Biology subjects

Lim, H.-Y.

Publications and source records attributed to Lim, H.-Y..

8 recordsLinked to original sources

bioRxiv2026

Coexisting but dissociable place and spatial view codes in the primate hippocampus

In rodents, hippocampal activity is classically described in terms of position-anchored place cells, whereas nonhuman primate work has emphasized spatial view cells, in which activity depends on the region of space being viewed. This contrast has fueled a longstanding debate over whether primate and rodent spatial codes are biologically distinct. We recorded single units in the hippocampus of macaques as they navigated linear tracks in two visually distinct contexts, intermittently making context-dependent object choices. Using a generalized linear model to dissociate position coding from spatial view coding, we identified three coexisting populations in the macaque hippocampus: Position cells, View cells, and Conjunctive cells encoding both variables. Position cells were prevalent and showed rodent-like properties--localized firing, directional tuning, and contextual remapping--even after accounting for visual sampling, whereas View cells stably encoded allocentric visual space. Population decoding confirmed this dissociation at the ensemble level. Robust position codes thus coexist with, yet remain dissociable from, view codes in the primate hippocampus, suggesting that the apparent scarcity of place-like responses in earlier primate work reflects methodological and task-related differences rather than a fundamental species-level divergence.

neuroscience↗

bioRxiv2025

Small molecule inhibitor of PPARγ acetylation promotes insulin sensitization and browning of white adipose tissue with improved safety

The nuclear receptor PPAR{gamma} is a primary therapeutic target for insulin resistance and type 2 diabetes (T2D); however, its thiazolidinedione (TZD) class of PPAR{gamma} agonists have substantial safety concerns in clinical utilization. Genetic inhibition of PPAR{gamma} acetylation at K268 and K293 dissociates the major adverse effects of TZDs from insulin sensitization and other metabolic improvements. We therefore posit that chemical inhibition of PPAR{gamma} acetylation would elicit insulin sensitization with improved safety. Here we describe the identification of a synthetic thiopyrimidine derivative (TPMD) that acts as a small molecule inhibitor of PPAR{gamma} acetylation. TPMD improves insulin sensitivity, promotes brown remodeling of white adipose tissue (WAT), increases energy expenditure, and decreases adiposity in dietary and genetic mouse models of T2D. Importantly, TPMD is deprived of the major side effects of TZDs, including weight gain, fluid retention, cardiac hypertrophy, bone marrow adiposity, and bone loss. X-ray crystallography at 2.0 [A] resolution reveals a unique binding mode of TPMD molecules to the PPAR{gamma} ligand-binding domain and provides structural and molecular basis for the acetylation inhibitory activity of TPMD together with site-directed mutagenesis studies. These findings identify TPMD as a first-in-class compound that specifically targets PPAR{gamma} acetylation and possesses the potential of developing into a safe insulin sensitizer to treat and prevent T2D and obesity.

cell biology↗

bioRxiv2025

Sequential development of task representation from hippocampus to prefrontal cortex supports goal-directed spatial navigation

Successful goal-directed navigation requires the coordination between the hippocampus and medial prefrontal cortex. However, it is not fully confirmed that the medial prefrontal cortex learns its spatial code from the hippocampus. To test this, we examined spatial representations of the intermediate hippocampus and medial prefrontal cortex while rats learned a spatial navigation task. Rats performed a goal-directed spatial navigation task in 2D VR to find an unmarked goal zone, and we discovered robust directional tuning of single neurons in both regions. Neural manifold analysis further confirmed population-level directional tuning in both regions, with manifolds having ring-like geometry. We found that this ring-like structure evolved after learning, in a way that the hippocampal-prefrontal manifolds converged to a shared geometry. Furthermore, this evolution of ring-like structure was preceded by the hippocampus at the trial level. It was further verified that the evolution of the ring-like structure is linked to phase locking to the hippocampal theta rhythm, particularly in the prefrontal manifolds. Our findings provide compelling evidence that spatial representations of the hippocampal-prefrontal network become aligned after learning, and also highlight the information flow from the hippocampus to the medial prefrontal cortex during this geometry synchronization.

neuroscience↗

bioRxiv2024

Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in obesity

Overnutrition engenders the expansion of adipose tissue and the accumulation of immune cells, in particular, macrophages, in the adipose tissue, leading to chronic low-grade inflammation and insulin resistance. In obesity, several proinflammatory subpopulations of adipose tissue macrophages (ATMs) identified hitherto include the conventional "M1-like" CD11C-expressing ATM and the newly discovered metabolically activated CD9-expressing ATM; however, the relationship among ATM subpopulations is unclear. The ER stress sensor inositol-requiring enzyme 1 (IRE1) is activated in the adipocytes and immune cells under obesity. It is unknown whether targeting IRE1 is capable of reversing insulin resistance and obesity and modulating the metabolically activated ATMs. We report that pharmacological inhibition of IRE1 RNase significantly ameliorates insulin resistance and glucose intolerance in male mice with diet-induced obesity. IRE1 inhibition also increases thermogenesis and energy expenditure, and hence protects against high fat diet-induced obesity. Our study shows that the "M1-like" CD11c+ ATMs are largely overlapping with but yet non-identical to CD9+ ATMs in obese white adipose tissue. Notably, IRE1 inhibition diminishes the accumulation of obesity-induced metabolically activated ATMs and "M1-like" ATMs, resulting in the curtailment of adipose inflammation and ensuing reactivation of thermogenesis, without augmentation of the alternatively activated M2 macrophage population. Our findings suggest the potential of targeting IRE1 for the therapeutic treatment of insulin resistance and obesity.

