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Uchida, N.

Publications and source records attributed to Uchida, N..

At least 19 recordsLinked to original sources

Dopaminergic reward signals shape foraging decisions through learned value expectations

A fundamental function of the nervous system is to direct animals towards life-sustaining resources and enable adaptive strategies for acquiring them. Foraging, the challenge of securing these resources from the environment, requires making decisions that balance local gains against costs, opening a window on value-based decision making in ecological context. Yet despite the centrality of foraging in life, the algorithms and neural mechanisms underlying foraging decisions are not well understood. We studied mice making stay-or-leave patch foraging decisions for water across poor- and rich-resource environments with dynamic local reward outcomes. We found that mice integrate immediate rewards, local reward history, and reward (i.e. value) expectations to guide foraging decisions, favoring greater time investment in rich-environment patches. Computational models revealed influence of a time-varying bias which mirrored the shape of a learned value function. Consistent with a reinforcement learning mechanism, dopamine in the ventral striatum signaled a temporal-difference reward prediction error, which could be used as a teaching signal to construct value functions, and calibrated optogenetic manipulation of dopamine to create fictive reward signals recapitulated the value-related decision bias. Taken together, our results shed new light on the neurocomputational basis of foraging, revealing a novel role for value expectations in dynamic environments. Further, they establish generalized function of biological reinforcement learning in ecological context, demonstrating a specific role for the canonical dopamine reward circuit in shaping temporally resolved value expectations to guide behavior and cognition. The unification of this framework with foraging opens a new avenue to elucidate principles of how animals learn and dynamically adjust cognitive strategies for real-world ecological problems.

neuroscience↗

Dynamic belief representation and updating through learned attractor-like dynamics in the frontal cortex

To act adaptively, animals must infer hidden states of the world from incomplete sensory information and update beliefs as new observations accrue. While dopamine signals are well explained by reinforcement learning models that incorporate belief states, how the brain implements belief-state inference remains unknown. Prior modeling work showed that recurrent neural networks trained to predict value (Value-RNN) develop task-specific, attractor-like dynamics that mirror evolution of beliefs. Here we performed high-density electrophysiological recordings from orbitofrontal cortex (OFC) and other brain areas of mice performing two variants of a Pavlovian task that differ in reward probability, which produce different within-trial belief dynamics. We find that OFC population activity exhibits task-specific attractor-like dynamics that mirror the within-trial dynamics in the Value-RNN. These dynamics are absent in motor and olfactory regions, are not explained by behavioral differences, and emerge progressively with learning. Our findings indicate that the brain approximates belief-state inference through learned, task-specific attractor-like dynamics.

neuroscience↗

Chemical Boosting of Foldase Condensates Accelerates Oxidative Protein Folding

Dynamic biomolecular condensates play crucial roles in intracellular compartmentalization and physiological functions. While engineering tools for compartmentalization have expanded add-on functionalities, directly amplifying the inherent catalytic machinery within biological phase-separated droplets has remained elusive. Herein, we developed a phase-separated oxidative folding reaction chamber based on protein disulfide isomerase A6 (PDIA6) by chemically targeting its active site CxxC motif to enhance enzymatic activity within PDIA6 droplets. A para-substituted N-methylated pyridinylmethanethiol (pMePySH) enhanced the catalytic oxidative folding of bovine pancreatic trypsin inhibitor, proinsulin, and antibody up to 12-fold within in vitro PDIA6 droplets. Furthermore, pMePySH targeted PDIA6 foci within the endoplasmic reticulum, significantly promoting insulin secretion. These findings offer a powerful platform for the spatiotemporal manipulation of protein folding, with profound implications for the scalable manufacturing of therapeutic antibodies and other complex biopharmaceuticals.

bioengineering↗

Isolation of postnatal human neural stem cells

While it was once thought that neurogenesis is complete by birth, it is now apparent that the human brain continues to generate new neurons postnatally, at least into childhood. While much attention has been focused on postnatally-born neurons, their presumed progenitor - the postnatal neural stem cell (NSC) - remains poorly characterized. Using index sorting, we identify and prospectively isolate two subsets of NSCs from the postnatal human brain, and describe their differentiation dynamics using clonal barcoding and in vivo xenotransplantation. We demonstrate an A2B5+EGFR+ population biased towards interneuron and oligodendrocyte fates (NINO), and an A2B5-EGFRhi population biased towards an astrocyte fate (NAC). Profiling of human brains across lifespan shows that the frequency of NSCs declined exponentially across the first two decades of life, but stabilized thereafter, still present in the brains of donors as old as 90 years. Our study provides a framework for the functional study of postnatal human NSCs and their potential roles in development, aging, and disease.

