Biology subjects

Cutler, M.

Publications and source records attributed to Cutler, M..

13 recordsLinked to original sources

bioRxiv2026

Chemogenetic Inhibition of the Ventrolateral Orbitofrontal Cortex Disrupts Prediction Error and Salience-Guided Memory-Updating at the Hippocampal Engram Level

RationaleAdaptive behavior requires revising memories when outcomes deviate from expectations. The orbitofrontal cortex (OFC) is implicated in representing outcome expectancies, but its role in memory-updating, beyond value-based learning, remains unclear. ObjectivesWe tested whether the ventrolateral OFC (VLO) contributes to hippocampal-dependent memory-updating in the Objects in Updated Locations (OUL) task, where novelty-driven exploration provides a behavioral readout consistent with successful updating of spatial information MethodsUsing inhibitory DREADDs, in male and female (Swiss Webster and C57BL/6) mice, we suppressed VLO activity during the Updating session, when new object-location information was introduced. ResultsControl mice preferentially explored the updated object-location configuration during Updating and discriminated between updated and novel object-location configurations at Test, whereas VLO-inhibited mice did not. VLO inhibition when no updating demand was present did not alter exploration of novel object-location configurations or memory for the original spatial configuration at Test. ConclusionsThese results indicate that VLO activity is selectively required when novelty must be interpreted relative to prior experience, implicating this region in evaluating change rather than detecting it. To assess hippocampal ensemble dynamics, we tagged neuronal ensembles, in the dorsal dentate gyrus (dDG) recruited during Updating, followed by quantification of overlap between Updating-tagged cells and ensembles reactivated at Test. We found that VLO inhibition reduced reactivation of Updating-tagged dDG ensembles, paralleling the behavioral impairments observed in the OUL task. These findings support a role for the VLO in hippocampal-dependent memory-updating and extend OFC models beyond reward contexts to include predictive updating of spatial memory representations. Significance StatementUsing a spatial paradigm that distinguishes detection of changed information from incorporation of that information into an updated hippocampal representation, we found that ventrolateral orbitofrontal cortex (VLO) activity is required for memory-updating when new information is present. We found behavioral deficits accompanied by impairments in hippocampal ensemble representations, indicating VLO activity is necessary for memory-updating at the hippocampal engram level. Through this mechanism, the OFC supports the flexible updating of expected outcomes when environmental conditions shift, allowing for the re-evaluation of previously learned associations. These findings extend models of orbitofrontal cortex function beyond reward-guided behavior and identify a cortical contribution to predictive spatial memory processes. Disruption of this computation may contribute to the cognitive rigidity observed in neuropsychiatric disorders.

neuroscience↗

bioRxiv2026

Artificial Reactivation of a Cocaine-Associated Engram in the Dorsal Dentate Gyrus Attenuates Cocaine Prime-Induced Reinstatement of Drug-Seeking

Relapse-prevention strategies aimed at reducing relapse following abstinence, primarily focus on reducing cravings that lead to drug-seeking triggered by stress, drug-related cues, or re-exposure to the drug. Because addictive drugs form persistent associative contextual memories, we investigated how reactivation of cocaine-related hippocampal memories influences subsequent drug-seeking. Here, we tagged dorsal dentate gyrus (dDG) memory ensembles involved in encoding either a first or fourth cocaine exposure (15mg/kg, i.p) in male and female c57BL/6 mice using a TetTag approach. Mice underwent cocaine conditioned place preference (CPP), extinction, and reinstatement. We assessed whether optical reactivation of tagged cocaine-related ensembles could substitute for a cocaine priming injection to reinstate CPP, whether reactivation altered cocaine-induced reinstatement, and if these effects differed depending on stage of drug exposure. We also compared these effects to reactivation of saline-associated ensembles. Cocaine produced robust locomotor activation during conditioning, and sensitization developed across repeated drug exposures. Reactivation of a cocaine-related engram alone did not reinstate CPP. However, reactivation of the first cocaine exposure engram attenuated cocaine-induced reinstatement. In contrast, reactivation of the fourth exposure engram did not confer this protective effect. Interestingly, reactivation of saline-associated ensembles also reduced cocaine-induced reinstatement specifically in females, suggesting dDG ensemble reactivation may modulate relapse-related behavior through interference or neuromodulatory disruption of cocaine-associated representations, consistent with our prior work. These findings raise the possibility that early contextual experiences form competing or destabilizing representations that interfere with later cocaine-seeking when reactivated. Females also displayed greater sensitivity to locomotor-inducing effects of cocaine memory reactivation, although this was dissociated from CPP. Together, these findings show that cocaine memories are distinct across drug experience and selective reactivation of dDG engrams can differentially influence drug-seeking.

