Biology subjects

Choi, J.-W.

Publications and source records attributed to Choi, J.-W..

12 recordsLinked to original sources

bioRxiv2026

MC1R residue 223 is a convergent target for coat-colour lightening in domestic and wild bovids

Whether similar phenotypes evolve through shared substitutions or alternative molecular routes is a central question in evolutionary genomics. Grey-coated taurine cattle provide a powerful system for investigating this question using geographically distinct Podolian and Alpine lineages. We combined whole-genome resequencing data, complementary selection scans (hapFLK, DCMS and FST) and contrasts between grey-coated and non-grey-coated breeds to investigate the molecular evolution of grey coat colour. Selection analyses identified candidate regions associated with Podolian/steppe divergence and a prominent pigmentation-related signal on BTA18 contaning FANCA, MC1R, and SPIRE2. Most grey breeds shared a BTA18 haplotype containing MC1R p.Arg223Trp and additional candidate variants. Tyrolean Grey cattle lacked this predominant haplotype but carried the coding duplication p.Gly220_Arg223dup, together with differentiation near the ASIP regulatory region. Thus, different candidate coding changes affect the same MC1R residue in different cattle lineages. Haplotype comparisons supported independent Podolian and Alpine origins for p.Arg223Trp and p.Gly220_Arg223dup insertion, respectively. Ancient-genome screening yielded no validated evidence of either variant except p.Arg223Trp in medieval cattle. Comparisons across 1,108 mammalian taxa identified independent recurrence of p.Arg223Trp in the white-coated mountain goat, Oreamnos americanus, where the derived allele was fixed in surveyed individuals (JTT-based neutral probability = 0.0043). Our findings support a model in which grey coat colour in cattle evolved through at least two partially distinct molecular routes within interacting pigmentation pathways. More broadly, they identify MC1R residue 223 as a candidate recurrent target of coat-colour lightening and illustrate how domesticated and wild lineages can repeatedly target constrained functional positions during phenotypic evolution.

evolutionary biology↗

bioRxiv2026

Muscarinic signaling sustains delay-period selectivity in prefrontal cortex by preserving thalamic drive

Short-term memory (STM) requires the temporary maintenance of task-relevant information in prefrontal cortex (PFC). Reciprocal interactions between the mediodorsal thalamus (MD) and PFC have been implicated in sustaining this activity, but how thalamofrontal communication is maintained despite the biophysical constraints of repetitive synaptic transmission remains unclear. Here, we show that MD--PFC synapses exhibit profound frequency-dependent short-term depression, causing repetitive thalamic input to progressively lose its ability to drive PFC neurons. During STM performance, acetylcholine (ACh) levels in PFC rose rapidly following cue presentation and remained elevated throughout the delay period. Muscarinic ACh receptor (mAChR) activation did not alleviate synaptic depression, but instead increased the intrinsic excitability of PFC neurons, thereby preserving their responsiveness to weakened thalamic input. Conversely, mAChR blockade impaired STM performance and progressively disrupted delay-period directional representations at both the single-neuron and population levels, while largely sparing initial encoding. These findings identify muscarinic signaling as a postsynaptic gain mechanism that compensates for declining thalamofrontal efficacy and sustains task-relevant prefrontal representations during STM.

neuroscience↗

bioRxiv2026

Membrane-Free Alveolus-on-a-Chip via Biodegradable Scaffold Recapitulates Interstitial Mechanics, Immune Trafficking, and Aerosolized mRNA Delivery