neuroscience↗

Dopamine in the ventral and tail of striatum supports global and local evaluation in reward-threat conflict

Survival requires balancing reward seeking and threat avoidance, yet how distinct dopamine systems coordinate to support this remains unclear. Using a naturalistic foraging paradigm in which mice pursue water reward under threat from a monster object, we examined roles of dopamine projections to the ventral striatum (VS) and tail of the striatum (TS). Ablation of VS- projecting dopamine neurons impaired both distal reward pursuit and threat avoidance, with the impairment in threat avoidance paralleling effects of TS dopamine ablation. However, simultaneous recordings revealed different activity rules: VS dopamine tracked radial velocity towards the current goal as animals changed goals (reward or shelter), consistent with a temporal-difference error of spatial value, while TS dopamine encoded proximity and orientation to the threat, reflecting immediate sensory experience. Taken together, VS and TS dopamine evaluates distinct state information for avoidance. VS dopamine facilitates allocentric, goal- directed navigation, while TS dopamine facilitates egocentric, stimulus-driven threat responses.

neuroscience↗

Claudin-1 Inhibitor PDS-0330 Ameliorates Diabetic Kidney Disease by Suppressing Src/Akt/mTOR Signaling Pathway in Podocytes

IntroductionRecent studies have reported that claudin-1, which is reactively expressed in malignant tumors and inflammatory diseases, plays an important role in disease progression. In diabetic kidney disease (DKD), upregulated expression of claudin-1 in podocytes has also been shown to contribute to disease progression. However, it remains unclear whether claudin-1 itself could be a therapeutic target in DKD. In this study, we investigated whether the claudin-1 inhibitor PDS-0330 could ameliorate DKD. MethodsFive-week-old male C57BL/6J mice were fed either a high-fat diet (HFD) or a normal diet (ND). At 15 weeks of age, PDS-0330 (Inh) or vehicle as control (Ctrl) was administered orally once per week for 4 weeks. At the end of the treatment period, blood, urine, and kidney samples were collected. In in vitro study, immortalized podocytes were treated with Inh or Ctrl and cultured for 48 hours in either normal glucose medium (5.5 mM; NG) or high glucose medium (25 mM; HG), after which proteins were extracted for analysis. ResultsMice fed an HFD showed significant increases in body weight and serum glucose levels compared with ND mice, and these parameters were not significantly affected by Inh treatment. HFD mice treated with Ctrl (HFD-Ctrl) exhibited significantly higher urinary albumin excretion than ND mice treated with Ctrl (ND-Ctrl), whereas the Inh-treated HFD mice (HFD-Inh) showed a significant reduction. Transmission electron microscopy revealed foot process effacement in HFD-Ctrl podocytes, which was markedly improved in HFD-Inh mice. Immunofluorescence staining demonstrated claudin-1 expression in podocytes of HFD mice. Furthermore, phospho-mTOR staining in podocytes was significantly increased in HFD-Ctrl compared with ND-Ctrl and was significantly attenuated in HFD-Inh. Western blot analysis of kidney samples revealed activation of the Src/Akt/mTOR signaling pathway in HFD-Ctrl mice, which was significantly reduced in HFD-Inh mice. In in vitro study, Ctrl-treated podocytes cultured in HG (HG-Ctrl) showed significant activation of Src/Akt/mTOR signaling compared with those in NG (NG-Ctrl). This activation was significantly suppressed in Inh-treated podocytes (HG-Inh). ConclusionThese findings suggest that podocyte claudin-1 could be a potential therapeutic target in DKD.

