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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2019

Physiological and Molecular Responses Suggest Local Adaptation of the Lobe Coral Porites lobata to the Nearshore Environment

Corals in nearshore marine environments are increasingly exposed to reduced water quality, which is the primary local threat to Hawaiian coral reefs. It is unclear if corals surviving in such conditions have adapted to withstand sedimentation, pollutants, and other environmental stressors. Lobe coral populations from Maunalua Bay, Hawaii showed clear genetic differentiation between the polluted, high-stress nearshore site and the lower-stress offshore site. To understand the driving force of the observed genetic partitioning, reciprocal transplant and common-garden experiments were conducted to assess phenotypic differences between these two populations. Physiological responses were significantly different between the populations, revealing more stress-resilient traits in the nearshore corals. Changes in protein profiles between the two populations highlighted the inherent differences in the cellular metabolic processes and activities; nearshore corals did not significantly alter their proteome between the sites, while offshore corals responded to nearshore transplantation with increased abundances of proteins associated with detoxification, antioxidant defense, and regulation of cellular metabolic processes. The response differences across multiple phenotypes between the populations suggest local adaptation of nearshore corals to reduced water quality. Our results provide insight into corals adaptive potential and its underlying processes, and reveal potential protein biomarkers that could be used to predict resiliency.

ecology↗
bioRxiv2019

Varietal differences in physiological and biochemical responses to salinity stress in six finger millet plants

Finger millet is one of the most important cereals that are often grown in semiarid and arid regions of East-Africa. Salinity is known to be a major impediment for the crop growth and production. This study was aimed to understand the mechanisms of physiological and biochemical responses to salinity stress of Kenyan finger millet varieties (GBK043137, GBK043128, GBK043124, GBK043122, GBK043094, GBK043050) grown across different agroecological zones under NaCl-induced salinity stress. Seeds were germinated on the sterile soil and treated using various concentrations of NaCl (100, 200 and 300 mM) for two weeks. Again, the early-seedling stage of germinated plants was irrigated with the same salt concentrations for 60 days. Results indicated depression in germination percentage, shoot and root growth rate, leaf relative water content, chlorophyll content contents, leaf K+ concentration, and leaf K+/Na+ ratios increased salt levels. Contrary, proline and malonaldehyde (MDA) contents reduced sugar content and leaf total proteins. At the same time, the leaf Na+ and Cl- amounts of all plants increased substantially with rising stress levels. Clustering analysis revealed that GBK043094 and GBK043137 were placed together and identified as salt-tolerant varieties based on their performance under salt stress. Overall, our findings indicated a significant varietal variability for most of the parameters analysed. These superior varieties identified could be potentially used as promising genetic resources in future breeding programmes development directed towards salt-tolerant finger millet hybrids. Further analysis at genomic level need to be undertaken to better understand the genetic factors that promote salinity tolerance in finger millet.

plant biology↗
bioRxiv2019

Transmigration of Trypanosoma cruzi trypomastigotes through 3D cultures resembling a physiological environment

