Biology subjects

Cho, C.

Publications and source records attributed to Cho, C..

17 recordsLinked to original sources

bioRxiv2026

Nicotinic modulation of frontal circuits breaks the cycle of attentional performance failure

The ability to recover from consecutive failures is critical for adaptive behavior, yet the underlying neural mechanisms remain unclear. In vivo screening of neuromodulatory inputs onto frontal-sensory cognitive control circuit identified a frontal cholinergic mechanism that counteracts lapses in attentional engagement following repeated errors. Cholinergic input from the basal forebrain to the frontal cortex was necessary and sufficient to restore performance after errors, specifically after repeated-but not after a single-failure. This effect was mediated by 7-nicotinic acetylcholine receptors in frontal-sensory cortical neurons, which sustained cortical circuit activity and frontal-sensory cortical oscillations during attentional engagement. Targeted optogenetic activation of these frontal-sensory neurons disrupted cycles of attentional performance failure and reinstated behavioral performance in a mouse model of neuropsychiatric syndrome. These findings reveal a circuit-level mechanism of cholinergic control that confers cognitive resilience under conditions of persistent failure.

neuroscience↗

bioRxiv2026

Safety learning produces rapid fear suppression and distinct amygdala-prefrontal engagement

Animals detect and evaluate signs of danger and safety in their environment to ensure survival, yet the neural mechanisms that distinguish safety learning from other forms of conditioned inhibition, remain poorly understood. Here, we directly compared fear and safety learning in male rats. Fear conditioned rats showed high freezing to the tone and the conditioning context, whereas safety conditioned rats showed significant tone-specific reduction in freezing. This safety cue could also generalize to a novel, previously unassociated threat context leading to suppressed freezing when presented demonstrating that inhibitory actions of safety cues are not tied to its original training environment but can modify fear expression across settings. Fear and safety learning also produced unique patterns of neuronal activation and glutamatergic receptor expression in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and central amygdala (CeA), as measured by c-Fos immunohistochemistry and Western blotting. Fear conditioning induced greater Fos expression in the BLA and CeA, as well as elevated amygdalar NMDA receptor (GluN1) levels, whereas safety learning increased amygdalar PSD-95 and AMPA receptor (GluA1) expression. Both safety and fear learning increased mPFC Fos expression without affecting glutamatergic receptors levels. Finally, safety conditioning was associated with lower tone-evoked freezing than fear conditioned rats across early extinction sessions and was accompanied by distinct patterns of prefrontal and amygdala activation across extinction. Together, these findings suggest that safety learning engages neural and behavioral mechanisms distinct from fear learning and extinction, while modifying amygdala-prefrontal circuits towards more rapid fear suppression.

neuroscience↗

bioRxiv2026

Whole-brain analyses identify anterior cingulate μ-opioid signaling as a critical mediator of placebo analgesia in neuropathic pain

Placebo analgesia reflects the capacity of learning and expectation to engage endogenous pain-control systems, yet the neural circuits that support this phenomenon remain poorly understood. Here, we establish a conditioning-based placebo analgesia paradigm in mice following peripheral nerve injury and combine behavioral assessment with whole-brain activity mapping and targeted circuit manipulations to define its neural substrates. Conditioning with morphine produced robust placebo analgesia, expressed as reduced sensory sensitivity in the absence of drug. Brain-wide mapping of c-Fos expression revealed distributed changes across cortical and subcortical regions accompanied by a reorganization of functional connectivity, consistent with coordinated network-level engagement. Network analyses identified shifts in hub structure and selective strengthening and weakening of inter-regional interactions during placebo analgesia. Causal manipulations demonstrated a critical role for the anterior cingulate cortex, with excitatory activation of this region blocking placebo analgesia, whereas inhibitory manipulations had no effect. In contrast, perturbation of other candidate regions, including the basomedial amygdala and paraventricular thalamus, did not alter placebo responses. Finally, selective targeting of -opioid receptor-expressing neurons in the anterior cingulate cortex revealed that this cell population is necessary for the expression of placebo analgesia. Together, these findings reveal a brain-wide reorganization of network interactions underlying placebo analgesia and identify a specific cortical opioid circuit that gates its expression. One-Sentence SummaryUsing a mouse model of nerve injury, this study shows that placebo analgesia arises from coordinated brain-wide network reorganization and is gated by -opioid receptor-expressing neurons in the anterior cingulate cortex.