The pulmonary alveolus is a highly specialized microenvironment where epithelial, interstitial, and immune components interact to maintain gas exchange and tissue homeostasis. In vivo, the air-blood barrier consists of an epithelial layer and a capillary endothelium separated by an ultrathin interstitium composed of extracellular matrix (ECM) and lung fibroblasts. However, most existing lung-on-a-chip platforms rely on permanent synthetic membranes, which fail to recapitulate the dynamic biological and mechanical properties of the native interstitium. Here, we present a membrane-free human alveoli-on-a-chip enabled by a biodegradable poly(lactic-co-glycolic acid) (PLGA) scaffold that is progressively replaced by fibroblast-derived ECM. This process reconstructs a biologically formed interstitial layer while preserving an alveolus-like dome architecture. The resulting system supports multicellular organization under air-liquid interface conditions, enabling epithelial barrier formation and surfactant-related phenotypes. Additionally, direct epithelial-fibroblast interactions enhanced surfactant-related phenotypes, as evidenced by increased SPC and LAMP3 expression. Importantly, we demonstrate that conventional rigid substrates promote fibroblast-to-myofibroblast differentiation, leading to elevated reactive oxygen species (ROS) production, increased epithelial cell death, and compromised barrier integrity. In contrast, the membrane-free PLGA system mitigates stiffness-driven myofibroblast activation, preserving epithelial viability and maintaining barrier function. These findings highlight the critical role of interstitial mechanics in regulating alveolar homeostasis and reveal limitations of conventional membrane-based platforms. The platform further enables chemokine-driven monocyte migration across the alveolar barrier, recapitulating key immune trafficking processes observed in vivo. In addition, aerosolized metal-organic framework (MOF) nanoparticles efficiently mediated mRNA delivery to epithelial and interstitial cells with minimal cytotoxicity and modest inflammatory responses. Together, this membrane-free alveoli-on-a-chip reconstructs essential structural, mechanical, and functional features of the human alveolar microenvironment and provides a physiologically relevant platform for studying pulmonary biology, fibrosis-related mechanisms, immune cell trafficking, and inhaled nanomedicine delivery.

bioengineering↗

bioRxiv2024

Short-term memory errors are strongly associated with a drift in neural activity in the posterior parietal cortex

Understanding the neural mechanisms behind short-term memory (STM) errors is crucial for unraveling cognitive processes and addressing deficits associated with neuropsychiatric disorders. This study examines whether STM errors arise from misrepresentation of sensory information or decay in these representations over time. Using 2-photon calcium imaging in the posterior parietal cortex (PPC) of mice performing a delayed match-to-sample task, we identified a subset of PPC neurons exhibiting both directional and temporal selectivity. Contrary to the hypothesis that STM errors primarily stem from mis-encoding during the sample phase, our findings reveal that these errors are more strongly associated with a drift in neural activity during the delay period. This drift leads to a gradual divergence away from the correct representation, ultimately leading to incorrect behavioral responses. These results emphasize the importance of maintaining stable neural representations in the PPC for accurate STM. Furthermore, they highlight the potential for therapeutic interventions aimed at stabilizing PPC activity during delay periods as a strategy for mitigating cognitive impairments in conditions like schizophrenia.

animal behavior and cognition↗

bioRxiv2023

Modulation of premotor cortex excitability mitigates the behavioral and electrophysiological abnormalities in a Parkinson's Disease Mouse Model

