Biology subjects

Chung, J. M.

Publications and source records attributed to Chung, J. M..

13 recordsLinked to original sources

bioRxiv2026

Criterion-selective neurons in the human medial frontal cortex track decision thresholds during memory-based decision making

The decision criterion is foundational to theories of decision-making, yet little is known about its neural underpinnings. In memory-based decision making, the criterion sets the minimal memory strength for something to be familiar, but whether or how it is distinctly represented from memory strength is unknown. We recorded single neurons in the medial frontal cortex (MFC) and medial temporal lobe (MTL), both implicated in memory-based decisions, while participants made decisions under different decision criteria. We identified criterion-selective (CS) neurons in the MFC that tracked the criterion regardless of memory strength, and memory-selective (MS) neurons in both regions that tracked memory strength regardless of the criterion. CS neurons signaled the criterion before MS neurons signaled memory strength, and a race model incorporating both neuron types outperformed one using MS neurons alone. These findings reveal two independent cellular substrates, one for the decision criterion and one for memory strength, whose joint activity underlies memory-based decisions.

neuroscience↗

bioRxiv2026

Choice-driven remapping of action- and stimulus-anchored value in human single neurons

Whether stimulus- and action-based choices rely on a shared neural architecture remains intensely debated. While lesion and fMRI studies show conflicting regional dissociation and overlap, the underlying single neuron substrates remain unknown. We recorded single neuron activity from the human ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), pre-supplementary motor area (preSMA), and amygdala during distinct action- and stimulus-based reward tasks. Prior to decision-making, neurons across all regions broadly encode value for both choice domains. However, choice commitment triggers domain segregation across the prefrontal cortex. While ACC and vmPFC neurons flexibly track both chosen actions and stimuli, they exhibit a double dissociation for chosen valuation: ACC neurons selectively maintain action-based values, whereas vmPFC neurons selectively maintain stimulus-based values. Conversely, preSMA neurons invariant to task domain track chosen action identity and value. These findings reveal how prefrontal networks transition from domain-general evaluation to domain-segregated choice execution.

neuroscience↗

bioRxiv2025

β-Amyloid Induces Microglial Expression of GPC4 and APOE Leading to Increased Neuronal Tau Pathology and Toxicity

To elucidate the impact of A{beta} pathology on microglia in Alzheimers disease pathogenesis, we profiled the microglia surfaceome following treatment with A{beta} fibrils. Our findings reveal that A{beta}-associated human microglia upregulate Glypican 4 (GPC4), a GPI-anchored heparan sulfate proteoglycan (HSPG). In a Drosophila amyloidosis model, glial GPC4 expression exacerbates motor deficits and reduces lifespan, indicating that glial GPC4 contributes to a toxic cellular program during neurodegeneration. In cell culture, GPC4 enhances microglia phagocytosis of tau aggregates, and shed GPC4 can act in trans to facilitate tau aggregate uptake and seeding in neurons. Additionally, our data demonstrate that GPC4-mediated effects are amplified in the presence of APOE. These studies offer a mechanistic framework linking A{beta} and tau pathology through microglial HSPGs and APOE.

neuroscience↗

bioRxiv2025

Yeast DNA Polymerase δ Proofreading Nuclease Suppresses Translesion Synthesis and Facilitates Recombination in DNA Lesion Bypass.

Translesion synthesis (TLS) employs specialized polymerases to incorporate nucleotides opposite DNA lesions, allowing replication to continue temporarily without repairing the lesions, while sacrificing replication fidelity (1). TLS depends on a ubiquitin molecule attached to the clamp PCNA at residue Lys164 (2, 3); the precise biochemical and molecular basis how PCNA modification stimulates TLS is still elusive (4-10). In this study, we discovered that DNA polymerase {delta} (Pol {delta}) 3 to 5 "proofreading" exonuclease degrades nascent TLS synthesis opposite pyrimidine dimers and inhibits TLS on both leading and lagging strands. Rad18 E3 ligase and PCNA ubiquitylation become dispensable for TLS when Pol {delta} exonuclease is inactive. Biochemical reconstitution showed that the major UV lesion bypass polymerase Rad30 is intrinsically inefficient at bypassing thymidine dimers and requires multiple turnovers. Pol {delta} exonuclease impedes Rad30 activity both catalytically and non-catalytically during and post-lesion bypass. Importantly, PCNA and PCNA ubiquitylation enhance processivity of Rad30 after thymidine dimer bypass, a critical step for further DNA synthesis extension and overcoming Pol {delta} inhibition. Our study reveals a new paradigm how PCNA ubiquitylation facilitates TLS and the new role of Pol {delta} nuclease in lesion bypass pathway choice and replication fidelity at fork-blocking DNA lesions.

