Biology subjects

Yadav, R.

Publications and source records attributed to Yadav, R..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Photomodulation of Kv Channel Activity

Voltage-gated potassium (Kv) channels shape action potentials, with their activity dependent on anionic lipids and modulated by membrane tension. However, the mechanism by which lipids regulate channel gating is not entirely clear. Cryo-electron microscopy studies suggest that in the down state-- typically associated with the inactive channel--arginines of the voltage sensor interact with lipid phosphates, pulling them upward and locally thinning the membrane by [~]5 [A]. This thinning is absent in the up state of the sensor, which is typically associated with the active channel. To test whether membrane thickness influences gating, we reconstituted Aeropyrum pernix Kv (KvAP) channels into planar lipid bilayers containing photoswitchable lipids. Blue light increased membrane thickness and KvAP activity, while UV light reversed these effects. Our results indicate that membrane thickening disrupts voltage sensor-lipid phosphate interactions, lowering the activation barrier for the up-movement of the voltage sensor and thus, channel opening. The resulting leftward shift in the current-voltage relationship demonstrates a light-driven approach to modulating Kv channel activity, with potential applications in neuronal excitability control. SignificanceVoltage-gated Kv channels respond to membrane voltage in a manner influenced by lipid composition and membrane tension. In the inactive state, voltage-sensing arginines interact with lipid phosphates, and when these interactions are strained--such as by membrane thickening or possibly by membrane tension--less voltage is required for channel opening. We demonstrate this interdependence by showing that a light-triggered increase in membrane thickness reversibly enhances Kv channel activity, directly linking membrane mechanics to voltage sensing. This work also establishes a light-based strategy for spatially precise Kv channel modulation.

biophysics↗

bioRxiv2025

Phototriggered proton-selective carrier currents through photoswitchable membranes

Controlling the flux of specific ions across lipid bilayers is a central challenge for cellular life. Here, we present a general strategy for the precise, noninvasive, and reversible photoregulation of specific ion transport across lipid bilayer membranes: using embedded azobenzene-containing photolipids as dopants that effectively photo-control the membrane permeation of specific ion carriers. Photolipid (OptoDArG) embedding and photoisomerization causes only minor changes in background ion conductance, consistent with classical models of membrane transport wherein small changes in bilayer thickness have little effect on ion permeability. Yet, in the presence of ion carriers, photoisomerization instead results in order-of-magnitude jumps in ion flux. These jumps are observed with both cationic and anionic carriers; particular protonophores deliver exceptional performance, with proton currents amplified by up to {approx}200-fold upon UV illumination yet reversed by blue light exposure. A model in which interfacial uptake and release reactions are modulated by light-induced membrane changes explains these results. Doping photolipids together with well-established selective ion carriers into membranes thus presents a flexible and general chemical strategy for reversible, millisecond-scale photoregulation of specific ion trans-port across lipid bilayers. It achieves large currents, long-lasting effects, its ion scope is easily tuned by carrier choice, no genetic modifications are needed, and it has the potential to harness recent photoswitch advances to rationally shift its single-photon action spectra from the UV/Vis right up to the NIR/SWIR: a convenient all-chemical approach toward light-based ion permeability regulation in the biological or synthetic cell. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/632814v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@ed17aborg.highwire.dtl.DTLVardef@1ace648org.highwire.dtl.DTLVardef@42aef6org.highwire.dtl.DTLVardef@1eccced_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

biophysics↗

bioRxiv2024

Integrated structural model of the palladin-actin complex using XL-MS, docking, NMR, and SAXS