animal behavior and cognition↗

bioRxiv2026

Calorie Restriction Up-regulates Islet PD-L1 Signaling and Decreases the Risk of Auto-immune Diabetes Onset in NOD Mice.

Type 1 diabetes (T1D) is an autoimmune disease where beta cells are destroyed by cytotoxic T cells. Calorie restriction (CR) enhances glucose homeostasis and promotes beta cell longevity and was used as therapeutic strategy for T1D prior to the discovery of insulin. However, a significant knowledge gap remains regarding its effects on beta cells during the pathogenesis of autoimmunity. We demonstrate that CR enhances glucose homeostasis, reduces beta cell load, and delays T1D onset in NOD mice. CR induced a largely post-mitotic beta cell state marked by selective loss of beta cell identity markers, reduced DNA damage and beta cell senescence, and increased PD-L1 within the islet microenvironment. This beta cell phenotype correlates with anti-inflammatory and exhausted immune cell states in the NOD islet. Together, these findings indicate that CR improves glucose homeostasis and remodels the islet microenvironment to promote beta cell longevity via a pro-tolerogenic immune microenvironment that reduces the risk for autoimmune diabetes.

cell biology↗

bioRxiv2025

Three-dimensional shape cues affect human and artificial recognition systems differently

Humans and neural networks use shape and texture information differently. While shape is the primary cue in human object recognition, neural networks are more biased towards texture cues. Many tests of shape vs. texture bias have focused on shape recognition from an objects external contour. However, shape information is also conveyed through internal contours, shading, and attached shadows, especially when an object is viewed from noncanonical perspectives. Using models from ShapeNet, we created datasets of 120,000 texture-substituted images of objects from many viewpoints with and without shading and attached shadows. We tested humans and several neural networks ability to classify these objects by both their shape and their texture. Humans were much better at classifying texture-substituted objects by their shape than any network, although these differences were greater when shape was defined only by the external contour than when 3D cues were included. Our findings suggest that networks texture bias is reduced when 3D cues are included in images. We next tested whether the inclusion of 3D cues benefitted humans and neural networks more for images of objects viewed from canonical or noncanonical perspectives. Consistent with earlier research, we found that 3D cues primarily benefitted humans for noncanonical images. For neural networks, the greatest performance gains were for canonical images. These findings suggest fundamental differences in how humans and networks use shading and attached shadows for object recognition. We argue that humans use these cues to infer objects 3D structures while neural networks use them as another surface-level cue like texture.

animal behavior and cognition↗

bioRxiv2025

Calorie Restriction modulates beta cell IP3R activity to regulate Ca2+ homeostasis and cell network connectivity

