Biology subjects

Yagishita, S.

Publications and source records attributed to Yagishita, S..

11 recordsLinked to original sources

bioRxiv2025

Blockade of associative spine enlargement impairs awake cortical function

Awake cognition is usually attributed to arousal systems and ongoing electrical activity, yet these do not explain how cortical processing is coupled to prior context and memory formation. Associative synaptic plasticity provides a cellular mechanism for such coupling, but is viewed as memory-related rather than an online requirement for cognition. Here we developed SynC, an A/C-activated chemogenetic perturbation that selectively and reversibly blocks associative spine enlargement while sparing non-associative spine dynamics, excitability, synaptic transmission and NMDA receptor-mediated responses. In mice with broad frontoparietal SynC expression, acute A/C reversibly impaired open-field centre exploration, abolished laser-dot chasing, and delayed feeding initiation. During quiet-wake immobile epochs, cortical firing rates and {gamma}-band power were preserved, but pairwise spike correlations were reduced. Mice also intermittently showed sudden behavioural arrest with reduced {gamma} activity but without the robust {delta} elevation of slow-wave sleep. Critically, in vivo two-photon glutamate uncaging induced seconds-scale associative spine enlargement in [~]24% of neocortical spines, acutely blocked by SynC-A/C. These A/C-induced behavioural, circuit and spine-enlargement effects recovered within 1 h. Thus, wake-like firing and {gamma} activity are not sufficient to sustain awake cognitive function. Rapid associative spine enlargement is required to maintain functional cortical coupling and stable wakefulness.

neuroscience↗

bioRxiv2025

tugMedi: simulator of cancer-cell evolution for personalized medicine based on the genomic data of patients

Cancer comprehensive genomic profiling tests are increasingly used, but drug response rates remain limited. Simulations forecasting cancer progression could aid targeted therapies; however, existing simulations focus mainly on basic biology. We present tugMedi, a cancer-cell evolution simulator designed for cancer genome medicine. By integrating patient-specific genomic and imaging data, tugMedi reconstructs each tumors genomic features and growth behavior, enabling real-time predictions of clonal dynamics under virtual drug regimens. tugMedi explicitly models copy number alterations and SNVs on parental chromosomes in recessive and dominant modes, capturing loss-of-heterozygosity and yielding precise variant allele frequencies and tumor contents. It handles mutations in cancer-related genes with real exon-intron structures by a fast algorithm. For TCGA samples, it provided ensemble predictions of clonal dynamics, allowing extraction of drug response, tumor-size shrinkage rates, and time to recurrence under specific drug conditions. tugMedi represents a first step toward simulation-driven genome medicine based on a patient-derived virtual tumor.

bioinformatics↗

bioRxiv2025

Noradrenaline and microglia maintain plasticity-rigidity balance to safeguard rapid emotional learning in the prefrontal cortex

Synaptic plasticity is governed by rules that determine how patterns of neural activity are converted into changes in synaptic weights. While neocortical plasticity rules appear to shift from Hebbian to three-factor forms during development, the cellular mechanisms underlying this transition remain unclear. Here, we show that microglia mediate the developmental transition of plasticity rules at individual dendritic spines in the medial prefrontal cortex (mPFC) during juvenile-to-adolescent maturation. After maturation, microglia suppressed Hebbian activity-induced spine enlargement via a humoral factor. This suppression was relieved by noradrenaline through microglia-intrinsic cAMP signaling, thereby enabling a three-factor rule for gating plasticity. The adolescent mPFC required three-factor plasticity signaling for the acquisition of socially learned fear. Local microglial ablation enhanced learning efficiency but also altered pain sensitivity in a learning-dependent manner, suggesting that microglial suppression safeguards pre-existing emotional circuits. Together, these findings identify microglia as critical regulators of developmental plasticity-rule transitions in the mPFC.

neuroscience↗

bioRxiv2024

Distinct classes of antidepressants commonly act to shape pallidal structure and function in mice

Antidepressants including selective serotonin reuptake inhibitors, ketamine, and psilocybin are all effective for treating depression despite their distinct primary mechanisms. We hypothesized that these drugs may share a common mechanism that underlies their therapeutic actions. We treated mice with one of the following: escitalopram, R-/S-/RS-ketamine, or psilocin. Additionally, groups exposed to electroconvulsive stimulation and a saline control were included. Following treatment, fixed brains underwent structural magnetic resonance imaging, and voxel-based morphometry was performed to evaluate brain-wide volumetric changes. Compared with control treatment, we observed greater volumes in the nucleus accumbens, ventral pallidum, and external globus pallidus across all antidepressant treatments, and a smaller volume in the mediodorsal thalamus. Specifically, R-ketamine, RS-ketamine, and psilocin induced more pronounced hypertrophy of the ventral pallidum, whereas selective serotonin reuptake inhibitors and S-ketamine predominantly increased the volume of the external globus pallidus. Further analyses using super-resolution microscopy and imaging mass spectrometry revealed corresponding microstructural and molecular changes. Greater pallidal volume was associated with striatal medium spiny neuron terminal hypertrophy and elevated {gamma}-aminobutyric acid (GABA) levels. Interestingly, all antidepressants were also associated with higher striatal dopamine content. Moreover, striatal vesicular GABA transporter overexpression reproduced the medium spiny neuron terminal hypertrophy and increased pallidal GABA content, and was associated with a reduction in innate anxiety. These findings indicate that despite their pharmacological diversity, antidepressant treatments lead to shared pallidum-centered structural and molecular changes. We propose that these shared changes may potentiate the striato-pallidal inhibitory circuit, thereby contributing to the overall antidepressant effect.