Palladin is an actin binding protein that accelerates actin polymerization and is linked to metastasis of several types of cancer. Previously, three lysine residues in an immunoglobulin-like domain of palladin have been identified as essential for actin binding. However, it is still unknown where palladin binds to F-actin. Evidence that palladin binds to the sides of actin filaments to facilitate branching is supported by our previous study showing that palladin was able to compensate for Arp2/3 in the formation of Listeria actin comet tails. Here, we used chemical crosslinking to covalently link palladin and F-actin residues based on spatial proximity. Samples were then enzymatically digested, separated by liquid chromatography, and analyzed by tandem mass spectrometry. Peptides containing the crosslinks and specific residues involved were then identified for input to HADDOCK docking server to model the most likely binding conformation. Small angle X-ray scattering was used to provide further insight into palladin flexibility and the binding interface, and NMR spectra identified potential interactions between palladins Ig domains. Our final structural model of the F-actin:palladin complex revealed how palladin interacts with and stabilizes F-actin at the interface between two actin monomers. Three actin residues that were identified in this study also appear commonly in the actin binding interface with other proteins such as myotilin, myosin, and tropomodulin. An accurate structural representation of the complex between palladin and actin extends our understanding of palladins role in promoting cancer metastasis through regulation of actin dynamics. SignificanceIn this study we have combined various advanced structural biology techniques to provide the first comprehensive model of the palladin-actin complex. Considering palladins role in cancer cell metastasis, this structure could be useful in screening and developing chemotherapeutic agents that target this interaction and prevent cancer cell metastasis.

biochemistry↗

bioRxiv2024

Single-molecule tracking reveals the dynamics of Ipl1 recruitment to the kinetochores and spindles in S. cerevisiae

Aurora kinase B, Ipl1 in Saccharomyces cerevisiae, is the master regulator of cell division required for checkpoint regulation, spindle assembly and disassembly, chromosome segregation, and cytokinesis. Decades of research employed ensemble averaging methods to understand its dynamics and function; however, the dynamic information was lost due to population-based averaging. Here, we use single-molecule imaging and tracking (SMIT) to quantify the recruitment dynamics of Ipl1 at the kinetochores and spindles in live cells. Our data suggest that Ipl1 is recruited to these locations with different dynamics. We have demonstrated how the recruitment dynamics of Ipl1 at the kinetochores during metaphase changes in the presence and absence of tension across the kinetochore, in the absence of protein phosphatase 1 (Glc7), and the absence of its known recruiters (Ctf19 and Bub1). The SMIT of other chromosome passenger complex members suggests its hierarchical assembly at the kinetochore. Hence, SMIT provides a dynamic view of the Ipl1 trafficking at the kinetochores and spindles.

cell biology↗

bioRxiv2024

IL-12/IL23 blockade reveals patterns of asynchronous inflammation in pyoderma gangrenosum

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis causing chronic and recalcitrant painful ulcerations. Pathogenic mechanisms are yet poorly understood limiting therapeutic options, however, IL-12/IL-23 inhibition via ustekinumab has previously been associated with positive outcomes. We aimed to elucidate the dysregulated immune landscape of PG and lesional skin changes associated with IL-12/IL-23 blockade. We applied spatial transcriptomics and comparative computation analysis on lesional biopsies from two patients obtained before and after IL-12/IL-23 blockade with ustekinumab. Our data indicate lesional PG skin exhibits complex patterns of inflammation, including a not previously described major infiltration of B cells and establishment of tertiary lymphoid structures. In both patients, IL-12/IL-23 blockade led to marked clinical improvement but was associated with amelioration of contrasting inflammatory pathways. Notably, plasma cell markers and tertiary structures were recalcitrant to the treatment regime suggesting that B cells might play a role in the refractory nature of PG.

immunology↗

bioRxiv2024

High-resolution fleezers reveal duplex opening and stepwise assembly by an oligomer of the DEAD-box helicase Ded1p