The subthalamic nucleus (STN) is important in halting ongoing behaviors, referred to as stop-signal responses. The prefrontal regions innervating the STN exhibit increased activity during the stop-signal responses, and optogenetic activation of these neurons inhibits impulsive actions in rodents. High-frequency electrical stimulation of the STN effectively treats motor symptoms of Parkinsons disease (PD), yet its underlying circuit mechanisms are unclear. Here, we investigated the involvement of STN-projecting premotor (M2) neurons in PD mouse models and the impact of deep brain stimulation targeting the STN (DBS-STN). We found that M2 neurons exhibited enhanced burst firing and synchronous oscillations in the PD mouse model. Remarkably, high-frequency stimulation of STN-projecting M2 neurons, simulating antidromic activation, during DBS-STN relieved motor symptoms and hyperexcitability. These changes were attributed to reduced firing frequency vs. current relationship through normalized hyperpolarization-activated inward current (Ih). The M2 neurons in the PD model mouse displayed increased Ih, which was reversed by high-frequency stimulation. Additionally, the infusion of ZD7288, an HCN channel blocker, into the M2 replicated the effects of high-frequency stimulation. In conclusion, our study unveils excessive excitability and suppressive motor control through M2-STN synapses in the PD mouse model. Antidromic excitation of M2 neurons during deep brain stimulation of the STN alleviates this suppression, thereby improving motor impairment. These findings provide insights into the circuit-level dynamics underlying deep brain stimulations therapeutic effects in PD. Targeting M2-STN synapses may be useful for future therapeutic strategies. Significance StatementOur study provides insight into the mechanisms underlying motor impairment in Parkinsons disease (PD) and the therapeutic effect of deep brain stimulation (DBS). By elucidating the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in modulating the hyperexcitability of M2 neurons, we identify potential targets for future PD treatment strategies. Understanding the excessive excitability and suppressive motor control through M2-STN synapses in PD mouse models contributes to our knowledge of circuit-level dynamics underlying DBS effects. These findings have significant implications for improving motor symptoms and advancing the development of more precise and effective interventions for PD patients. HighlightsO_LISTN-projecting M2 neurons show increased burst firing in PD mice. C_LIO_LIHigh-frequency stimulation relieves M2 hyperexcitability and motor symptoms. C_LIO_LIReduction in M2 hyperexcitability by DBS linked to normalized Ih. C_LIO_LIZD7288 infusion in M2 replicates high-frequency stimulation effects. C_LIO_LITargeted modulation of M2 neurons may alleviate PD symptoms. C_LI

neuroscience↗

bioRxiv2023

Irregularity of instantaneous gamma frequency in the motor control network characterize visuomotor and proprioceptive information processing

BackgroundGoal-directed movements involve integrating proprioceptive and visuo-motor information. Although the neural correlates of such information processing are known, the details of how sensory-motor integration occurs are still largely unknown. ObjectiveThe study aims to characterize movements with different sensory goals, by contrasting the neural activity involved in processing proprioceptive and visuo-motor information. To accomplish this, we have developed a new methodology that utilizes the irregularity of the instantaneous gamma frequency parameter for characterization. ApproachIn this study, 8 essential tremor patients undergoing an awake deep brain stimulation (DBS) implantation surgery repetitively touched the clinicians finger (forward visually-guided/FV movement) and then ones own chin (backward proprioceptively-guided/BP movement). Neural electrocorticographic (ECoG) recordings from the motor (M1), somatosensory (S1), and posterior parietal cortex (PPC) were obtained and band-pass filtered in the gamma range (30-80Hz). The irregularity of the inter-event intervals (IEI; inverse of instantaneous gamma frequency) were examined as: 1) correlation between the amplitude and its proceeding IEI, and 2) auto-information of the IEI time series. We further explored the network connectivity after segmenting the FV and BP movements by periods of accelerating and decelerating forces, and applying the IEI parameter to transfer entropy methods. ResultsConceptualizing that the irregularity in IEI reflects active new information processing, we found the highest irregularity in M1 during BP movement, highest in PPC during FV movement, and the lowest during rest at all sites. Also, connectivity was the strongest from S1 to M1 and from S1 to PPC during FV movement with accelerating force and weakest during rest. SignificanceWe introduce a novel methodology that utilize the instantaneous gamma frequency (i.e., IEI) parameter in characterizing goal-oriented movements with different sensory goals, and demonstrate its use to inform the directional connectivity within the motor cortical network. This method successfully characterizes different movement types, while providing interpretations to the sensory-motor integration processes.

neuroscience↗

bioRxiv2022

High-order thalamic and motor cortex inputs integrate sublinearly into tuft dendrites of pyramidal neurons in mouse somatosensory cortex