neuroscience↗

bioRxiv2026

Distinct Neural Systems Supporting Afferent and Efferent Autonomic Activity

Numerous studies have reported brain correlates of autonomic activity. However, ambiguity exists regarding whether those correlates reflect receiving or sending out autonomic signals. Additionally, little is known about how emotion and aging interact with brain-autonomic coordination. Based on time-varying heart rate variability (HRV) and blood oxygenation level dependent (BOLD) data (N = 104 younger; N = 51 older adults), we found insular and cingulate activity was negatively correlated with HRV during emotion regulation. We further examined the afferent and efferent nature of HRV-BOLD correlations during rest (N = 102 younger; N = 51 older adults). Functionally afferent regions where decreases in HRV were associated with subsequently increased BOLD activity included the posterior insula, postcentral gyrus and frontal pole. Functionally efferent regions where increased activity was associated with subsequently increased HRV included the anterior insula and cingulate. Information appeared to flow in one direction as the afferent regions activity Granger-predicted the efferent regions activity. Together, our findings suggest a feedback loop where decreased HRV increases the afferent regions activity, which activates the efferent regions, leading to increased HRV. Aging seems to affect this system; the efferent and afferent regions scarcely overlapped for younger adults, but did overlap for older adults.

neuroscience↗

bioRxiv2026

Modeling a Shared Reality of Tractography through Varied Structural Imaging

Though diffusion MRI (dMRI) is the gold standard for white matter tractography, fundamental questions remain about whether captured patterns reflect diffusion-specific phenomena or general structural properties accessible through alternative imaging approaches. This work investigates structural probabilities within the human brain as a complex manifold and examines structural-functional relationships of anatomical bundles to clarify what dMRI specifically captures in white matter architecture. We introduce a framework to extract white matter pathways from FLAIR images without additional subject-specific anatomical context. Using a teacher-student model, we capture systemic information from dMRI-based tractography to guide FLAIR-based tractogram creation. The teacher model trains on dMRI features to generate diffusion tractography, while the student utilizes frozen teacher layers to extract tractography features using only FLAIR input. In our pilot analysis of 14 randomly selected subjects from the Baltimore Longitudinal Study of Aging (BLSA), we performed additional inference on 9 withheld subjects to evaluate robustness. We assessed FLAIR-template generated streamlines using bundle adjacency and Dice coefficient at the voxel level across 39 white matter bundles compared to gold standard diffusion streamlines. Statistical evaluations compared our method against other non-diffusion tractography algorithms using T1-weighted and FLAIR images with subject-specific anatomical context. Results demonstrate our proposed method offers statistically similar performance to other non-diffusion methods when compared to diffusion streamlines These findings suggest that without diffusion data, our method captures unconditional subject-specific prior probabilities of tractography, indicating that tractography patterns may sample from a shared latent space of structural information not unique to any single imaging sequence.

bioengineering↗

bioRxiv2024

An Infralimbic Cortex Neuronal Ensemble Encoded During Learning Attenuates Fear Generalization Expression