DEAD-box RNA helicases are ubiquitous in all domains of life where they bind and remodel RNA and RNA-protein complexes. DEAD-box helicases unwind RNA duplexes by local opening of helical regions without directional movement through the duplexes and some of these enzymes, including Ded1p from Saccharomyces cerevisiae, oligomerize to effectively unwind RNA duplexes. Whether and how DEAD-box helicases coordinate oligomerization and unwinding is not known and it is unclear how many base pairs are actively opened. Using high-resolution optical tweezers and fluorescence, we reveal a highly dynamic and stochastic process of multiple Ded1p protomers assembling on and unwinding an RNA duplex. One Ded1p protomer binds to a duplex-adjacent ssRNA tail and promotes binding and subsequent unwinding of the duplex by additional Ded1p protomers in 4-6 bp steps. The data also reveal rapid duplex unwinding and rezipping linked with binding and dissociation of individual protomers and coordinated with the ATP hydrolysis cycle.

biophysics↗

bioRxiv2023

Conservation of heat stress acclimation by the inositol polyphosphate multikinase, IPMK responsible for 4/6-InsP7 production in land plants

Inositol pyrophosphates (PP-InsPs) are soluble cellular messengers that integrate environmental cues to induce adaptive responses in eukaryotes. In plants, the biological functions of various PP-InsP species are poorly understood, largely due to the absence of canonical enzymes present in other eukaryotes. The recent identification of a new PP-InsP isomer with yet unknown enantiomeric identity, 4/6-InsP7 in the eudicot Arabidopsis thaliana, further highlights the intricate PP-InsP signalling network employed by plants. The abundance of 4/6-InsP7 in land plants, the enzyme(s) responsible for its synthesis, and the physiological functions of this species are all currently unknown. In this study, we show that 4/6-InsP7 is the major PP-InsP species present across land plants. Our findings demonstrate that the Arabidopsis inositol polyphosphate multikinase (IPMK) homolog, AtIPK2 generates 4/6-InsP7 in vitro. Furthermore, the cellular level of 4/6-InsP7 is controlled by the two Arabidopsis IPMK isoforms, AtIPK2 and AtIPK2{beta}. Notably, the activity of these IPMK proteins is critical for heat stress acclimation in Arabidopsis. During heat stress, the expression of genes encoding various heat shock proteins controlled by the heat shock factors (HSFs) is affected in the AtIPK2-deficient plants. Furthermore, we show that the transcription activity of HSF is regulated by the AtIPK2 proteins. Our parallel investigations using the liverwort Marchantia polymorpha suggest that the InsP6 kinase activity of IPMK and the role of IPMK in regulating the heat stress response are evolutionarily conserved. Collectively, our study indicates that IPMK has played a critical role in transducing environmental cues for biological processes during land plant evolution.

plant biology↗

bioRxiv2023

Fibrinogen and complement factor H: The two crucial markers of Parkinson's disease with cognitive impairment

Animal model-assisted validation is vital for biomarker studies. It provides better means for understanding disease pathogenesis and opens avenues for addressing therapeutics. Our earlier non-targeted label free proteomics-based biomarker study on CSF of Parkinsons disease (PD) patients with cognitive impairment (PDCI), revealed the presence of elevated levels of fibrinogen and complement factor H (CFAH) in PDCI-CSF. In the present study, we aimed to determine if these proteins harbor a pathogenic potential, when present above physiological levels. Native fibrinogen and recombinant CFAH were intraperitoneally injected in adult C57BL/6J mice and 48h later, motor and cognitive behavioral deficits as well as their neuroanatomical correlates were noted. The reduction in stride length in fibrinogen and CFAH injected mice indicate shuffling gait, often seen in PD patients. Motor deficit was complemented by the loss of dopaminergic (DA) neurons in SNpc, compensatory hypertrophy of the surviving neurons, and reduction in TH expression in striatum, thus reminiscing PD pathology. The low discrimination index in (novel object recognition) NOR test complemented by morphological alterations in Nissl-stained CA-1 and subiculum neurons in the fibrinogen-injected mice imply recognition memory deficits. Thus, our study provides objective evidence that fibrinogen and CFAH harbor the potential to induce motor deficits and cognitive impairments in mice, akin to the PDCI-associated neuro-pathological deficits, and thus are potential biomarkers.

neuroscience↗

bioRxiv2023

Transcriptome analysis in a humanized mouse model of familial dysautonomia reveals tissue-specific gene expression disruption in the peripheral nervous system.