physiology↗

Transition from plasticity to dynamics-based value update for meta-learning

The ability to estimate the value associated with a specific stimulus or action is essential for adaptive behavior. Value can be updated either incrementally through experience or rapidly by inference based on latent environmental structure. Yet, how the brain implements and transitions between these modes of value computation remains unclear. To address this question, we examined the neuronal mechanisms underlying reversal learning. Mice were trained in an odor-outcome association task either with stable contingencies or with dynamically changing contingencies. Mice trained on stable contingencies formed long-term value representations that depended on synaptic plasticity in the basolateral amygdala (BLA). In contrast, mice exposed to repeated reversals acquired the ability to infer values, independent from plasticity in BLA, enabling faster learning but with more rapid memory decay. Recurrent neural network models (RNNs) trained with continuous weight updates recapitulated this transition, shifting from plasticity-based to dynamics-based value computation. Neural activity in the BLA encoded both value and contextual information necessary for computing value based on latent task structure, similar to those found in the RNNs. Disrupting BLA activity before cue delivery preferentially impaired dynamics-based value updating. Furthermore, mice could learn distinct correlation structures that enabled structure-specific value inference. Together, these findings provide a mechanistic framework for fast value updates via inference, a core feature of intelligent behavior.

neuroscience↗

Context-specific configuration of orthogonal integrator dynamics for flexible foraging decisions

The capacity to adapt behavior and cognition across contexts is fundamental to intelligence. Context-dependent decision making is an exemplar of flexible cognition in animals, yet its biological basis remains poorly understood. At the neural level, a critical mechanistic question is whether context largely alters the inputs to a common decision process or reconfigures decision activity itself to create context-specific functional modes. To study this problem, we developed a patch foraging task in which mice forage in two environment contexts defined by distinct reward dynamics. Mice made patch leaving decisions across environments using different context-specific parameterizations of a drift-diffusion integrator process. Using high-density acute and chronic neural recordings, we find that foraging environments recruit separate activity subspaces which organize orthogonal coding of context-specific decision variables. Unlike the context-invariant decision coding used for perceptual choice problems, foraging decision variables were encoded in orthogonal population vectors within largely separate neural subpopulations - a subspace configuration mechanism which can support modular learning, independent readout, and flexible toggling of decision strategies across environments. In the dorsal frontal cortex, orthogonal integrators emerge with experience, are preserved across three distinct task settings, and are required for rapid and volitional strategy switching. Our findings establish orthogonal integrator dynamics as a general solution for context-dependent decision making and open a new avenue to investigate the cell- and circuit-level basis of flexible cognition in the mammalian brain.

neuroscience↗

Hydrodynamic coupling drives bacterial flagellar synchrony

Synchronization is a fundamental phenomenon observed across a wide range of physical, chemical, and biological systems. Even under the low-Reynolds-number conditions that govern microbial motility, synchronization of rhythmic processes is considered essential for diverse activities ranging from single cells to populations, yet experimental evidence remains scarce. Here, we performed rotation measurements of microbeads attached to two truncated bacterial flagella and observed the emergence of phase synchronization between these nanoscale active motors. The resulting intermittent in-phase synchronization was analyzed using a hydrodynamic model incorporating elastic deformation of the flagella, showing that stronger hydrodynamic coupling promotes more stable phase-locking. This study experimentally demonstrates fluid-mediated biological synchronization using bacterial rotary machinery, deepening our understanding of the physical principles underlying rhythmic phenomena and self-organization in living systems.

biophysics↗

A hardwired neural circuit for temporal difference learning

The neurotransmitter dopamine plays a major role in learning by acting as a teaching signal to update the brains predictions about rewards. A leading theory proposes that this process is analogous to a reinforcement learning algorithm called temporal difference (TD) learning, and that dopamine acts as the error term within the TD algorithm (TD error). Although many studies have demonstrated similarities between dopamine activity and TD errors1-5, the mechanistic basis for dopaminergic TD learning remains unknown. Here, we combined large-scale neural recordings with patterned optogenetic stimulation to examine whether and how the key steps in TD learning are accomplished by the circuitry connecting dopamine neurons and their targets. Replacing natural rewards with optogenetic stimulation of dopamine axons in the nucleus accumbens (NAc) in a classical conditioning task gradually generated TD error-like activity patterns in dopamine neurons by specifically modifying the task-related activity of NAc neurons expressing the D1 dopamine receptor (D1 neurons). In turn, patterned optogenetic stimulation of NAc D1 neurons in naive animals drove dopamine neuron spiking according to the TD error of the stimulation pattern, indicating that TD computations are hardwired into this circuit. The transformation from D1 neurons to dopamine neurons could be described by a biphasic linear filter, with a rapid positive and delayed negative phase, that effectively computes a temporal difference. This finding suggests that the time horizon over which the TD algorithm operates--the temporal discount factor--is set by the balance of the positive and negative components of the linear filter, pointing to a circuit-level mechanism for temporal discounting. These results provide a new conceptual framework for understanding how the computations and parameters governing animal learning arise from neurobiological components.