genetics↗

bioRxiv2024

A shared code for perceiving and imagining objects in human ventral temporal cortex

Mental imagery is a remarkable phenomenon that allows us to remember previous experiences and imagine new ones. Animal studies have yielded rich insight into mechanisms for visual perception, but the neural mechanisms for visual imagery remain poorly understood. Here, we first determined that [~]80% of visually responsive single neurons in human ventral temporal cortex (VTC) use a distributed axis code to represent objects. We then used that code to reconstruct objects and generate maximally effective synthetic stimuli. Finally, we recorded responses from the same neural population while subjects imagined specific objects and found that [~]40% of axis-tuned VTC neurons recapitulated the visual code. Our findings reveal that visual imagery is supported by reactivation of the same neurons involved in perception, providing single neuron evidence for the existence of a generative model in human VTC. One Sentence SummarySingle neurons in human temporal cortex use feature axes to encode objects, and imagery reactivates this code.

neuroscience↗

bioRxiv2023

Hippocampal Theta Phase Precession Supports Memory Formation and Retrieval of Naturalistic Experience in Humans

Linking different experiences together is a key aspect of episodic memory. A potential neural mechanism for linking sequential events over time is phase precession, which causes neurons to fire progressively earlier in time relative to theta-frequency local field potential oscillations. However, no direct link between phase precession and behaviorally assessed memory encoding or retrieval success has been established. We recorded the activity of single neurons and local field potentials in the human medial temporal lobe (MTL) while participants encoded and retrieved memories of movie clips. Transient brief theta bouts and theta phase precession were observed following cognitive boundaries during movie watching as well as following stimulus onset during memory retrieval. Phase precession was dynamic, with different neurons exhibiting phase precession in different task periods. The strength of phase precession provided information about memory encoding and retrieval success that was not available in firing rates, thereby linking the temporal code established by phase precession to behaviorally assessed memory strength. These data reveal phase precession during non spatial memory in humans and provide direct neural evidence for a functional role of phase precession in episodic memory.

neuroscience↗

bioRxiv2022

Intraoperative Spinal Cord Stimulation Mitigates Pain after Spine Surgery in Mice

BackgroundManaging postoperative pain after spine surgery is challenging, and up to 40% of operated patients develop failed back surgery syndrome (FBSS) resulting in intractable back and/or leg pain. While spinal cord stimulation (SCS) has been shown to effectively alleviate such chronic pain, it is unknown if intraoperative SCS can mitigate the development of central sensitization that potentially causes intense postoperative pain and FBSS after spine surgery. MethodsAs an experimental spine surgery, unilateral T13 laminectomy was performed in mice to expose the dorsal part of L4-5 spinal segments that receive sensory inputs from the hind limb. After the laminectomy, a group of mice received intraoperative SCS epidurally applied to the exposed side of the dorsal part of the spinal cord for an hour under anesthesia before closing the surgical wounds. Secondary mechanical hypersensitivity, a behavioral manifestation of central sensitization, was measured in hind paws using von Frey assay one day before and at predetermined times after surgery. In addition, because von Frey assay is a nocifensive reflex-based analysis that primarily assesses the sensory-discriminative domain of pain, we also performed a conflict avoidance test to capture the affective-motivational domain of pain at selected timepoints post-laminectomy. ResultsMice that underwent unilateral T13 laminectomy developed mechanical hypersensitivity in both hind paws, which gradually resolved in 1-2 weeks. The extent of the hypersensitivity was significantly less in the contralateral hind paw (relative to the laminectomy) than in the ipsilateral hind paw only in females. Intraoperative SCS applied to the exposed side of the dorsal -spinal cord significantly inhibited the development of hind paw mechanical hypersensitivity only in the SCS-applied side. When paws were mechanically stimulated in their preferred place to present a conflict between pain/discomfort and natural preference, mice avoided the conflict after laminectomy, spending less time in the place than before the surgery. However, mice treated with intraoperative SCS after laminectomy did not avoid the conflict. ConclusionThese results demonstrate that spine surgery for unilateral laminectomy induces central sensitization that results in postoperative pain hypersensitivity. Intraoperative SCS after laminectomy can mitigate the development of this hypersensitivity in the SCS-applied side.