Familial dysautonomia (FD) is a rare recessive neurodevelopmental disease caused by a splice mutation in the Elongator acetyltransferase complex subunit 1 (ELP1) gene. This mutation results in a tissue-specific reduction of ELP1 protein, with the lowest levels in the central and peripheral nervous systems (CNS and PNS, respectively). FD patients exhibit complex neurological phenotypes due to the loss of sensory and autonomic neurons. Disease symptoms include decreased pain and temperature perception, impaired or absent myotatic reflexes, proprioceptive ataxia, and progressive retinal degeneration. While the involvement of the PNS in FD pathogenesis has been clearly recognized, the underlying mechanisms responsible for the preferential neuronal loss remain unknown. In this study, we aimed to elucidate the molecular mechanisms underlying FD by conducting a comprehensive transcriptome analysis of neuronal tissues from the phenotypic mouse model TgFD9; Elp1{Delta}20/flox. This mouse recapitulates the same tissue-specific ELP1 mis-splicing observed in patients while modeling many of the disease manifestations. Comparison of FD and control transcriptomes from dorsal root ganglion (DRG), trigeminal ganglion (TG), medulla (MED), cortex, and spinal cord (SC) showed significantly more differentially expressed genes (DEGs) in the PNS than the CNS. We then identified genes that were tightly co-expressed and functionally dependent on the level of full-length ELP1 transcript. These genes, defined as ELP1 dose-responsive genes, were combined with the DEGs to generate tissue-specific dysregulated FD signature genes and networks. Within the PNS networks, we observed direct connections between Elp1 and genes involved in tRNA synthesis and genes related to amine metabolism and synaptic signaling. Importantly, transcriptomic dysregulation in PNS tissues exhibited enrichment for neuronal subtype markers associated with peptidergic nociceptors and myelinated sensory neurons, which are known to be affected in FD. In summary, this study has identified critical tissue-specific gene networks underlying the etiology of FD and provides new insights into the molecular basis of the disease.

genomics↗

bioRxiv2023

Photolipid excitation triggers depolarizing optocapacitive currents and action potentials

Optically-induced changes in membrane capacitance may regulate neuronal activity without requiring genetic modifications. Previously, they mainly relied on sudden temperature jumps due to light absorption by membrane-associated nanomaterials or water. Yet, nanomaterial targeting or the required high infrared light intensities obstruct broad applicability. Now, we propose a very versatile approach: photolipids (azobenzene-containing diacylglycerols) mediate light-triggered cellular de- or hyperpolarization. As planar bilayer experiments show, the respective currents emerge from millisecond-timescale changes in bilayer capacitance. UV light changes photolipid conformation, which awards embedding plasma membranes with increased capacitance and evokes depolarizing currents. They open voltage-gated sodium channels in cells, generating action potentials. Blue light reduces the area per photolipid, decreasing membrane capacitance and eliciting hyperpolarization. If present, mechanosensitive channels respond to the increased mechanical membrane tension, generating large depolarizing currents that elicit action potentials. Membrane self-insertion of administered photolipids and focused illumination allows cell excitation with high spatiotemporal control. HighlightsO_LIRapid photolipid photoisomerization generates optocapacitive currents in planar lipid bilayers and HEK293 cells. C_LIO_LIThese currents originate from photo-induced changes in membrane capacitance C_LIO_LIUV light-triggered membrane depolarization opens NaV1.3, evoking action potentials. C_LIO_LIBlue light-induced mechanosensitive channel opening gives rise to depolarizing currents, which may evoke NaV1.3-mediated action potentials. C_LI