Generalization allows previous experience to adaptively guide behavior when conditions change. The infralimbic (IL) subregion of the ventral medial prefrontal cortex plays a known role in generalization processes, although mechanisms remain unclear. A basic physical unit of memory storage and expression in the brain are sparse, distributed groups of neurons known as ensembles (i.e., the engram). Here, we set out to determine whether neuronal ensembles established in the IL during learning contribute to generalized responses. Generalization was tested in male and female mice by presenting a novel, ambiguous, tone generalization stimulus following Pavlovian defensive (fear) conditioning. The first experiment was designed to test a role for IL in generalization using chemogenetic manipulations. Results show IL regulates defensive behavior in response to ambiguous stimuli. IL silencing led to a switch in defensive state, from vigilant scanning to generalized freezing, while IL stimulation reduced freezing in favor of scanning. Leveraging activity-dependent "tagging" technology (ArcCreERT2 x eYFP system), a neuronal ensemble, preferentially located in IL Layer 2/3, was associated with the generalization stimulus. Remarkably, in the identical discrete location, fewer reactivated neurons were associated with the generalization stimulus at the remote timepoint (30 days) following learning. When an IL neuronal ensemble established during learning was selectively chemogenetically silenced, generalization increased. Conversely, IL neuronal ensemble stimulation reduced generalization. Overall, these data identify a crucial role for IL in suppressing generalized responses. Further, an IL neuronal ensemble, formed during learning, functions to later attenuate the expression of generalization in the presence of ambiguous threat stimuli.

neuroscience↗

bioRxiv2024

Sarm1-Dependent Metabolic Reprogramming of Schwann Cells Following Nerve Injury

Schwann cells (SCs) transition into a Repair state after peripheral nerve injury; however, the early SC injury response preceding this transition remains poorly understood. We demonstrate that Sarm1, a key regulator of axon degeneration, is expressed and upregulated in SCs after nerve injury. Cell-type-specific Sarm1 knockout SCs exhibit enhanced axon protection in vitro, and SC- and glia-specific Sarm1 deletion confers axon protection in mouse sciatic nerve and Drosophila wing injury models. Single-nucleus RNA sequencing revealed that Sarm1-deficient SCs are enriched in a distinct cluster expressing genes with developmental roles in axon and myelin protection, with increased oxidative phosphorylation gene expression across all injured SC states. We propose that Sarm1 gates the transition from a Protection-Associated Schwann Cell (PASC) state to a Repair SC state, establishing Sarm1 as a multi-functional regulator with implications for peripheral neuropathies and neurodegenerative diseases.

neuroscience↗

bioRxiv2024

Abo1 ATPase facilitates the dissociation of FACT from chromatin.

The histone chaperone FACT is a heterodimeric complex consisting of Spt16 and Pob3, crucial for preserving nucleosome integrity during transcription and DNA replication. Loss of FACT leads to cryptic transcription and heterochromatin defects. FACT was shown to interact with Abo1, an AAA+ family histone chaperone involved in nucleosome dynamics. Depletion of Abo1 causes FACT to stall at transcription start sites (TSS) and mimics FACT mutants, indicating a functional association between Abo1 and FACT. However, the precise role of Abo1 in FACT function remains poorly understood. Here, we reveal that Abo1 directly interacts with FACT and facilitates the dissociation of FACT from chromatin. Specifically, the N-terminal region of Abo1 utilizes its FACT interacting (FIN) helix to bind to the N-terminal domain (NTD) of Spt16. In addition, using single-molecule fluorescence imaging, we discovered that Abo1 facilitates the ATP-dependent dissociation of FACT from nucleosomes. Furthermore, we demonstrate that the interaction between Abo1 and FACT is essential for maintaining heterochromatin in fission yeast. In summary, our findings suggest that Abo1 regulates FACT turnover in an ATP-dependent manner, proposing a model of histone chaperone recycling driven by inter-chaperone interactions.

biochemistry↗

bioRxiv2023

EnsDTI-kinase: Web-server for Predicting Kinase-Inhibitor Interactions with Ensemble Computational Methods and Its Applications