neuroscience↗

Chromatin organizer ASCL1 governs gene programs in thymic epithelial cells, defining immunological self

Immunological self-tolerance depends on medullary thymic epithelial cells (mTECs), which express a broad repertoire of self-antigens to support negative selection of autoreactive T cells and the development of regulatory T cells. Although the autoimmune regulator AIRE is essential for this process, additional factors are required to establish the full mTEC gene expression program. Because thymoma is frequently associated with autoimmunity, implicating defective thymic tolerance, we performed single-cell RNA sequencing of TECs from thymoma patients and identified the transcription factor ASCL1 as selectively downregulated in tumor mTECs. Deletion of Ascl1 in mouse TECs resulted in spontaneous autoimmunity without inducing thymic tumorigenesis. Transcriptomic and chromatin accessibility analyses revealed that ASCL1 influences mTEC gene expression programs and is associated with corresponding changes in chromatin accessibility. Genetic interaction analyses further suggested that ASCL1 activity in immature mTECs modulates the AIRE dependency of gene expression in mature mTECs. Together, these findings identify ASCL1 as a key regulator of mTEC function and central tolerance, providing insight into mechanisms that safeguard immune homeostasis and whose disruption may contribute to autoimmune disease.

immunology↗

TCR repertoire analysis quantifies effect of irradiation to homeostasis of iNKT cell development in the thymus of mice

Thymic T cell development shows homeostasis in which T cell production recovers after temporal impairment by various stressors. Invariant natural killer T (iNKT) cells in the thymus contribute to recovery of thymic development after irradiation owing to their greater tolerance to irradiation compared to conventional thymocytes. However, whether and how iNKT cell development recovers from irradiation remains unknown. Here we show that iNKT cells in the thymus exhibits much slower post-irradiation recovery than conventional thymocytes. We compared T cell receptor (TCR) alpha chain repertoire of the thymus in 42 days after irradiation and quantified the sustained decline in the number of iNKT cells against other thymocytes. We found that fluctuation of V and J genes usage does not correlate with the number iNKT cells suggesting that differentiation process of iNKT cells after TCR gene rearrangement is impaired by irradiation. Mathematical modelling of recovery dynamics of iNKT cells implied that lack of rapid proliferation immediately after irradiation unlike conventional thymocytes contributes to the prolonged reduction of iNKT cell population. These findings may suggest possibility on association between the prolonged reduction of iNKT cells after irradiation and autoimmune diseases caused by irradiation in bone marrow transplantation.

immunology↗

Development and Validation of a Stem Cell-Based Kidney Organoid Platform for Nephrotoxicity Assessment