Tuft dendrites of pyramidal neurons housed in layer 1 of the neocortex form extensive excitatory synaptic connections with long-range cortical and high-order thalamic axons, along with diverse inhibitory inputs. Recently, we reported that synapses from the vibrissal primary motor cortex (vM1) and posterior medial thalamic nucleus (POm) are spatially clustered together in the same set of distal dendrites, suggesting a close functional interaction. In this study, we evaluated how these two types of synapses interact with each other using in vivo two-photon Ca2+ imaging and electrophysiology. We observed that dendritic Ca2+ responses could be efficiently evoked by electrical stimulation of POm or vM1 in the overlapping set of dendritic branches, rejecting the idea of branch-wise origin-selective synaptic wiring. Surprisingly, the Ca2+ responses upon coincident POm and vM1 stimulation summed sublinearly. We attribute this sublinearity to mutual inhibition via inhibitory neurons because synaptic currents generated by POm and vM1 also integrated sublinearly, but pharmacologically isolated direct synaptic currents summed linearly. Inhibitory neurons receiving POm inputs in the superficial cortical layer negatively regulated vM1-evoked responses. Finally, POm and vM1 innervated overlapping but distinct populations of somatostatin-expressing inhibitory neurons. Thus, POm and vM1 inputs negatively modulate each other in the mouse somatosensory cortex.

neuroscience↗

bioRxiv2021

ICoRD: Iterative Correlation-Based ROI Detection Method for the Extraction of Neural Signals in Calcium Imaging

In vivo calcium imaging is a standard neuroimaging technique that allows selective observation of target neuronal activities. In calcium imaging, neuron activation signals provide key information for the investigation of neural circuits. For efficient extraction of the calcium signals of neurons, selective detection of the region of interest (ROI) pixels corresponding to the active subcellular region of the target neuron is essential. However, current ROI detection methods for calcium imaging data exhibit a relatively low signal extraction performance from neurons with a low signal-to-noise power ratio (SNR). This is problematic because a low SNR is unavoidable in many biological experiments. Therefore, we propose an iterative correlation-based ROI detection (ICoRD) method that robustly extracts the calcium signal of the target neuron from a calcium imaging series with severe noise. ICoRD extracts calcium signals closer to the ground-truth calcium signal than the conventional method from simulated calcium imaging data in all low SNR ranges. Additionally, this study confirmed that ICoRD robustly extracts activation signals against noise, even within in vivo environments. ICoRD showed reliable detection from neurons with a low SNR and sparse activation, which were not detected by conventional methods. ICoRD will facilitate our understanding of neural circuit activity by providing significantly improved ROI detection in noisy images.

neuroscience↗

bioRxiv2021

Dopamine depletion can be predicted by the aperiodic component of subthalamic local field potentials

Electrophysiological biomarkers reflecting the pathological activities in the basal ganglia are essential to gain an etiological understanding of Parkinsons disease (PD) and develop a method of diagnosing and treating the disease. Previous studies that explored electrophysiological biomarkers in PD have focused mainly on oscillatory or periodic activities such as beta and gamma oscillations. Emerging evidence has suggested that the nonoscillatory, aperiodic component reflects the firing rate and synaptic current changes corresponding to cognitive and pathological states. Nevertheless, it has never been thoroughly examined whether the aperiodic component can be used as a biomarker that reflects pathological activities in the basal ganglia in PD. In this study, we examined the parameters of the aperiodic component and tested its practicality as an electrophysiological biomarker of pathological activity in PD. We found that a set of aperiodic parameters, aperiodic offset and exponent, were significantly decreased by the nigrostriatal lesion. To further prove the usefulness of the parameters as biomarkers, acute levodopa treatment reverted the aperiodic offset. We then compared the aperiodic parameters with a previously established periodic biomarker of PD, beta frequency oscillation. We found a significantly low negative correlation with beta power. We showed that the performance of the machine learning-based prediction of pathological activities in the basal ganglia can be improved by using the lowly correlated parameters, beta power and aperiodic component. We suggest that the aperiodic component will provide a more sensitive measurement to early diagnosis PD and have the potential to use as the feedback parameter for the adaptive deep brain stimulation.