MotivationKinase inhibitors are a major category of drugs. Experimental panel assay protocols are routinely used as a standard procedure to evaluate the efficiency and selectivity of a drug candidate to target kinase. However, current kinase panel assays are time-consuming and expensive. In addition, the panel assay protocols neither provide insights on binding sites nor allow experiments on mutated sequences or newly-characterized kinases. Existing virtual screening or docking simulation technologies require extensive computational resources, thus it is not practical to use them for the panel of kinases. With rapid advances in machine learning and deep learning technologies, a number of DTI tools have been developed over the years. However, these methods are yet to achieve prediction accuracies at the level of practical use. In addition, the performances of current DTI tools vary significantly depending on test sets. In this case, an ensemble model can be used to improve and stabilize DTI prediction accuracies. ResultsIn this work, we propose an ensemble model, EnsDTI-kinase, that integrates eight existing machine learning and deep learning models into a unified model deployed as a web-server. Upon submission of a compound SMILES string, potential target kinases are automatically predicted and evaluated on the web-server. Importantly, EnsDTI-kinase is a computational platform where newly developed DTI tools can be easily incorporated without modifying core components so that its DTI prediction quality can improve over time. Besides, many useful functionalities are provided on our platform for users to further investigate predicted DTI: it allows confidence experiments by changing the amino acid (AA) at a specific position in a kinase sequence, named in silico mutagenesis, to investigate the effect of AA changes in binding affinity; it predicts kinase sequential regions where the query compound likely binds to by slidingly masking the sequence of selected kinases so that confidence in the predicted binding sites can be evaluated. Our model was evaluated in three experimental settings using four independent datasets, and showed accuracy of 0.82 compared to the average accuracy of 0.69 from five deep learning methods on the ChEMBL dataset. It achieved average selectivity of 0.95 within kinase families such as TK, CAMK and STE. For 8 out of 17 recent drugs, our model successfully predicted their interactions with 404 proteins at average accuracy of 0.82. Availabilityhttp://biohealth.snu.ac.kr/software/ensdti Contactsunkim.bioinfo@snu.ac.kr

bioinformatics↗

bioRxiv2022

Structure of the Human ATAD2 AAA+ Histone Chaperone Reveals Mechanism of Regulation and Inter-subunit Communication

ATAD2 is a non-canonical ATP-dependent histone chaperone and a major cancer. Despite widespread efforts to design drugs targeting the ATAD2 bromodomain, little is known about the overall structural organization and AAA+ domains of ATAD2. Here, we present the 3.1 [A] cryo-EM structure of human ATAD2 in the ATP state, showing a shallow hexameric spiral that binds a peptide substrate at the central pore. The spiral conformation is locked by an N-terminal linker domain (LD) that wedges between the seam subunits, thus limiting ATP-dependent symmetry breaking of the AAA+ ring. In contrast, a structure of the ATAD2-histone H3H4 complex shows the LD undocked from the seam, suggesting that H3H4 binding unlocks the AAA+ spiral by allosterically releasing the LD. These findings, together with the discovery of an inter-subunit signaling mechanism, reveal a unique regulatory mechanism for ATAD2 and lay the foundation for developing new ATAD2 inhibitors.

molecular biology↗

bioRxiv2022

Microphysiological vascular malformation model reveals a role of dysregulated Rac1 and mTORC1/2 in lesion formation.

Somatic activating mutations of PIK3CA are associated with the development of vascular malformations (VMs). Here, we describe a microfluidic model of PIK3CA-driven VMs consisting of human umbilical vein endothelial cells (HUVECs) expressing PIK3CA activating mutations embedded in 3D hydrogels. We observed enlarged and irregular vessel phenotypes, consistent with clinical signatures and concomitant with PI3K-driven upregulation of Rac1/PAK, MEK/ERK, and mTORC1/2 signaling. We observed differential effects between Alpelisib, a PIK3CA inhibitor, and Rapamycin, an mTORC1 inhibitor, in mitigating matrix degradation and vascular network topology. While both drugs are effective in preventing vessel enlargement, Alpelisib suppressed mTORC2-dependent AKT1 phosphorylation and MEK/ERK signaling. Rapamycin failed to reduce MEK/ERK and mTORC2 activity and resulted in vascular hyperbranching, while inhibiting PAK, MEK1/2, and mTORC1/2 signaling mitigates abnormal growth and vascular dilation. Collectively, these findings establish an in vitro platform for modeling VMs and confirm a role of dysregulated Rac1/PAK and mTORC1/2 signaling in PIK3CA-driven VMs.