cell biology↗

bioRxiv2023

Neural correlates of modality-specific and modality-invariant object recognition in the perirhinal cortex

The perirhinal cortex (PER) supports multimodal object recognition, but how multimodal information of objects is integrated within the PER remains unknown. Here, we recorded single units within the PER while rats performed a PER-dependent multimodal object-recognition task. In this task, audiovisual cues were simultaneously (multimodally) or separately (unimodally) presented. We identified two types of object-selective neurons in the PER: crossmodal cells, showing constant firing patterns for an object irrespective of its modality, and unimodal cells, showing a preference for a specific modality. Unimodal cells further dissociated unimodal and multimodal versions of the object by modulating their firing rates according to the modality condition. A population-decoding analysis confirmed that the PER could perform both modality-invariant and modality-specific object decoding - the former for recognizing an object as the same in various conditions and the latter for remembering modality-specific experiences of the same object.

neuroscience↗

bioRxiv2023

Designing Efficient Enzymes: Eight Predicted Mutations Convert a Hydroxynitrile Lyase into an Efficient Esterase

Hydroxynitrile lyase from rubber tree (HbHNL) shares 45% identical amino acid residues with the homologous esterase from tobacco, SABP2, but the two enzymes catalyze different reactions. The x-ray structures reveal a serine-histidine-aspartate catalytic triad in both enzymes along with several differing amino acid residues within the active site. Previous exchange of three amino acid residues in the active site of HbHNL with the corresponding amino acid residue in SABP2 (T11G-E79H-K236M) created variant HNL3, which showed low esterase activity toward p-nitrophenyl acetate. Further structure comparison reveals additional differences surrounding the active site. HbHNL contains an improperly positioned oxyanion hole residue and differing solvation of the catalytic aspartate. We hypothesized that correcting these structural differences would impart good esterase activity on the corresponding HbHNL variant. To predict the amino acid substitutions needed to correct the structure, we calculated shortest path maps for both HbHNL and SABP2, which reveal correlated movements of amino acids in the two enzymes. Replacing four amino acid residues (C81L-N104T-V106F-G176S) whose movements are connected to the movements of the catalytic residues yielded variant HNL7TV (stabilizing substitution H103V was also added), which showed an esterase catalytic efficiency comparable to that of SABP2. The x-ray structure of an intermediate variant, HNL6V, showed an altered solvation of the catalytic aspartate and a partially corrected oxyanion hole. This dramatic increase in catalytic efficiency demonstrates the ability of shortest path maps to predict which residues outside the active site contribute to catalytic activity.

bioengineering↗

bioRxiv2020

Inhibition of inositol-requiring enzyme 1 RNase activity protects pancreatic beta cell and improves diabetic condition in insulin mutation-induced diabetes

Proinsulin misfolding in the endoplasmic reticulum (ER) plays an important role in {beta}-cell dysfunction and death and the pathogenesis of mutant INS-gene-induced diabetes of youth (MIDY). There is no effective treatment for MIDY except the insulin administration. Here, we found that the ER stress sensor inositol-requiring enzyme 1 (IRE1) was activated in the Akita mice, a mouse model of MIDY. Normalization of IRE1 RNase hyperactivity by pharmacological inhibitors significantly ameliorated the hyperglycemic conditions and increased serum insulin levels in Akita mice. These benefits were accompanied by a concomitant protection of functional {beta}-cell mass, as shown by the suppression of {beta}-cell apoptosis, increase in mature insulin production and reduction of proinsulin level. At the molecular level, we observed that the expression of genes associated with {beta}-cell identity and function was significantly up-regulated and ER stress and its associated inflammation and oxidative stress were suppressed in islets from Akita mice treated with IRE1 RNase inhibitors. This study provides the first evidence of the in vivo efficacy of IRE1 RNase inhibition in Akita mice, pointing to the possibility of targeting IRE1 RNase as a therapeutic direction for the treatment of MIDY diabetes.

pharmacology and toxicology↗

bioRxiv2019

The fasciola cinereum of the hippocampus is important in the acquisition, but not the retrieval, of visual contextual memory

The fasciola cinereum (FC) is a subregion of the hippocampus that has received relatively little research attention compared with other hippocampal subregions with respect to anatomical characteristics and functional significance. Here, we show that the FC exhibits clear anatomical borders with CA1. The FC consists of granule cells, but adult neurogenesis was not found. The FC receives inputs from the lateral entorhinal cortex and perirhinal cortex while projecting to the crest of the dentate gyrus (DG). Neurotoxic lesioning of the FC using colchicine impaired the acquisition, but not retrieval, of visual contextual memory in rats. FC lesions also impaired place recognition and object-in-place memory. Place cells in the FC showed robust place fields but fired only transiently in their fields compared with those in CA1. Our findings suggest that the FC may play critical roles in learning a novel environment by facilitating pattern separation in the DG of the hippocampus.

neuroscience↗