Calorie restriction (CR) promotes beta cell longevity by regulating cell identity, organelle and protein homeostasis, and metabolism pathways. CR beta cells have higher cAMP levels and mitochondria with an elevated potential to generate ATP. However, CR beta cells have reduced insulin secretion due to increased peripheral insulin sensitivity. How CR impacts beta cell Ca2+ homeostasis to regulate beta cell insulin release remains unknown. We investigated this question using acute pancreatic tissue slices prepared from ad-libitum (AL) or CR mice loaded with a low affinity Ca2+ indicator and recorded cytosolic Ca2+ gradients with fast confocal imaging. We exposed these slices to increasing glucose concentrations and applied our semi-automatic analysis pipeline to detect thousands of individual beta cells followed by identification of individual Ca2+ spiking events. We observed that CR beta cells have fast short-amplitude Ca2+ oscillations that correlate with largely disconnected beta cell networks across the islet. Using acetylcholine stimulation, we found that faster IP3R-driven Ca2+ oscillations linked to higher cytosolic cAMP levels protect beta cells against acute depletion of ER Ca2+ stress. Therefore, this study provides new mechanistic insight into adaptation of beta cell and of beta cell networks to CR interventions. Article highlightsO_LIBeta cells from calorie restricted (CR) mice have decreased insulin release, however the mechanisms underlying this adaptive response remain unknown. C_LIO_LICR beta cells have elevated basal cytosolic cAMP ([cAMP]cyt) compared to beta cells in control ad libitum fed (AL) mice, and they operate with faster and shorter cytosolic Ca2+ oscillations. C_LIO_LIWhile AL beta cells form interconnected activity networks, CR beta cells are largely disconnected and fire more independently of each other. C_LIO_LIIslets of CR mice can sustain prolonged activity during ER stressing conditions due to elevated IP3R activity and improved Ca2+ homeostasis. C_LI Why did we undertake this study?We have previously shown that calorie restriction (CR) promotes beta cell longevity by enhancing beta cell identity and organelle homeostasis mechanisms. This long-lived phenotype correlated with the onset of enhanced peripheral insulin sensitivity and reduced beta cell insulin release in vivo despite higher cAMP levels and increased potential for mitochondrial ATP generation. However, the mechanisms underlying the reduced cell insulin release phenotype of CR beta cells remains unknown. Therefore, we investigated the underlying Ca2+ homeostasis mechanisms regulating insulin release in AL and CR beta cells. What is the specific question(s) we wanted to answer?We were interested in determining what are the cell Ca2+ activity patterns during basal and glucose-stimulated conditions in AL and CR beta cells. In addition, we also investigated how CR beta cells respond to epinephrine inhibition and supra-stimulatory concentrations of acetylcholine (ACh), which drive acute beta cell stress by disrupting normal cAMP and ER Ca2+ signaling, respectively. Finally, we investigate whether CR beta cells formed more interconnected beta cell networks driven by changes in Ca2+ activity patterns. What did we find?We found that CR beta cells are more active with significantly higher rates of Ca2+ oscillation at basal and high glucose concentrations. In fact, CR beta cells have shorter inter-Ca2+ event intervals that are more resistant to depletion of cAMP by epinephrine application. In contrast, stimulation of IP3R activity (to force depletion of ER Ca2+ stores) by supraphysiological ACh concentrations revealed that CR beta cells were able to sustain a prolonged Ca2+ activity versus AL beta cells. Surprisingly, this enhanced beta cell activity profile reduced beta cell activity network connectivity. What are the implications of our findings?Our work demonstrates that CR beta cells have higher baseline and glucose-stimulated Ca2+ activity due to higher cAMP levels. These cells also have dominant IP3R activity that grants improved ER Ca2+ homeostasis and significantly reduces beta cell network connectivity to tone down insulin secretion. These studies provide a mechanistic understanding of how beta cells adapt to CR and to CR-associated enhanced insulin sensitivity.

cell biology↗

bioRxiv2025

Calorie restriction suppresses aging alpha cell pro-inflammatory signaling

Aging increases risk for type 2 diabetes (T2D), partly through loss of beta cell identity and function driven by metabolic stress and islet inflammation. While calorie restriction (CR) promotes beta cell longevity in young animals, its impact on cellular aging and inflammatory burden in older individuals is unclear. Using SCENIC regulon and multiomic analyses, we find that aging human alpha cells adopt a coordinated inflammatory phenotype marked by IFN-{gamma} signaling to increase major histocompatibility complex (MHC) class I presentation, and CD8+ T cell recruitment and activation towards islets. In T2D, CD8+ T cells further progress towards an effector memory state. CR reduces alpha cell MHC-I expression while subsequently suppressing CD8+ effector status and accompanied by reduced islet inflammation and immune cell infiltration in mice. Together, these findings highlight an alpha cell-immune signaling axis in aging and T2D that may underlie fibrosis and disease pathophysiology.

physiology↗

bioRxiv2023

Caloric restriction promotes beta cell longevity and delays aging and senescence by enhancing cell identity and homeostasis mechanisms.