bioengineering↗

bioRxiv2021

Functionalizing lipid sponge droplets with DNA

Nucleic acids are among the most versatile molecules for the construction of biomimetic systems because they can serve as information carriers and programmable construction materials. How nucleic acids interact with membranous coacervate compartments such as lipid sponge droplets is not known. Here we systematically characterize the potential of DNA to functionalize lipid sponge droplets and demonstrate a strong size dependence for sequestration into the sponge phase. Double stranded DNA molecules of more than 300 bp are excluded and form a corona on the surface of droplets they are targeted to. Shorter DNA molecules partition efficiently into the lipid sponge phase and can direct DNA-templated reactions to droplets. We demonstrate repeated capture and release of labeled DNA strands by dynamic hybridization and strand displacement reactions that occur inside droplets. Our system opens new opportunities for DNA-encoded functions in lipid sponge droplets such as cargo control and signaling.

synthetic biology↗

bioRxiv2021

Emotion Down- and Up-Regulation Act on Spatially Distinct Brain Areas:Interoceptive Regions to Calm Down and Other Affective Regions to Amp Up

Prior studies on emotion regulation identified a set of brain regions specialized for generating and controlling affect. Researchers generally agree that when up- and down-regulating emotion, control regions in the prefrontal cortex turn up or down activity in affect-generating areas. However, the assumption that turning up and down emotions produces opposite effects in the same affect-generating regions is untested. We call this assumption the affective dial hypothesis. Our study tested this hypothesis by examining the overlap between the sets of regions activated during up-regulation and those deactivated during down-regulation in a large number of participants (N=105). We found that up- and down-regulation both recruit regulatory regions such as the inferior frontal gyrus and dorsal anterior cingulate gyrus but act on distinct affect-generating regions. While up-regulation increases BOLD signal in regions associated with emotion such as the amygdala, anterior insula, striatum and anterior cingulate gyrus as well as in regions associated with sympathetic vascular activity such as periventricular white matter, down-regulation decreases signal in regions receiving interoceptive input such as the posterior insula and postcentral gyrus. These findings indicate that up- and down-regulation do not generally exert opposing effects on the same affect-generating regions. Instead, they target different brain circuits. Significance StatementMany contexts require modulating ones own emotions. Identifying the brain areas implementing these regulatory processes should advance understanding emotional disorders and designing potential interventions. The emotion regulation field has an implicit assumption we call the affective dial hypothesis: that both emotion up- and down-regulation modulate the same emotion-generating brain areas. Countering the hypothesis, our findings indicate that up- and down-modulating emotions target different brain areas. Thus, the mechanisms underlying emotion regulation differ more than previously appreciated for up- versus down-regulation. In addition to their theoretical importance, these findings are critical for researchers attempting to target activity in particular brain regions during an emotion regulation intervention.

neuroscience↗

bioRxiv2021

Task Demand-dependent Contribution of Frontal-Sensory Cortical Projections to Attentional Behavior in Mice

Top-down attention is a dynamic cognitive process that facilitates the detection of the task-relevant stimuli from our complex sensory environment. A neural mechanism capable of deployment under specific task-demand conditions would be crucial to efficiently control attentional processes and improve promote goal-directed attention performance during fluctuating attentional demand. Previous studies have shown that frontal top-down neurons projecting from the anterior cingulate area (ACA) to the visual cortex (VIS; ACAVIS) are required for visual attentional behavior during the 5-choice serial reaction time task (5CSRTT) in mice. However, it is unknown whether the contribution of these projecting neurons is dependent on the extent of task demand. Here, we first examined how behavior outcomes depend on the number of locations for mice to pay attention and touch for successful performance, and found that the 2-choice serial reaction time task (2CSRTT) is less task demanding than the 5CSRTT. We then employed optogenetics to demonstrate that suppression ACAVIS projections immediately before stimulus presentation has no effect during the 2CSRTT in contrast to the impaired performance during the 5CSRTT. These results suggest that ACAVIS projections are necessary when task demand is high, but once a task demand is lowered, ACAVIS neuron activity becomes dispensable to adjust attentional performance. These findings support a model that the frontal-sensory ACAVIS projection regulates visual attention behavior during specific high task demand conditions, pointing to a flexible circuit-based mechanism for promoting attentional behavior.