biophysics↗

bioRxiv2023

In-Silico analysis of Human Insulin Gene for Mirror repeat sequences

The genetic material contains all the instructions necessary for the development, functioning & regulation of biological processes. This is also considering as a regulatory molecule. The structure constitute by its unique pattern of bases make it unique for every living being consider from bacteria to human. The varied pattern of bases in genomes or genes represents different types of repeats. These repeats types constitute the major fraction of the genomes. Among varied types Mirror repeats (MRs) play crucial roles in the genome especially in formation of H-DNA structure by Non Watson pairing. Some studies suggest that mirror sequences responsible for neurological diseases also. Now days in modern era of technology in silico techniques were develop to extract any type of repeat sequences from any gene or genome. The major focus of current work is on identification of mirror repeats (MRs) from human insulin gene sequence using an in silico approach. The approach is refer to as FPCB (FASTA Parallel Complement Analysis) were utilized to extract MR sequences. From the current study a total no of 210 MR sequenced were identified in Human insulin gene. The identified repeats vary in their length and majority of them are imperfect in nature. The maximum no of MR were reported in the region 3 & minimum is in the region 8 (8). In the remaining regions the no of MR sequences were lies in between maximum & minimum values. These sequences may be helpful in many molecular level studies.

bioinformatics↗

bioRxiv2023

ITPK1 regulates jasmonate-controlled root development in Arabidopsis thaliana

Jasmonic acid (JA) is a plant hormone that regulates a plethora of physiological processes including immunity and development and is perceived by the F-Box protein, Coronatine-insensitive protein 1(COI1). The discovery of inositol phosphates (InsPs) in the COI1 receptor complex highlights their role in JA perception. InsPs are phosphate-rich signaling molecules that control many aspects of plant physiology. Inositol pyrophosphates (PP-InsPs) are diphosphate containing InsP species of which InsP7 and InsP8 are the best characterized ones. Different InsP and PP-InsP species are linked with JA-related plant immunity. However, role of PP-InsP species in regulating JA-dependent developmental processes are poorly understood. Recent identification of ITPK1 kinase responsible for the production of 5-InsP7 from InsP6 in planta provides a platform to interrogate possible involvement of ITPK-derived InsP species in JA-related plant development. Herein this study, we report that ITPK1-defective plants exhibit increased root growth inhibition to bioactive JA treatment. The itpk1 plants also show increased lateral root density when treated with JA. Notably, JA treatment does not induce ITPK1 protein level. Gene expression analyses revealed that JA-biosynthetic genes are not differentially expressed in the ITPK1-deficient plants. We further demonstrate that genes encoding different JAZ repressor proteins are severely downregulated in the ITPK1-defective plants. Taken together, our study highlights the role of ITPK1 in regulating JA-dependent root architecture development through controlling expression of different JAZ repressor proteins.

plant biology↗

bioRxiv2023

A marker chromosome in psychosis identifies glycine decarboxylase (GLDC) as a novel regulator of neuronal and synaptic function in the hippocampus

The biological significance of a small supernumerary marker chromosome that results in dosage alterations to chromosome 9p24.1, including triplication of the GLDC gene encoding glycine decarboxylase, in two patients with psychosis is unclear. In an allelic series of copy number variant mouse models, we identify that triplication of Gldc reduces extracellular glycine levels as determined by optical fluorescence resonance energy transfer (FRET) in dentate gyrus (DG) but not in CA1, suppresses long-term potentiation (LTP) in mPP-DG synapses but not in CA3-CA1 synapses, reduces the activity of biochemical pathways implicated in schizophrenia and mitochondrial bioenergetics, and displays deficits in prepulse inhibition, startle habituation, latent inhibition, working memory, sociability and social preference. Our results thus provide a link between a genomic copy number variation, biochemical, cellular and behavioral phenotypes, and further demonstrate that GLDC negatively regulates long-term synaptic plasticity at specific hippocampal synapses, possibly contributing to the development of neuropsychiatric disorders.