neuroscience↗

bioRxiv2021

The geometry of domain-general performance monitoring representations in the human medial frontal cortex

Controlling behavior to flexibly achieve desired goals depends on the ability to monitor ones own performance. It is unknown how performance monitoring can be both flexible to support different tasks and specialized to perform well on each. We recorded single neurons in the human medial frontal cortex while subjects performed two tasks that involve three types of cognitive conflict. Neurons encoding predicted conflict, conflict, and error in one or both tasks were intermixed, forming a representational geometry that simultaneously allowed task specialization and generalization. Neurons encoding conflict retrospectively served to update internal estimates of control demand. Population representations of conflict were compositional. These findings reveal how representations of evaluative signals can be both abstract and task-specific and suggest a neuronal mechanism for estimating control demand.

neuroscience↗

bioRxiv2021

Development of opioid-induced hyperalgesia depends on reactive astrocytes controlled by Wnt5a signaling

Opioids are the frontline analgesics for managing various types of pain. Paradoxically, repeated use of opioid analgesics may cause an exacerbated pain state known as opioid-induced hyperalgesia (OIH), which significantly contributes to dose escalation and consequently opioid overdose. Neuronal malplasticity in pain circuits has been the predominant proposed mechanism of OIH expression. Although glial cells are known to become reactive in OIH animal models, their biological contribution to OIH remains to be defined and their activation mechanism remains to be elucidated. Here, we show that reactive astrocytes (a.k.a. astrogliosis) are critical for OIH development in both male and female mice. Genetic ablation of astrogliosis inhibited the expression of OIH and morphine-induced neural circuit polarization (NCP) in the spinal dorsal horn (SDH). We found that Wnt5a is a neuron-to-astrocyte signal that is required for morphine-induced astrogliosis. Conditional knock-out of Wnt5a in neurons or its co-receptor ROR2 in astrocytes blocked not only morphine-induced astrogliosis but also OIH and NCP. Furthermore, we showed that the Wnt5a-ROR2 signaling-dependent astrogliosis contributes to OIH via inflammasome-regulated IL-1{beta}. Our results reveal an important role of morphine-induced astrogliosis in OIH pathogenesis and elucidate a neuron-to-astrocyte intercellular Wnt signaling pathway that controls the astrogliosis.

neuroscience↗

bioRxiv2021

Cryo-EM reveals new species-specific proteins and symmetry elements in the Legionella pneumophila Dot/Icm T4SS

Legionella pneumophila is an opportunistic pathogen that causes the potentially fatal pneumonia known as Legionnaires Disease. The pathology associated with infection depends on bacterial delivery of effector proteins into the host via the membrane spanning Dot/Icm type IV secretion system (T4SS). We have determined sub-3.0 [A] resolution maps of the Dot/Icm T4SS core complex by single particle cryo-EM. The high-resolution structural analysis has allowed us to identify proteins encoded outside the Dot/Icm genetic locus that contribute to the core T4SS structure. We can also now define two distinct areas of symmetry mismatch, one that connects the C18 periplasmic ring (PR) and the C13 outer membrane cap (OMC) and one that connects the C13 OMC with a 16-fold symmetric dome. Unexpectedly the connection between the PR and OMC is DotH, with five copies sandwiched between the OMC and PR to accommodate the symmetry mismatch. Finally, we observe multiple conformations in the reconstructions that indicate flexibility within the structure. We hypothesize this conformational flexibility is likely to facilitate the Dot/Icm T4SSs ability to translocate a remarkably large set of [~]300 putative substrates across the inner and outer membranes of the bacterial cell.