Chaga disease, caused by the kinetoplastid parasite Trypanosoma cruzi, presents a variety of chronic clinical manifestations whose determinants are still unknown but probably influenced by the host-parasite interplay established during the first stages of the infection, when bloodstream circulating trypomastigotes disseminate to different organs and tissues. After leaving the blood, trypomastigotes must migrate through tissues to invade cells and establish a chronic infection. How this process occurs remains unexplored. Three-dimensional (3D) cultures are physiologically relevant because mimic the microarchitecture of tissues and provide an environment similar to the encountered in natural infections. In this work, we combined the 3D culture technology with host-pathogen interaction, by studying transmigration of trypomastigotes into 3D spheroids. T. cruzi strains with similar infection dynamics in 2D monolayer cultures but with different in vivo behavior (CL Brener, virulent; SylvioX10 no virulent) presented different infection rates in spheroids (CL Brener [~]40%, SylvioX10 <10%). Confocal microscopy images evidenced that trypomastigotes from CL Brener and other highly virulent strains presented a great ability to transmigrate inside 3D spheroids: as soon as 4 hours post infection parasites were found at 50 {micro}m in depth inside the spheroids. CL Brener trypomastigotes were evenly distributed and systematically observed in the space between cells, suggesting a paracellular route of transmigration to deepen into the spheroids. On the other hand, poor virulent strains presented a weak migratory capacity and remained in the external layers of spheroids (<10{micro}m) with a patch-like distribution pattern. The invasiveness -understood as the ability to transmigrate deep into spheroids- was not a transferable feature between strains, neither by soluble or secreted factors nor by co-cultivation of trypomastigotes from invasive and non-invasive strains. We also studied the transmigration of recent T. cruzi isolates from children that were born congenitally infected, which showed a high migrant phenotype while an isolate form an infected mother (that never transmitted the infection to any of her 3 children) was significantly less migratory. Altogether, our results demonstrate that in a 3D microenvironment each strain presents a characteristic migration pattern and distribution of parasites in the spheroids that can be associated to their in vivo behavior. Certainly, the findings presented here could not have been studied with traditional 2D monolayer cultures.\n\nAuthor SummaryTrypanosoma cruzi is the protozoan parasite that causes Chaga disease, also known as American trypanosomiasis. Experimental models of the infection evidence that different strains of the parasite present different virulence in the host, which cannot be always reproduced in 2D monolayer cultures. Three dimensional (3D) cultures can be useful models to study complex host-parasite interactions because they mimic in vitro the microarchitecture of tissues and provide an environment similar to the encountered in natural infections. In particular, spheroids are small 3D aggregates of cells that interact with each other and with the extracellular matrix that they secrete resembling the original microenvironment both functionally and structurally. Spheroids have rarely been employed to explore infectious diseases and host-parasite interactions. In this work we studied how bloodstream trypomastigotes transmigrate through 3D spheroids mimicking the picture encountered by parasites in tissues soon after leaving circulation. We showed that the behavior of T. cruzi trypomastigotes in 3D cultures reflects their in vivo virulence: virulent strains transmigrate deeply into spheroids while non-virulent strains remain in the external layers of spheroids. Besides, this work demonstrates the usefulness of 3D cultures as an accurate in vitro model for the study of host-pathogen interactions that could not be addressed with conventional monolayer cultures.

microbiology↗
bioRxiv2019

SEN virus genotype H distribution in β-thalassemic patients and in healthy donors in Iraq: Molecular and physiological study

The SEN virus (SENV) has been linked to transfusion-associated non-A-E hepatitis; however, information regarding SENV infections in patients with thalassemia, particularly in those with hepatitis virus co-infections, remains limited. This study investigated the frequency of SENV (genotypes D and H) infections in Iraqi patients with thalassemia who were and were not infected with hepatitis C virus (HCV). The study involved 150 {beta}-thalessemia patients (75 with HCV infections and 75 without) and 75 healthy blood donors. Patient levels of vitamins C and E, liver function markers, and glutathione peroxidase (GPX) were determined. Recovered viral nucleic acids were amplified using the conventional polymerase chain reaction (SENV DNA) or the real-time polymerase chain reaction (HCV RNA) techniques. Only 10% of healthy donors had evidence of SENV infection. Among patients with thalassemia, 80% and 77% of patients with and without concurrent HCV infections, respectively, had SENV infections. DNA sequencing analyses were performed on blood samples obtained from 29 patients. Patients with thalassemia, particularly those with SENV infections, had higher levels of several enzymatic liver function markers and total serum bilirubin (P < 0.05) than did healthy blood donors. Among the examined liver function markers, only gamma-glutamyl transferase demonstrated significantly higher levels in HCV-negative patients infected with SENV-H than in those infected with SENV-D (P = 0.01). There were significantly lower vitamin C, vitamin E, and glutathione peroxidase levels in patients than in healthy donors (P < 0.05), but only glutathione peroxidase levels were significantly lower in HCV-negative thalassemia patients infected with SENV than in those without SENV infections (P = 0.04). The SENV-H genotype sequences were similar to the global standard genes in GenBank. These results increase our understanding of the nature of the SENV-H genotype and the differential role of SENV-H infections, compared to SENV-D infections, in patients with thalassemia, in Iraq.\n\nAuthor summaryIn patients with {beta}-thalassemia, regular blood transfusions increase patient survival but increase the risk of acquiring blood-borne viral infections, especially viral hepatitis. The SEN virus (SENV) is associated with non-A-E hepatitis but its exact role in the pathogenesis of liver disease remains unknown. This study investigated the frequency of SENV infections among Iraqi patients with thalassemia, with and without hepatitis C infections. The study revealed that the prevalence of SENV infections is significantly higher in patients with {beta}-thalassemia, regardless of their hepatitis C infection status, than in a healthy population of blood donors. The two most common genotypes of the virus (D and H) have generally similar physiological impacts as both increase the levels of markers of hepatic dysfunction in thalassemia patients. However, SENV-H infections were associated with significantly higher levels of gamma-glutamyl transferase in HCV-negative patients with thalassemia, potentially predicting hepatocellular carcinoma development. Although thalassemia patients demonstrated significantly lower levels of the antioxidants vitamins C and E, compared with healthy donors, only the levels of glutathione peroxidase (another antioxidant) were significantly lower in SENV-infected patients than in non-SENV-infected patients. This study aids our understanding of the differential effects of SENV-D and SENV-H infections in {beta}-thalassemia patients.