neuroscience↗

bioRxiv2023

Identification of Mirror Repeats in Viral Genomes using FPCB Analysis

The majority of living domains consist of DNA as genetic material with the minor exception of viruses. The unique nature of every species determines by its unique pattern of genome or gene products. The genomic features become an evident example of evolutionary study also. Different types of repeat patterns are observed in genomes of living domains including human beings whose two third portion of the genome is repetitive. Among the varied type of repeat sequences Mirror Repeats (MR) play crucial roles at the genetic level in every species. The major focus of our research is on identification & to check the distribution of mirror repeat. For this, we employed a bioinformatics-based approach refer as FASTA PARALLEL COMPLEMENT BLAST (FPCB) to identify unique mirror repeat (MR) sequences in some selected viral genomes from three different categories (Animal, Plant & Human). The identified repeats vary in their length as well as found to be distributed throughout the selected viral genomes. The maximum no of MR were reported in the case of Dengue virus (229) & minimum is in the case of TMV (97). In the remaining selected viruses - HCV, HPV, HTLV-1, PVY, Rabies virus 178, 156, 175, 203 & 204 MR sequences were reported. These sequences can be utilized in many ways like in molecular diagnosis, drug delivery target as well as evolutionary study, etc. The present research also helps in the development of novel tools of bioinformatics to study mirror repeats and their functional perspective in the context of their occurrence in all domains.

bioinformatics↗

bioRxiv2023

Structural insights into agonist-binding and activation of the human complement C3a receptor

The complement cascade is an integral part of innate immunity, and it plays a crucial role in our bodys innate immune response including combating microbial infections. Activation of the complement cascade results in the generation of multiple peptide fragments, of which complement C3a and C5a are potent anaphylatoxins. The complement C3a binds and activates a G protein-coupled receptor (GPCR) known as C3aR while C5a activates two distinct receptors namely C5aR1 and C5aR2. Our current understanding of complement peptide recognition by their corresponding receptors is limited primarily to biochemical studies, and direct structural visualization of ligand-receptor complexes is still elusive. Here, we present structural snapshots of C3aR in complex with heterotrimeric G-proteins, with the receptor in ligand-free state, activated by full-length complement C3a, and a peptide agonist EP54, derived based on the carboxyl-terminal sequence of C5a. A comprehensive analysis of these structures uncovers the critical residues involved in C3a-C3aR interaction, and also provides molecular insights to rationally design carboxyl-terminal fragments of C3a and C5a to act as potent agonists of the receptor. Surprisingly, a comparison of C3a-C3aR structure with C5a-C5aR1 structure reveals diagonally opposite placement of these two complement peptides on their respective receptors, which helps explain the subtype selectivity of these complement peptides. Finally, taking lead from the structural insights, we also identify EP141, a peptide derived from the carboxyl-terminus of C3a, as a G-protein-biased agonist at C3aR. Taken together, our study illuminates the structural mechanism of complement C3a recognition by C3aR, and it also offers the first structural template for designing novel C3aR ligands with therapeutic potential for inflammatory disorders.

biochemistry↗

bioRxiv2023

Mechanistic basis of staphylococcal interspecies competition for skin colonization

Staphylococci, whether beneficial commensals or pathogens, often colonize human skin, potentially leading to competition for the same niche. In this multidisciplinary study we investigate the structure, binding specificity, and mechanism of adhesion of the Aap lectin domain required for Staphylococcus epidermidis skin colonization and compare its characteristics to the lectin domain from the orthologous Staphylococcus aureus adhesin SasG. The Aap structure reveals a legume lectin-like fold with atypical architecture, showing specificity for N-acetyllactosamine and sialyllactosamine. Bacterial adhesion assays using human corneocytes confirmed the biological relevance of these Aap-glycan interactions. Single-cell force spectroscopy experiments measured individual binding events between Aap and corneocytes, revealing an extraordinarily tight adhesion force of nearly 900 nN and a high density of receptors at the corneocyte surface. The SasG lectin domain shares similar structural features, glycan specificity, and corneocyte adhesion behavior. We observe cross-inhibition of Aap- and SasG-mediated staphylococcal adhesion to corneocytes. Together, these data provide insights into staphylococcal interspecies competition for skin colonization and suggest potential avenues for inhibition of S. aureus colonization.

