuated D2 plasticity during DA dips (modeling methamphetamine-induced changes/schizophrenia-related dysregulation) selectively disrupted discrimination while sparing conditioning. Finally, we demonstrate efficient scaling on the Fugaku supercomputer to rodent and non-human primate–relevant sizes, supporting large-scale, biologically grounded BG simulations. Together, the results highlight how pathway overlap and D2 collateral dynamics jointly regulate the speed and reliability of discrimination learning, and how specific DA perturbations map to distinct learning impairments.

Abstract Familial neurohypophysial diabetes insipidus (FNDI) is an autosomal dominant disorder caused by mutations in the arginine vasopressin (AVP) gene. In AVP neurons in a mouse model of FNDI, aggregates of mutant AVP precursors accumulate within a specific compartment of the endoplasmic reticulum (ER). However, as FNDI mice aged, or were exposed to repeated water deprivation, the ER lumen dilated and mutant aggregates dispersed throughout the ER. Meanwhile, autophagic isolation membranes, known as phagophores, emerged to envelop ER containing these aggregates, indicating induction of ER-phagy. Previous in vitro studies showed that phagophores originate from ER membranes, but the structural relationship between phagophores and the ER membrane in vivo remains unknown. In this study, we used serial block-face scanning electron microscopy to investigate the structural relationship between phagophores, ER membranes, and protein aggregates within dilated ER of AVP neurons from FNDI mice subjected to intermittent water deprivation for 4 weeks. Three-dimensional analysis revealed that phagophores enveloped aggregates located within the dilated ER. Serial imaging further demonstrated a physical connection between these phagophores and intact ER membranes. This study provides the first in vivo evidence of the structural continuity between phagophores and the ER membrane in AVP neurons in a mouse model of FNDI.

Abstract Liquid–liquid phase separation (LLPS) of biological macromolecules leads to the formation of various membraneless organelles. LLPS can not only form homogenous condensates but also multilayered and multiphase condensates, which can mediate complex cellular functions. However, the factors that determine the topological features of multiphase condensates are not fully understood. Herein, we focused on Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), a major postsynaptic protein that undergoes various forms of LLPS with other postsynaptic proteins, and present a minimalistic computational model that reproduces these forms of LLPS, including a form of two-phase condensates, phase-in-phase (PIP) organization. Analyses of this model revealed that the competitive binding of two types of client proteins is required for the PIP formation. The PIP only formed when CaMKII had high valency and a short linker length. Such CaMKII proteins exhibited a low surface tension, a modular structure, and slow diffusion. These properties are consistent with the functions required by CaMKII to store information at the synaptic level. Thus, the computational modeling reveals new structure–function relationships for CaMKII as a synaptic memory unit.

This study developed a three-dimensional ultrastructural analysis application using serial block-face scanning electron microscopy (SBF-SEM) to investigate surgically acquired human skin tissues containing the arrector pili muscle. We utilized the en bloc staining, including reduced osmium, thiocarbohydrazide, and lead aspartate, as well as the embedding using a carbon-based conductive resin. Next, we obtained serial images with SBF-SEM. The results revealed dense nerve fiber networks branching from nearby nerve fiber bundles outside the muscle and running among muscle fibers. Additionally, the dense nerve network running through and along arrector pili muscle fibers rarely penetrates the connective tissues between smooth muscle fibers and epithelial cells. Furthermore, in the observation area, no individual smooth muscle fibers formed adhesion structures with the epithelial cells of the hair follicle, ending in the dermal extracellular matrix near the epithelial cells. These results indicate the usefulness of this approach for three-dimensional ultrastructural analyses of human skin tissues comprising follicular units and revealing structural changes in skin tissues, especially the arrector pili muscle and nerve fibers with hair follicular epithelium, in aging and diseased conditions.