Background and hypothesisRecent cases of acute kidney injury (AKI) in Japan have been linked to the Beni-koji CholesteHelp supplement. Renal biopsies from affected patients revealed tubular damage, and puberulic acid was subsequently identified as a potential nephrotoxic contaminant. Recognizing the urgent need for a reliable in vitro nephrotoxicity testing platform, we hypothesized that a kidney organoid-based system could replicate nephrotoxic injury and help identify novel nephrotoxicants. In this study, we developed a screening model using kidney organoids derived from adult rat kidney stem (KS) cells and applied it to evaluate the toxicity of puberulic acid. MethodsKidney organoids were generated from KS cells and exposed to established nephrotoxicants, including cisplatin and gentamicin, to validate the model. The nephrotoxicity of puberulic acid was evaluated using both KS cell-derived organoids and wild-type mice. Nephrotoxicity was assessed by morphological changes, Kim-1 mRNA expression, transmission electron microscopy (TEM), and analysis of markers related to mitochondrial injury, oxidative stress, and apoptosis. ResultsThe kidney organoids reproduced morphological features of injury induced by known nephrotoxins and showed significant upregulation of Kim-1 mRNA. Puberulic acid-treated organoids displayed ultrastructural features consistent with acute tubular necrosis (ATN) and increased Kim-1 expression. In vivo, puberulic acid-exposed mice exhibited impaired renal function and histological findings consistent with ATN. Both in vitro and in vivo models revealed mitochondrial structural abnormalities and reduced expression of cytochrome c oxidase subunit IV (COX-IV). Additionally, oxidative stress and apoptotic markers, including 8-hydroxy-2-deoxyguanosine (8-OHdG) and cleaved caspase-3, were significantly elevated, suggesting that puberulic acid induces mitochondrial dysfunction and oxidative stress, leading to tubular cell death. ConclusionPuberulic acid-induced nephrotoxicity was demonstrated using our kidney organoid model. KS cell-derived kidney organoids provide a simple, reproducible, and rapid platform for nephrotoxicity assessment, which contribute to a reduction of animal use in toxicology research.

pharmacology and toxicology↗

Application of environmental DNA-based assessment for upstream-downstream comparison of river macroinvertebrates in a metal-contaminated river

Environmental DNA (eDNA) is a powerful tool for biological monitoring with the potential to overcome weaknesses of conventional macroinvertebrate surveys in running waters. However, the ability of eDNA to detect changes of macroinvertebrate communities immediately downstream of a perturbation, particularly in upstream-downstream comparisons, has not been adequately explored. To address this issue, we investigated the potential of eDNA-based assessment of a perturbation by comparing the results with macroinvertebrate surveys in a river influenced by the inflow of a metal-contaminated tributary. Both methods revealed distinctly lower richness of taxa and zero-radius operational taxonomic units (ZOTUs) at the metal-contaminated tributary site compared to other study sites. Results from collection of macroinvertebrates indicated that most richness and abundance metrics were significantly reduced at three metal-contaminated sites located 150-750 m downstream from the inflow of the tributary. In contrast, the eDNA-based assessment revealed similar ZOTU richness at a reference site and the downstream, contaminated sites. Although statistically not significant because sample sizes were small, eDNA-based non-metric multidimensional scaling revealed some separation between the reference site and two downstream sites. However, no separation was apparent between the reference site and the site immediately downstream. This result suggested that eDNA at a site 150 m downstream from the inflow was likely affected by downstream drift of eDNA from the upstream reference area. That drift complicated assessment of the community a short distance from the perturbation. The site separation detected by eDNA-based assessment was promising, but the ZOTUs that contributed to the separation were mainly from dipteran taxa rather than from metal-sensitive mayflies, which were significantly lower in abundance at the downstream, contaminated sites. Developing reliable local DNA barcoding information, particularly for these mayflies, may help overcome the limitations of making evaluations over relatively small spatial scales, such as upstream-downstream comparisons.

ecology↗

Hunger modulates exploration through suppression of dopamine signaling in the tail of striatum

Caloric depletion leads to behavioral changes that help an animal find food and restore its homeostatic balance. Hunger increases exploration and risk-taking behavior, allowing an animal to forage for food despite risks; however, the neural circuitry underlying this change is unknown. Here, we characterize how hunger restructures an animals spontaneous behavior as well as its directed exploration of a novel object. We show that hunger-induced changes in exploration are accompanied by and result from modulation of dopamine signaling in the tail of the striatum (TOS). Dopamine signaling in the TOS is modulated by internal hunger state through the activity of agouti-related peptide (AgRP) neurons, putative "hunger neurons" in the arcuate nucleus of the hypothalamus. These AgRP neurons are poly-synaptically connected to TOS-projecting dopaminergic neurons through the lateral hypothalamus, the central amygdala, and the periaqueductal grey. We thus delineate a hypothalamic-midbrain circuit that coordinates changes in exploration behavior in the hungry state.

neuroscience↗

Multi-timescale neural adaptation underlying long-term musculoskeletal reorganization.