microbiology↗
bioRxiv2019

Bioengineering a novel 3D in-vitro model to recreate physiological oxygen levels and tumor-immune interactions

Oxygen deprivation within tumors is one of the most prevalent causes of resilient cancer cell survival and increased immune evasion in breast cancer (BCa). Current in vitro models do not adequately mimic physiological oxygen levels relevant to breast tissue and its tumor-immune interactions. Here, we propose an approach to engineer a three-dimensional (3D) model (named 3D engineered oxygen, 3D-O) that supports growth of BCa cells and generates physio- and pathophysiological oxygen levels. Low oxygen-induced changes within the 3D-O model supported known tumor hypoxia characteristics such as reduced BCa cell proliferation, increased extracellular matrix protein expression, increased extracellular vesicle secretion and enhanced immune surface marker expression on BCa cells. We further demonstrated that low oxygen-induced changes mimicked tumor-immune interactions leading to immune evasion mechanisms. CD8+ T cell infiltration was significantly impaired under pathophysiological oxygen levels and we were able to establish that hypoxia inhibition re-sensitize BCa cells to cytotoxic CD8+ T cells. Therefore, our novel 3D-O model could serve as a promising platform for the evaluation of immunological events and as a drug-screening platform tool to overcome hypoxia-driven immune evasion.

cancer biology↗
bioRxiv2019

Individual and concurrent effects of drought and chilling stresses on morpho-physiological characteristics and oxidative metabolism of maize cultivars

Maize belongs to tropical environment and is extremely sensitive to drought and chilling stress, particularly at early developmental stages. The present study investigated the individual and combine effects of drought (15% PEG-Solution) and chilling stress (15{degrees}C/12{degrees}C) on the morpho-physiological growth, osmolyte accumulation, production and regulations of reactive oxygen species (ROS) and the activities of antioxidants in two maize hybrids i.e., XD889 and XD319 and two inbred cultivars i.e., Yu13 and Yu37. Individual and combined drought and chilling stresses stimulated the production of O2{square}, H2O2, OH{square} and enhanced malondialdehyde (MDA) contents which led to reduced photosynthetic pigments and morphological growth. Drought, chilling and drought + chilling stress conditions induced the compatible osmolytes, ROS detoxifying proteins and antioxidants to counterbalanced the oxidative damage. It was found that the concurrent occurrence of drought + chilling stress was more lethal for maize seedling growth than the drought and chilling individual stresses. However, the performance of hybrid maize cultivars (XD889 and XD319) was better than the inbred maize cultivars (Yu13 and Yu37). For improving tolerance to individual and concurrent drought and chilling stress in maize, future research focus should be on developing genetically engineer plants that have the ability to generate specific response against sub-optimal temperature and water deficit conditions.