Caloric restriction (CR) extends organismal lifespan and health span by improving glucose homeostasis mechanisms. How CR affects organellar structure and function of pancreatic beta cells over the lifetime of the animal remains unknown. Here, we used single nucleus transcriptomics to show that CR increases the expression of genes for beta cell identity, protein processing, and organelle homeostasis. Gene regulatory network analysis link this transcriptional phenotype to transcription factors involved in beta cell identity (Mafa) and homeostasis (Atf6). Imaging metabolomics further demonstrates that CR beta cells are more energetically competent. In fact, high-resolution light and electron microscopy indicates that CR reduces beta cell mitophagy and increases mitochondria mass, increasing mitochondrial ATP generation. Finally, we show that long-term CR delays the onset of beta cell aging and senescence to promote longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cells during aging and diabetes.

cell biology↗

bioRxiv2022

Improved Neutralization of Omicron BA.4/5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 with Bivalent BA.4/5 Vaccine

The BNT162b2 bivalent BA.4/5 COVID-19 vaccine has been authorized to mitigate COVID-19 due to current Omicron and potentially future variants. New sublineages of SARS-CoV-2 Omicron continue to emerge and have acquired additional mutations, particularly in the spike protein, that may lead to improved viral fitness and immune evasion. The present study characterized neutralization activities against new Omicron sublineages BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 after a 4th dose (following three doses of BNT162b2) of either the original monovalent BNT162b2 or the bivalent BA.4/5 booster in individuals >55 years of age. For all participants, the 4th dose of monovalent BNT162b2 vaccine induced a 3.0x, 2.9x, 2.3x, 2.1x, 1.8x, and 1.5x geometric mean neutralizing titer fold rise (GMFR) against USA/WA1-2020 (a strain isolated in January 2020), BA.4/5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1, respectively; the bivalent vaccine induced 5.8x, 13.0x, 11.1x, 6.7x, 8.7x, and 4.8x GMFRs. For individuals without SARS-CoV-2 infection history, BNT162b2 monovalent induced 4.4x, 3.0x, 2.5x, 2.0x, 1.5x, and 1.3x GMFRs, respectively; the bivalent vaccine induced 9.9x, 26.4x, 22.2x, 8.4x, 12.6x, and 4.7x GMFRs. These data suggest the bivalent BA.4/5 vaccine is more immunogenic than the original BNT162b2 monovalent vaccine against circulating Omicron sublineages, including BQ.1.1 that is becoming prevalent globally.

microbiology↗

bioRxiv2022

Neutralization of Omicron sublineages and Deltacron SARS-CoV-2 by 3 doses of BNT162b2 vaccine or BA.1 infection

Distinct SARS-CoV-2 Omicron sublineages have evolved showing increased fitness and immune evasion than the original Omicron variant BA.1. Here we report the neutralization activity of sera from BNT162b2 vaccinated individuals or unimmunized Omicron BA.1-infected individuals against Omicron sublineages and "Deltacron" variant (XD). BNT162b2 post-dose 3 immune sera neutralized USA-WA1/2020, Omicron BA.1-, BA.2-, BA.2.12.1-, BA.3-, BA.4/5-, and XD-spike SARS-CoV-2s with geometric mean titers (GMTs) of 1335, 393, 298, 315, 216, 103, and 301, respectively; thus, BA.4/5 SARS-CoV-2 spike variant showed the highest propensity to evade vaccine neutralization compared to the original Omicron variants BA.1. BA.1-convalescent sera neutralized USA-WA1/2020, BA.1-, BA.2-, BA.2.12.1-, BA.3-, BA.4/5-, and Deltacron-spike SARS-CoV-2s with GMTs of 15, 430, 110, 109, 102, 25, and 284, respectively. The low neutralization titers of vaccinated sera or convalescent sera from BA. 1 infected individuals against the emerging and rapidly spreading Omicron BA.4/5 variants provide important results for consideration in the selection of an updated vaccine in the current Omicron wave.