The central nervous system (CNS) can effectively control body movements despite environmental changes. While much is known about adaptation to external environmental changes, less is known about responses to internal bodily changes. This study investigates how the CNS adapts to long-term alterations in the musculoskeletal system using a tendon transfer model in non-human primates. We surgically relocated finger flexor and extensor muscles to examine how the CNS adapts its strategy for finger movement control by measuring muscle activities during grasping tasks. Two months post-surgery, the monkeys demonstrated significant recovery of grasping function despite the initial disruption. Our findings suggest a two-phase CNS adaptation process: an initial phase enabling function with the transferred muscles, followed by a later phase abandoning this enabled function and restoring a control strategy that, while potentially less conflicted than the maladaptive state, resembled the original pattern, possibly representing a good enough solution. These results highlight a multi-phase CNS adaptation process with distinct time constants in response to sudden bodily changes, offering potential insights into understanding and treating movement disorders. SIGNIFICANCE STATEMENTAfter major changes to the bodys mechanics, the nervous system adapts using strategies on multiple timescales. Our primate tendon transfer study shows that core muscle synergy groupings remain stable, reflecting a default to modular control. However, the activation of these synergies changes dramatically; an initial, rapid swap of their timing proves to be maladaptive, impairing motor function. This conflict is only resolved through the gradual development of slower, compensatory strategies over several weeks. This process highlights the fundamental tension the CNS faces when its reliance on stable motor modules conflicts with the need for flexible control, offering insights into neural plasticity and staged rehabilitation.

neuroscience↗

Chemical genetics reveals cross-activation of plant developmental signaling by the immune peptide-receptor pathway

Cells sense and integrate multiple signals to coordinate development and defence. A receptor-kinase signaling pathway for plant stomatal development shares components with the immunity pathway. The mechanism ensuring their signal specificities remains unclear. Using chemical genetics, here we report the identification of a small molecule, kC9, that triggers excessive stomatal differentiation by inhibiting the canonical ERECTA receptor-kinase pathway. kC9 binds to and inhibits the downstream MAP kinase MPK6, perturbing its substrate interaction. Strikingly, activation of immune signaling by a bacterial flagellin peptide nullified kC9s effects on stomatal development. This cross-activation of stomatal development by immune signaling depends on the immune receptor FLS2 and occurs even in the absence of kC9 if the ERECTA-family receptor population becomes suboptimal. Furthermore, proliferating stomatal-lineage cells are vulnerable to the immune signal penetration. Our findings suggest that the signal specificity between development and immunity can be ensured by MAP Kinase homeostasis reflecting the availability of upstream receptors, thereby providing a novel view on signal specificity.

plant biology↗

A novel behavioral paradigm using mice to study predictive postural control

Postural control circuitry performs the essential function of maintaining balance and body position in response to perturbations that are either self-generated (e.g. reaching to pick up an object) or externally delivered (e.g. being pushed by another person). Human studies have shown that anticipation of predictable postural disturbances can modulate such responses. This indicates that postural control could involve higher-level neural structures associated with predictive functions, rather than being purely reactive. However, the underlying neural circuitry remains largely unknown. To enable studies of predictive postural control circuits, we developed a novel experimental paradigm for mice. In this paradigm, modeled after human studies, a dynamic platform generated reproducible translational perturbations. While mice stood bipedally atop a perch to receive water rewards, they experienced backward translations that were either unpredictable or preceded by an auditory cue. To validate the paradigm, we investigated the effect of the auditory cue on postural responses to perturbations across multiple days in three mice. These preliminary results serve to validate a new postural control experimental paradigm, opening the door to the types of neural recordings and circuit manipulations that are currently possible in mice. Significance StatementThe ability to anticipate disturbances and adjust ones posture accordingly--known as "predictive postural control"--is crucial for preventing falls and for advancing robotics. While human balance is often assessed via floor perturbations, rodent studies typically use rotarod tests. Here, we developed a postural perturbation task for freely moving mice, modeled after those used in human studies. Using a dynamic platform, we delivered reproducible perturbations with or without preceding auditory cues and quantified how the auditory cue affects postural responses to perturbations. Our work provides validation of a new postural control experimental paradigm, which opens the door to the types of neural population recordings and circuit manipulation that are currently possible in mice.

neuroscience↗