plant biology↗
bioRxiv2019

The Threat of Scream paradigm: A tool for studying sustained physiological and subjective anxiety

Progress in understanding the emergence of pathological anxiety depends on the availability of paradigms effective in inducing anxiety in a simple, consistent and sustained way. Much progress has been made using the Threat-of-Shock paradigm (TOS), which generates anxiety through the delivery of unpredictable electric shocks to participants. However, TOS may be problematic when testing vulnerable populations. Moreover, it is not clear whether anxiety can be sustained throughout experiments of long duration. Here, we bring support for an alternative approach called the Threat-of-Scream paradigm (TOSc), in which the tactile delivery of shocks is replaced by the auditory delivery of distress screams. We report on an one-hour long study (plus its replication) in which participants were exposed to blocks before which they were told that they could hear aversive screams at any time (threat blocks), vs. blocks before which they were told that no scream will be heard (safe blocks). Both the experiment and its replication showed higher subjective reports of anxiety, higher skin conductance level, and positive correlation between the two measures, in threat compared to safe blocks. Anxiety measures were sustained throughout the experiments, suggesting little emotional and physiological habituation. Our results suggest that the delivery of low intensity distress screams can be an efficient, stable and cheap methodology to assess the impact of sustained anxiety on a diversity of cognitive functions and populations. We therefore believe the TOSc will become an essential part of the psychological toolkit, particularly so for researchers interested in the emergence of pathological anxiety.

neuroscience↗
bioRxiv2019

Physiological and molecular responses of a newly evolved auxotroph of Chlamydomonas to B12 deprivation

The corrinoid B12 is synthesised only by prokaryotes yet is widely required by eukaryotes as an enzyme cofactor. Microalgae have evolved B12 dependence on multiple occasions and we previously demonstrated that experimental evolution of the non-requiring alga Chlamydomonas reinhardtii in media supplemented with B12 generated a B12-dependent mutant (hereafter metE7). This clone provides a unique opportunity to study the physiology of a nascent B12 auxotroph. Our analyses demonstrate that B12 deprivation of metE7 disrupted C1 metabolism, caused an accumulation of starch and triacylglycerides and a decrease in photosynthetic pigments, proteins and free amino acids. B12 deprivation also caused a substantial increase in reactive oxygen species (ROS), which preceded rapid cell death. Surprisingly, survival could be improved without compromising growth by simultaneously depriving the cells of nitrogen, suggesting a type of cross protection. Significantly, we found further improvements in survival under B12 limitation and an increase in B12 use-efficiency after metE7 underwent a further period of experimental evolution, this time in coculture with a B12-producing bacterium. Therefore, although an early B12-dependent alga would likely be poorly adapted to B12 deprivation, association with B12-producers can ensure long-term survival whilst also providing the environment to evolve mechanisms to better tolerate B12 limitation.

biochemistry↗
bioRxiv2019

Phenotypic and physiological responses to salt exposure in Sorghum reveal diversity among domesticated landraces

Soil salinity negatively impacts plant function, development, and yield. Sorghum bicolor is a staple crop known to be drought tolerant, to have adapted to a variety of conditions, and to contain significant standing genetic diversity, making it an exemplary species to study phenotypic and physiological variation in salinity tolerance. In our study, a diverse group of sorghum landraces and accessions was first rank-ordered for salinity tolerance and then individuals spanning a wide range of response were analyzed for foliar proline and ion accumulation. We found that, while proline is often a good indicator of osmotic adjustment and is historically associated with increased salt tolerance, proline accumulation in sorghum reflects stress-response injury rather than acclimation. When combining ion profiles with growth responses and stress tolerance indices, the variation observed in tolerance was similarly not a sole result of Na+ accumulation, but rather reflected accession-specific mechanisms that may integrate these and other metabolic responses. When we compared variation in tolerance to phylogenetic relationships, we conclude that the most parsimonious explanation for the variation observed among accessions is that salinity tolerance was acquired early during domestication and was subsequently maintained or lost in diverged lineages during improvement in areas that vary in soil salinity.

plant biology↗
bioRxiv2019

Economic, social, and physiological resilience predict brain structure and cognitive performance in 9 - 10-year-old children