neuroscience↗

bioRxiv2023

A Reinforcement Learning Model with Choice Traces for a Progressive Ratio Schedule

The progressive ratio (PR) lever-press task serves as a benchmark for assessing goal-oriented motivation. However, a well-recognized limitation of the PR task is that only a single data point, known as the breakpoint, is obtained from an entire session as a barometer of motivation. Because the breakpoint is defined as the final ratio of responses achieved in a PR session, variations in choice behavior during the PR task cannot be captured. We addressed this limitation by constructing four reinforcement learning models: a Simple Q- learning model, an Asymmetric model with two learning rates, a Perseverance model with choice traces, and a Perseverance model without learning. These models incorporated three behavioral choices: reinforced and non-reinforced lever presses and void magazine nosepokes (MNPs), because we noticed that mice performed frequent MNPs during PR tasks. The best model was the Perseverance model, which predicted a gradual reduction in amplitudes of reward prediction errors (RPEs) upon void MNPs. We confirmed the prediction experimentally with fiber photometry of extracellular dopamine (DA) dynamics in the ventral striatum of mice using a fluorescent protein (genetically encoded GPCR activation-based DA sensor: GRABDA2m). We verified application of the model by acute intraperitoneal injection of low-dose methamphetamine (METH) before a PR task, which increased the frequency of MNPs during the PR session without changing the breakpoint. The Perseverance model captured behavioral modulation as a result of increased initial action values, which are customarily set to zero and disregarded in reinforcement learning analysis. Our findings suggest that the Perseverance model reveals effects of psychoactive drugs on choice behaviors during PR tasks.

neuroscience↗

bioRxiv2023

Shared GABA transmission pathology in dopamine agonist- and antagonist-induced dyskinesia

Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist, L-DOPA, to treat Parkinsons disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we searched for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identified the enlarged axon terminals of striatal medium spiny neurons in both LID and TD model mice. The striatal overexpression of vesicular gamma-aminobutyric acid transporter (VGAT) was necessary and sufficient for modeling these structural changes; VGAT levels gated the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation, and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation. HighlightsO_LIEnhancement of GABAergic transmission is a shared mechanism between LID and TD. C_LIO_LIVGAT levels in MSNs govern the structure and function of MSN presynaptic terminals. C_LIO_LIGain and loss of VGAT function in MSNs exacerbates and ameliorates dyskinesia. C_LIO_LILowered D2 signaling with repetitive DA fluctuations causes VGAT overexpression. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=188 HEIGHT=200 SRC="FIGDIR/small/550763v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@15041b4org.highwire.dtl.DTLVardef@9bf41org.highwire.dtl.DTLVardef@1eb7ee4org.highwire.dtl.DTLVardef@1d7dae8_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

A multicolor suite for deciphering population coding in calcium and cAMP in vivo

cAMP is a pivotal second messenger regulated by various upstream pathways including Ca2+ and G protein-coupled receptors (GPCRs). To decipher in vivo cAMP dynamics, we rationally designed cAMPinG1, an ultrasensitive genetically encoded green cAMP indicator that outperformed its predecessors in both dynamic range and cAMP affinity. Two-photon cAMPinG1 imaging detected cAMP transients in the somata and dendritic spines of neurons in the mouse visual cortex on the order of tens of seconds. In addition, multicolor imaging with a highly sensitive new red Ca2+ indicator RCaMP3 allowed simultaneous measurement of population patterns in Ca2+ and cAMP in hundreds of neurons. We identified Ca2+-induced cAMP responses that represented specific information, such as direction selectivity in vision and locomotion, as well as GPCR-induced cAMP responses. Overall, our multicolor suite revealed that information encoded in Ca2+ and GPCRs signaling is integrated and stored as cAMP transients for longer periods in vivo. HighlightsO_LIDeveloping an ultrasensitive cAMP indicator, cAMPinG1, for visualizing cAMP transients in somata and dendritic spines in vivo. C_LIO_LIDeveloping a highly sensitive red Ca2+ indicator, RCaMP3, for visualizing Ca2+ transients in large neuronal population. C_LIO_LIDual-color Ca2+ and cAMP imaging for dissecting Ca2+-induced and GPCR-induced cAMP responses. C_LIO_LISingle-cell, single-timepoint cAMP imaging for GRCR biology and drug screening. C_LI