microbiology↗

bioRxiv2022

Transgenic Mouse Models Establish a Protective Role of Type 1 IFN Response in SARS-CoV-2 infection-related Immunopathology

Type 1 interferon (IFN-I) response is the first line of host defense against invading viruses. In the absence of definite mouse models, the role of IFN-I in SARS-CoV-2 infections remained to be perplexing. Here, we developed two mouse models, one with constitutively high IFN-I response (hACE2; Irgm1-/-) and the other with dampened IFN-I response (hACE2; Ifnar1-/-) to comprehend the role of IFN-I response during SARS-CoV-2 invasion. We found that hACE2; Irgm1-/- mice were resistant to lethal SARS-CoV-2 infection with substantially reduced cytokine storm and immunopathology. In striking contrast, a severe SARS-CoV-2 infection along with immune cells infiltration, inflammatory response, and enhanced pathology was observed in the lungs of hACE2; Ifnar1-/- mice. Additionally, hACE2; Ifnar1-/- mice were highly susceptible to SARS-CoV-2 neuroinvasion in the brain accompanied by immune cell infiltration, microglia/astrocytes activation, cytokine response, and demyelination of neurons. The hACE2; Irgm1-/- Ifnar1-/- double knockout mice or hACE2; Irgm1-/- mice treated with STING or RIPK2 pharmacological inhibitors displayed loss of the protective phenotypes observed in hACE2; Irgm1-/- mice suggesting that heightened IFN-I response accounts for the observed immunity. Taken together, we explicitly demonstrate that IFN-I protects from lethal SARS-CoV-2 infection, and Irgm1 (IRGM) could be an excellent therapeutic target. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/520843v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@a3aad4org.highwire.dtl.DTLVardef@12452fcorg.highwire.dtl.DTLVardef@1c43dc0org.highwire.dtl.DTLVardef@b2167d_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Dynamic hippocampal-cortical interactions during event boundaries support retention of complex narrative events

According to most memory theories, encoding involves continuous communication between the hippocampus and neocortex leaving the temporal dynamics of hippocampal-neocortical interactions often overlooked. Recent work has shown that we perceive complex events in our lives as dynamic, with relatively distinct starting and stopping points known as event boundaries. Event boundaries may be important for memory, as they are associated with increased activity in the hippocampus, and extended neocortical regions (the posterior cingulate cortex, lateral parietal cortex, and parahippocampal cortex). Our objective was to determine how functional connectivity between the hippocampus and neocortical regions during the encoding of naturalistic events (movies) related to subsequent retrieval and retention of those events. Participants encoded two 16-minute cartoon movies during fMRI scanning. After encoding, participants freely recalled one of the movies immediately, and the other after a 2-day delay. We quantified hippocampal-neocortical functional connectivity (FC) at time windows around each event onset, middle, and offset, and compared these FC measures with subsequent recall. These analyses revealed that higher FC between the hippocampus and the posterior medial network (PMN) at an events offset related to whether that event was subsequently recalled. In contrast, mid-event connectivity between the hippocampus and PMN was associated with poorer memory. Furthermore, hippocampal-PMN offset connectivity predicted not only whether events were retained in memory, but also the degree to which these events could be recalled in detail after a 2-day delay. These data demonstrate that the relationship between memory encoding and hippocampal-neocortical interaction is more dynamic than suggested by most memory theories, and they converge with recent modeling work suggesting that event offset is an optimal time for encoding.

neuroscience↗