microbiology↗

bioRxiv2022

Neutralization of Omicron SARS-CoV-2 by 2 or 3 doses of BNT162b2 vaccine

We report the antibody neutralization against Omicron SARS-CoV-2 after 2 and 3 doses of BNT162b2 mRNA vaccine. Vaccinated individuals were serially tested for their neutralization against wild-type SARS-CoV-2 (strain USA-WA1/2020) and an engineered USA-WA1/2020 bearing the Omicron spike glycoprotein. Plaque reduction neutralization results showed that at 2 or 4 weeks post-dose-2, the neutralization geometric mean titers (GMTs) were 511 and 20 against the wild-type and Omicron-spike viruses, respectively, suggesting that two doses of BNT162b2 were not sufficient to elicit robust neutralization against Omicron; at 1 month post-dose-3, the neutralization GMTs increased to 1342 and 336, respectively, indicating that three doses of vaccine increased the magnitude and breadth of neutralization against Omicron; at 4 months post-dose-3, the neutralization GMTs decreased to 820 and 171, respectively, suggesting similar neutralization decay kinetics for both variants. The data support a three-dose vaccine strategy and provide the first glimpse of the neutralization durability against Omicron.

microbiology↗

bioRxiv2021

BNT162b2-Elicited Neutralization of Delta Plus, Lambda, and Other Variants

BNT162b2-elicited human sera are known to neutralize the currently dominant Delta SARS-CoV-2 variant. Here, we report the ability of 20 human sera, drawn 2 or 4 weeks after two doses of BNT162b2, to neutralize USA-WA1/2020 SARS-CoV-2 bearing variant spikes from Delta plus (Delta-AY.1, Delta-AY.2), Delta-{Delta}144 (Delta with the Y144 deletion of the Alpha variant), Lambda, and B. 1.1.519 lineage viruses. Geometric mean plaque reduction neutralization titers against Delta-AY.1, Delta-AY.2, and Delta-{Delta}144 viruses are slightly lower than against USA-WA1/2020, but all sera neutralize the variant viruses to titers of [≥]80. Neutralization titers against Lambda and B. 1.1.519 variants and against USA-WA1/2020 are equivalent. The susceptibility of Delta plus, Lambda, and other variants to neutralization by the sera indicates that antigenic change has not led to virus escape from vaccine-elicited neutralizing antibodies and supports ongoing mass immunization with BNT162b2 to control the variants and to minimize the emergence of new variants.

microbiology↗

bioRxiv2021

Neutralization of spike 69/70 deletion, E484K, and N501Y SARS-CoV-2 by BNT162b2 vaccine-elicited sera

We engineered three SARS-CoV-2 viruses containing key spike mutations from the newly emerged United Kingdom (UK) and South African (SA) variants: N501Y from UK and SA; 69/70-deletion+N501Y+D614G from UK; and E484K+N501Y+D614G from SA. Neutralization geometric mean titers (GMTs) of twenty BTN162b2 vaccine-elicited human sera against the three mutant viruses were 0.81- to 1.46-fold of the GMTs against parental virus, indicating small effects of these mutations on neutralization by sera elicited by two BNT162b2 doses.

microbiology↗

bioRxiv2021

Neutralization of N501Y mutant SARS-CoV-2 by BNT162b2 vaccine-elicited sera

Rapidly spreading variants of SARS-CoV-2 that have arisen in the United Kingdom and South Africa share the spike N501Y substitution, which is of particular concern because it is located in the viral receptor binding site for cell entry and increases binding to the receptor (angiotensin converting enzyme 2). We generated isogenic N501 and Y501 SARS-CoV-2. Sera of 20 participants in a previously reported trial of the mRNA-based COVID-19 vaccine BNT162b2 had equivalent neutralizing titers to the N501 and Y501 viruses.

microbiology↗