neuroscience↗

bioRxiv2021

The dopamine dip amplitude is a quantitative measure of disappointment

The greater the reward expectations are, the more different the brains physiological response will be. Although it is well-documented that better-than-expected outcomes are encoded quantitatively via midbrain dopaminergic (DA) activity, it has been less addressed experimentally whether worse-than-expected outcomes are expressed quantitatively as well. We show that larger reward expectations upon unexpected reward omissions are associated with the preceding slower rise and following larger decrease (DA dip) in the DA concentration at the ventral striatum of mice. We set up a lever press task on a fixed ratio (FR) schedule requiring five lever presses as an effort for a food reward (FR5). The mice occasionally checked the food magazine without a reward before completing the task. The percentage of this premature magazine entry (PME) increased as the number of lever presses approached five, showing rising expectations with increasing proximity to task completion, and hence greater reward expectations. Fiber photometry of extracellular DA dynamics in the ventral striatum using a fluorescent protein (genetically encoded GPCR-activation-based-DA sensor: GRABDA2m) revealed that the slow increase and fast decrease in DA levels around PMEs were correlated with the PME percentage, demonstrating a monotonic relationship between the DA dip amplitude and degree of expectations. Computational modeling of the lever press task implementing temporal difference errors and state transitions replicated the observed correlation between the PME frequency and DA dip amplitude in the FR5 task. Taken together, these findings indicate that the DA dip amplitude represents the degree of reward expectations monotonically, which may guide behavioral adjustment.

neuroscience↗

bioRxiv2019

Computational characteristics of the striatal dopamine system described by reinforcement learning with fast generalization

Generalization enables applying past experience to similar but nonidentical situations. Therefore, it may be essential for adaptive behaviors. Recent neurobiological observation indicates that the striatal dopamine system achieves generalization and subsequent discrimination by updating corticostriatal synaptic connections in differential response to reward and punishment. To analyze how the computational characteristics in this system affect behaviors, we proposed a novel reinforcement learning model with multilayer neural networks in which the synaptic weights of only the last layer are updated according to the prediction error. We set fixed connections between the input and hidden layers so as to maintain the similarity of inputs in the hidden-layer representation. This network enabled fast generalization, and thereby facilitated safe and efficient exploration in reinforcement learning tasks, compared to algorithms which do not show generalization. However, disturbance in the network induced aberrant valuation. In conclusion, the unique computation suggested by corticostriatal plasticity has the advantage of providing safe and quick adaptations to unknown environments, but on the other hand has the potential defect which can induce maladaptive behaviors like delusional symptoms of psychiatric disorders. Author summaryThe brain has an ability to generalize knowledge obtained from reward- and punishment-related learning. Animals that have been trained to associate a stimulus with subsequent reward or punishment respond not only to the same stimulus but also to resembling stimuli. How does generalization affect behaviors in situations where individuals are required to adapt to unknown environments? It may enable efficient learning and promote adaptive behaviors, but inappropriate generalization may disrupt behaviors by associating reward or punishment with irrelevant stimuli. The effect of generalization here should depend on computational characteristics of underlying biological basis in the brain, namely, the striatal dopamine system. In this research, we made a novel computational model based on the characteristics of the striatal dopamine system. Our model enabled fast generalization and showed its advantage of providing safe and quick adaptation to unknown environments. By contrast, disturbance of our model induced abnormal behaviors. The results suggested the advantage and the shortcoming of generalization by the striatal dopamine system.

neuroscience↗

bioRxiv2019

The minimal behavioral time window for reward conditioning in the nucleus accumbens of mice

The temporal precision of reward-reinforcement learning is determined by the minimal time window of the reward action--theoretically known as the eligibility trace. In animal studies, however, such a minimal time window and its origin have not been well understood. Here, we used head-restrained mice to accurately control the timing of sucrose water as an unconditioned stimulus (US); we found that the reinforcement effect of the US occurred only within 1 s after a short tone of a conditioned stimulus (CS). The conditioning required the dopamine D1 receptor and CaMKII signaling in the nucleus accumbens (NAc). The time window was not reduced by replacing CS with optogenetic stimulation of the synaptic inputs to the NAc, which is in agreement with previous reports on the effective dopamine timing of NAc synapses. Thus, our data suggest that the minimal reward time window is 1 s, and is formed in the NAc.

neuroscience↗

bioRxiv2019

Stringent structural plasticity of dendritic spines revealed by two-photon glutamate uncaging in adult mouse neocortex in vivo

Two-photon uncaging of glutamate is widely utilized to characterize structural plasticity in brain slice preparations in vitro. In this study, we investigated spine plasticity by using, for the first time, glutamate uncaging in the neocortex of adult mice in vivo. Spine enlargement was successfully induced in a smaller fraction of spines in the neocortex (22%) than in young hippocampal slices (95%), even under a low magnesium condition. Once induced, the time course and mean amplitudes of long-term enlargement were the same (81%) as those in vitro. However, low-frequency (1-2 Hz) glutamate uncaging caused spine shrinkage in a similar fraction (34%) of spines as in vitro, but spread to the neighboring spines less frequently than in vitro. Thus, we found that structural plasticity can occur similarly in the adult neocortex in vivo as in the hippocampus in vitro, although it happens stringently in a smaller subset of spines.

neuroscience↗