microbiology↗

bioRxiv2021

Mechanism and role of astrogliosis in the pathogenesis of HIV-associated pain

Pathological pain is the most common neurological disorder in people living with HIV-1/AIDS (PLWHA), and rationale-based effective treatment is not available. Multiple neuropathologies develop in the pain transmission pathways in of HIV patients, consistent with their nociceptive dysfunction1,2. One of the prominent neuropathologies associating with the manifestation of pain in HIV patients is astrogliosis (a.k.a. reactive astrocytes) in the spinal dorsal horn (SDH)1, the spinal center for the transmission of pain signals from peripheral organs to the brain. However, the pathogenic role and the activation mechanism of astrogliosis are unclear. Here, we show that the astrogliosis is crucial for the pain pathogenesis induced by HIV-1 gp120, a key etiologically relevant protein2, and that a neuron-to-astrocyte Wnt5a signal controls the astrogliosis. We found that ablation of astrogliosis blocked the development of gp120-induced mechanical hyperalgesia, and concomitantly the expression of neural circuit polarization (NCP) in the SDH. In addition, we demonstrated that conditional knockout (CKO) of either Wnt5a in neurons or its receptor ROR2 in astrocytes abolished not only gp120-induced astrogliosis but also the hyperalgesia and the NCP. Furthermore, we found that the astrogliosis promoted expression of the NCP and the hyperalgesia via IL-1{beta} regulated by a Wnt5a-ROR2-MMP2 axis. Our results elucidate an important role and a novel mechanism of astrogliosis in the pathogenesis of HIV-associated pain. Targeting reactive astrocytes by manipulating the mechanistic processes identified here may lead to the development of effective therapy to treat the pain syndrome in HIV patients.

neuroscience↗

bioRxiv2020

Cryo-EM reveals species-specific components within the Helicobacter pylori Cag type IV secretion system core complex

The pathogenesis of Helicobacter pylori-associated gastric cancer is dependent on delivery of CagA into host cells through a type IV secretion system (T4SS). The H. pylori Cag T4SS includes a large membrane-spanning core complex containing 5 proteins, organized into an outer membrane cap (OMC), a periplasmic ring (PR) and a stalk. Here, we report cryo-EM reconstructions of a core complex lacking Cag3 and an improved map of the wild-type complex. We define the structures of two unique species-specific components (Cag3 and CagM) and show that Cag3 is structurally similar to CagT. Unexpectedly, components of the OMC are organized in a 1:1:2:2:5 molar ratio (CagY:CagX:CagT:CagM:Cag3). CagX and CagY are components of both the OMC and the PR and bridge the symmetry mismatch between these regions. These results reveal that assembly of the H. pylori T4SS core complex is dependent on incorporation of interwoven species-specific components.

microbiology↗

bioRxiv2020

Structural analysis of the Legionella pneumophila Dot/Icm Type IV Secretion System Core Complex

Legionella pneumophila is an opportunistic pathogen that causes the potentially fatal pneumonia Legionnaires Disease. This infection and subsequent pathology require the Dot/Icm Type IV Secretion System (T4SS) to deliver effector proteins into host cells. Compared to prototypical T4SSs, the Dot/Icm assembly is much larger, containing ~27 different components including a core complex reported to be composed of five proteins: DotC, DotD, DotF, DotG, and DotH. Using single particle cryo-electron microscopy (cryo-EM), we report reconstructions of the core complex of the Dot/Icm T4SS that includes a symmetry mismatch between distinct structural features of the outer membrane cap (OMC) and periplasmic ring (PR). We present models of known core complex proteins, DotC, DotD, and DotH, and two structurally similar proteins within the core complex, DotK and Lpg0657. This analysis reveals the stoichiometry and contact interfaces between the key proteins of the Dot/Icm T4SS core complex and provides a framework for understanding a complex molecular machine.

microbiology↗