neuroscience↗

bioRxiv2020

Bronchus-associated macrophages are positioned for soluble antigen capture from the airway lumen and for local Th2 cell activation

In allergic asthma, allergen inhalation leads to local Th2 cell activation and peribronchial inflammation. However, the mechanisms for local antigen capture and presentation remain unclear. By two-photon microscopy, we established that soluble antigens in the bronchial airway lumen were efficiently captured and presented by a population of CD11c+ interstitial macrophages with high CX3CR1-GFP and MHC class II expression. We refer to these cells as Bronchus-Associated Macrophages (BAMs) based on their localization underneath the bronchial epithelium. BAMs were enriched in collagen-rich regions near some airway branchpoints, where inhaled antigens are likely to deposit. BAMs engaged in extended interactions with effector Th2 cells and promoted Th2 cytokine production. BAMs were also often in contact with dendritic cells (DCs). After exposure to inflammatory stimuli, DCs migrated to draining lymph nodes, whereas BAMs remained lung resident. We propose that BAMs act as local antigen presenting cells in the lung and also transfer antigen to DCs.

immunology↗

bioRxiv2020

Norepinephrine, olfactory bulb and memory stability

Memory stability is essential for animal survival when environment and behavioral state change over short or long time spans. The stability of a memory can be expressed by its duration, its perseverance when conditions change as well as its specificity to the learned stimulus. Using optogenetic and pharmacological manipulations, we show that stability of an odor-reward association can be modulated by noradrenergic inputs to the first olfactory network, the olfactory bulb. We show that while manipulations of noradrenaline during an odor-reward acquisition have no acute effects, they impact learning flexibility as well as the duration and the specificity of the memory. We use a computational approach to propose a proof of concept model showing that a single, simple network effect of noradrenaline on olfactory bulb dynamics can underlie these seemingly different behavioral effects. Our results show how acute changes in network dynamics can have long term effects that extend beyond the network that was manipulated.

neuroscience↗

bioRxiv2018

Evaluating analgesic efficacy and administration route following craniotomy in mice using the grimace scale

Most research laboratories abide by guidelines and mandates set by their research institution regarding the administration of analgesics to control pain during the postoperative period. Unfortunately, measuring pain originating from the head is difficult, making adequate decisions regarding pain control following stereotaxic surgery problematic. In addition, most postsurgical analgesia protocols require multiple injections over several days, which may cause stress and distress during a critical recovery period. Here we sought to 1) assess the degree of postoperative pain following craniotomy in mice, 2) compare the efficacy of three common rodent analgesics (carprofen, meloxicam and buprenorphine) for reducing this pain and 3) determine whether the route of administration (injected or self-administered through the water supply) influenced pain relief post-craniotomy. Using the mouse grimace scale (MGS), we found that injectable analgesics were significantly more effective at relieving post-craniotomy pain, however, both routes of administration decreased pain scores in the first 24 h post-surgery. Specifically, buprenorphine administered independently of administration route was the most effective at reducing MGS scores, however, female mice showed greater sensitivity to carprofen when administered through the water supply. Although it is necessary to provide laboratory animals with analgesics after an invasive procedure, there remains a gap in the literature regarding the degree of craniotomy-related pain in rodents and the efficacy of alternative routes of administration. Our study highlights the limitations of administering drugs through the water supply, even at doses that are considered to be higher than those currently recommended by most research institutions for treating pain of mild to moderate severity.

neuroscience↗