neuroscience↗

bioRxiv2020

Clonal dynamics in early human embryogenesis inferred from somatic mutation

The trillions of cells that constitute the human body are developed from a fertilized egg through embryogenesis. However, cellular dynamics and developmental outcomes of embryonic cells in humans remain to be largely unknown due to the technical and ethical challenges. Here, we explored whole-genomes of 334 single-cell expanded clones and targeted deep-sequences of 379 bulk tissues obtained from various anatomical locations from seven individuals. Using the discovered 1,688,652 somatic mutations as an intrinsic barcode, we reconstructed cellular phylogenetic trees that provide novel insights into early human embryogenesis. Our findings suggest (1) endogenous mutational rate that is higher in the first cell division of life but decreases to ~1 per cell per cell division later in life, (2) universal unequal contribution of early cells into embryo proper resulting from early cellular bottlenecks that stochastically separate epiblasts from embryonic cells (3) uneven differential outcomes of early cells into three germ layers, left-right and cranio-caudal tissues, (4) emergence of a few ancestral cells that will contribute to the substantial fraction of adult blood cells, and (5) presence of mitochondrial DNA heteroplasmy in the fertilized egg. Our approach additionally provides insights into the age-related mutational processes including UV-mediated mutagenesis and loss of chromosome X or Y in normal somatic cells. Taken together, this study scrutinized somatic mosaicism, clonal architecture, and cellular dynamics in human embryogenesis at an unprecedented level and provides a foundation for future studies to complete cellular phylogenies in human embryogenesis.

genomics↗

bioRxiv2020

Impaired hand dexterity function in a non-human primate model with chronic Parkinson's disease

Symptoms of Parkinsons disease (PD) caused by loss of dopaminergic neurons are accompanied by movement disorders, including tremors, rigidity, bradykinesia, and akinesia. Non-human primate (NHP) models with PD play an essential role in the analysis of PD pathophysiology and behavior symptoms. As impairments of hand dexterity function can affect activities of daily living in patients with PD, research on hand dexterity function in NHP models with chronic PD is essential. Traditional rating scales previously used in the evaluation of animal spontaneous behavior were insufficient due to factors related to subjectivity and passivity. Thus, experimentally designed applications for an appropriate apparatus are necessary. In this study, we aimed to longitudinally assess hand dexterity function using hand dexterity task (HDT) in NHP-PD models. To validate this assessment, we analyzed an alteration in Parkinsonian tremor symptoms, loss of dopaminergic neuron, and positron emission tomography (PET) imaging of dopamine transporters (DAT) in these models. HDT latency significantly increased in NHP-PD models. In addition, a significant inverse correlation between HDT and DAT was identified, but no local bias was found. The correlation with intention tremor symptoms was lower than the resting tremor. In conclusion, the evaluation of HDT may reflect behavioral symptoms of NHP-PD models. Furthermore, HDT was effectively used to experimentally distinguish intention tremors from other tremors.

neuroscience↗

bioRxiv2020

Gait analysis of healthy rhesus monkeys using a pressure-sensing walkway system

Gait analysis in non-human primate models has been performed to elucidate the neural systems involved in controlling quadrupedal locomotor behavior. This study aimed to use a pressure-sensing walkway to identify characteristics of species-specific quadrupedal locomotion in rhesus monkeys. A total of nine healthy adult female rhesus monkeys (Macaca mulatta) were used for gait analysis. We measured the temporo-spatial and kinetic parameters of quadrupedal gait using a custom-built pressure-sensing walkway and compared the left- and right-side parameters to assess the symmetry of the gait pattern. All temporo-spatial and kinetic parameter values showed no significant differences among the nine rhesus monkeys for both the forelimbs and hindlimbs. However, significant differences were observed between forelimb and hindlimb kinetic parameters such as peak vertical force, vertical impulse, and the percentage of body weight distribution. All kinetic parameter values were higher for the forelimbs than for the hindlimbs. These data indicated that the center of gravity in healthy rhesus monkeys is located at the forelimbs rather than at the hindlimbs while walking. Furthermore, the symmetry indices considered for symmetric gait pattern showed a low variability. Most median symmetry index values were nearly zero, indicating no difference between the right and left sides. This study described valid methods for assessing gait parameters and demonstrated rhesus-specific characteristics of quadrupedal locomotion, providing a basis for the assessment of gait normality in rhesus monkeys.

animal behavior and cognition↗