While children with economic disadvantage are at risk for poorer outcomes in cognitive and brain development, less understood is the contribution of other factors in the broader socioeconomic context that may more closely index the underlying mechanisms influencing risk and resilience. We examined brain structure and cognitive test performance in association with economic disadvantage and 22 measures in the broader socioeconomic context among n = 8,158 demographically diverse 9-10-year-old children from the ABCD Study. Total cortical surface area and total cognition scores increased as a function of income-to-needs, with the steepest differences most apparent among children below and near poverty relative to their wealthier peers. We found three latent factors encompassing distinct relationships among our proximal measures, including social, economic, and physiological well-being, each associated with brain structure and cognitive performance independently of economic advantage. Our findings will inform future studies of risk and resilience in developmental outcomes for children with economic disadvantage.

neuroscience↗
bioRxiv2025

TaExpA6, VRT-A2 and TaGW2 genes differentially affect grain weight, grain number and yield of wheat through their physiological determinants

Physiological basis of the trade-off between grain number (GN) and thousand grain weight (TGW) is key to improve wheat yield. To that end, three wheat line groups were assessed at conventional (300-350 pl m-2) and low (44 pl m-2) plant rates in the field: TaExpA6 (ectopic expression), TaGW2 (TaGW2 triple mutant), and TaP1xGW2A (VRT-A2 ectopic expression and TaGW2-A knock-out), together with their wild-types (WT). Except TaP1xGW2A, the manipulated lines increased TGW over their WTs. However, only the transgenic TaExpA6 line reached higher grain yield (GY) than its WT, whereas increased TGW recorded by the triple knockout of TaGW2 was fully compensated by reduced spike number (SpN) and grain number per spike (GNS). Contrasting effects of TaExpA6 and TaGW2 lines were found on the ovary weight and floret dynamics, associated with the trade-off between GW and GN. Interestingly, the overexpression of TaExpA6 gene acts in grain tissues at post-anthesis avoiding the overlap with GN determination, while TaGW2 disruption constrains tillering, likely as a pleiotropic effect, and shifts intra-spike resource allocation promoting early ovary growth at the expense of distal floret development and GNS. Low plant rate increased resource allocation to the spike, mitigating the GW-GNS trade-off and increasing both traits simultaneously.

plant biology↗
bioRxiv2025

Prediction variability in physiologically based pharmacokinetic modeling of tissue disposition under deep uncertainty

Physiologically based pharmacokinetic (PBPK) models are increasingly invoked in virtual screening workflows for therapeutics. These mechanistic models project pharmacokinetic outcomes from molecular properties, with data-driven models acting as intermediaries to map molecular structure to PBPK input parameters. Errors in predicted parameters and unvalidated assumptions within PBPK models expose PK predictions to deep uncertainty. Herein, we examine how these uncertainties affect the prediction variability of dynamic, tissue-specific exposure. We validated four PBPK models against 1,854 experimental datapoints - to establish their predictive fidelity before introducing parameter uncertainty typical of property-prediction models. Depending on molecule properties and model choice, the coefficient of variation under parameter uncertainty ranged from 10-6 to 31 for predicted PK statistics. Further, we identified notable model disagreement for a subset of drug-like chemical space characterized by lipophilic, protonated molecules. Uncertainty quantification revealed biophysicochemical properties and parameter interactions that drove disagreement and highlighted model assumptions that exacerbated prediction variance. Our findings delineate the challenges presented by deep epistemic uncertainty in PBPK modeling.

systems biology↗
bioRxiv2025

Reconstructing physiological oxygen gradients reveals the role of hypoxia in colon epithelial organization

Oxygen gradients organize tissue architecture and metabolism1,2, yet their precise spatial profiles and mechanistic roles remain poorly understood because both in vivo measurement and in vitro control are technically challenging3,4. Here, we quantify the oxygen landscape of the mammalian intestine using microscale sensors, revealing a steep luminal-basal gradient of approximately 10-60 {micro}M mm-1 that collapses under antibiotic perturbation. We then recreate this physiological range ex vivo with a submerged chemostat microfluidic platform that fixes the oxygen boundary condition by coupling an oxygen-permeable PDMS chip to an external scavenger reservoir and integrating embedded optical sensors for real-time readout. This architecture suppresses ambient oxygen ingress and sustains programmable gradients of 10-20 {micro}M mm-1 across three-dimensional colorectal cancer organoid cultures while remaining compatible with live imaging and endpoint retrieval. The platform bridges quantitative in vivo oxygen mapping with controlled ex vivo modeling, establishing a generalizable approach to interrogate how spatial oxygen dynamics govern epithelial organization and disease progression.

bioengineering↗
bioRxiv2025

Physiological Arousal as a Predominant Source of Individual Differences in Functional Brain Networks

Individual differences in brain network function and organization are promising targets for fMRI-based biomarkers in precision psychiatry, yet the sources of individual variability remain poorly understood. We show that arousal, assessed by systemic low-frequency oscillation (sLFO) amplitude in the fMRI signal, accounts for a substantial portion of variance in brain network properties (e.g.: R= 0.70 for default mode network (DMN)-dorsal attention connectivity; R= -0.63 for DMN dynamics). These relationships replicated across sessions, across independent samples, and when assessed with traditional arousal indices. Critically, associations persisted after sLFO denoising, indicating a genuine brain-physiology relationship rather than hemodynamic artifact. Pharmacological manipulation showed that drug-induced sLFO-assessed arousal changes were accompanied by corresponding shifts in network connectivity and dynamics. This work identifies arousal as a prominent determinant of variability in functional brain networks, providing a new perspective on brain-based individual differences while offering an approach to measure arousal directly from fMRI data.

neuroscience↗
bioRxiv2025

Drought restructures multitrophic food webs through cascading eco-physiological constraints

Ecological communities are linked not only by energy flows, but also by sensory and behavioral pathways that allow organisms to locate, recognize, and interact with one another. Environmental stressors such as drought may disrupt these pathways by altering both resource availability and interactions that regulate both population and community dynamics. While species-level responses to drought are well documented, far less is understood about how drought-driven changes in plant resources initiate bottom-up effects that cascade through multiple trophic levels. Here, we tested how drought affects a plant-herbivore-carnivore system by quantifying plant physiological changes and their cascading effects on herbivore performance, nutritional quality, and carnivore behavior. Drought reduced plant growth and stomatal conductance, which lowered herbivore feeding efficiency, survival, and reproduction. Herbivores feeding on drought-stressed plants also displayed lower protein content and biomass. Drought also suppressed the emission of herbivore-induced plant volatiles (HIPVs), limiting the chemical cues carnivores use to locate prey. Despite higher prey consumption rates in no-choice assays, carnivores suppressed herbivore populations less effectively under drought. At the community level, these disruptions caused disproportionate declines in arthropod abundance and diversity, particularly among carnivores, leading to trophic simplification. These findings show that drought not just reduce resource availability, it disrupts chemical cues and trophic feedbacks that maintain food web structure. By linking changes in resource limitations to community-level responses, this study demonstrates how environmental stressors can weaken top-down control and destabilize multitrophic dynamics. Predicting ecological resilience depends not only on responses but on how stress disrupts the information signals that maintain ecosystem services and function.

ecology↗
bioRxiv2025

Physiologically Based Pharmacokinetic Modeling of mRNA-Encoded Therapeutics: A Multiscale Framework for LNP and Antibody Trafficking in Mice

Antibody-based therapeutics have revolutionized disease treatment, and recent advances in messenger RNA (mRNA) technologies have opened new opportunities for their intracellular production. In particular, in vitro-transcribed mRNA encapsulated in lipid nanoparticles (LNPs) enables targeted delivery to specific cells, where it can enable the synthesis of therapeutic antibodies with prolonged half-lives in a cost-effective manner. Despite rapidly growing experimental data, a modeling framework that integrates mRNA delivery, intracellular expression kinetics, and whole-body antibody disposition remains unavailable. To address this gap, we extended a Physiologically Based Pharmacokinetic model with a novel multiscale layer describing mRNA trafficking, cellular uptake, translation, and degradation. The integrated model was calibrated and validated using five datasets of mRNA-based cancer therapeutics, demonstrating strong predictive performance for the biodistribution of mRNA-encoded antibodies. The newly introduced mRNA layer, while minimally parameterized, effectively represents complex intracellular and systemic processes, enabling quantitative investigation of antibody biodistribution, optimization of dose scheduling, and providing an initial framework for future exploration of how LNP-mRNA formulation influences delivery and pharmacokinetics.

pharmacology and toxicology↗
bioRxiv2025

Chronic electroconvulsive shock disrupts hippocampal physiology and impairs associative memory in mice

Electroconvulsive therapy (ECT) is a highly effective treatment for depression but it has undesirable side effects on various aspects of cognition, including memory. Patients might display retrograde amnesia for autobiographical events and anterograde amnesia in tests of recall and recognition memory. These amnestic effects are likely to depend, at least in part, on changes in the hippocampus. ECT-induced volume increases in the hippocampus, and dentate gyrus subregion in particular, correlate with the cognitive deficits. However, the precise cellular and behavioral effects of ECT remain poorly understood. Here, we therefore subjected male and female mice to chronic electroconvulsive shock (ECS) and examined effects on hippocampal physiology and memory. Perforant path inputs onto dentate gyrus neurons were examined using whole cell patch clamp recordings in hippocampal slices. In the intact slice, perforant path stimulation did not result in any synaptic or spiking differences in mice given sham vs ECS treatments. However, GABAA blockade increased depolarization and spiking in sham, but not ECS-treated, mice. Voltage clamp recordings further revealed weaker perforant path excitation of dentate gyrus neurons in ECS-treated mice. Extrapolating these findings to the intact animal, we then used Fos expression as a proxy for neural activity, and found that ECS blunted exploration-induced hippocampal activation, which was most pronounced in the dentate gyrus. Finally, recognition memory tasks revealed that ECS impaired memory for object-context associations but not memory for objects or locations. Collectively, these experiments reveal that a clinically relevant schedule of ECS disrupts synaptic and circuit functions of the hippocampus and causes anterograde amnesia in a test of episodic-like associative memory.

neuroscience↗
bioRxiv2026

Altered Physiology and Ensemble Recruitment of Dentate Gyrus Semilunar Granule Cells in a Mouse Model of Epilepsy

The dentate gyrus is a major locus for structural and synaptic reorganization in temporal lobe epilepsy. While physiological changes during epileptogensis are well characterized in the principal dentate projection neuron, granule cells (GCs), epilepsy-related changes in semilunar granule cells (SGCs), a distinct subset of dentate projection neurons, remain unknown. Using a mouse pilocarpine model of epilepsy, we show that, unlike GCs, SGCs exhibit an increase in intrinsic excitability 1 week after status epilepticus (SE). GCs, not SGCs. have a lower threshold for action potential firing in mice 1-month post-SE. Both GCs and SGCs display increased frequency of spontaneous excitatory postsynaptic currents (EPSCs) 1-week and 1-month after SE. Uniquely, SGCs received more frequent spontaneous inhibitory postsynaptic currents (sIPSCs) and exhibited smaller afferent-evoked IPSCs early after SE. Additionally, evoked EPSC amplitude in SGCs was reduced 1-month post-SE. Behaviorally, mice 1-month post-SE showed impairments in their ability to use spatial search strategies in a Barnes maze paradigm. Post-SE TRAP2::tdT mice showed reduced activity dependent neuronal ensemble labeling, with fewer tdT-labeled neurons in both task-naive and trained conditions and reduced c-Fos co-expression following task re-acquisition compared to controls. Notably, the proportion of SGCs within labeled ensembles was reduced in task-naive epileptic mice but not in trained animals. Collectively, our findings identify selective changes in SGC intrinsic excitability during epileptogenesis that could contribute to enhanced network excitability. The cell-specific alterations in SGC circuit connectivity during epileptogenesis, alongside the apparent reduction in neuronal recruitment to behavioral ensembles likely contribute to spatial navigation deficits observed in epilepsy.

neuroscience↗