Biology subjects

Kulkarni, A.

Publications and source records attributed to Kulkarni, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Isoflurane anesthesia CNS recovery state: ultra-slow oscillations and cellular-stress-responsive gene expression

General anesthesia and NREM sleep share slow-wave EEG features, yet whether anesthesia substitutes for physiological sleep remains unclear. We compared recovery from 4h of isoflurane anesthesia (IA) with time-matched sleep and sleep deprivation (SD) in male C57BL/6J mice using continuous EEG/EMG recordings and frontal cortex RNA sequencing. IA recovery produced transient, rebound arousal, reduced early NREM and REM sleep, and, fragmented subsequent NREM bouts, and persistant, ultra-slow EEG-oscillations that normalized within two weeks. Whereas, SD induced consolidated rebound sleep and slow wave activity. Transcriptomic profiling at ZT6 showed that IA and SD induced largely distinct cortical gene-expression programs. IA preferentially enriched integrated stress response and unfolded protein response genes, whereas SD showed a comparatively orthogonal, growth-permissive, mTOR-associated profile. Although IA-induced gene-expression suggests cellular stress, corticosterone measurements argued against systemic stress as the primary driver. These findings indicate that isoflurane recovery is neurophysiologically and molecularly distinct from restorative sleep.

neuroscience↗

bioRxiv2026

The Red Blood Cell Surface Defines a Distinct Tumor DNA Compartment for Liquid Biopsy

Red blood cells (RBCs) modulate host inflammatory responses by scavenging mitochondrial and pathogen DNA. However, how RBC surface properties govern the capture of tumor-derived DNA remains poorly understood. We show that RBCs tether and retain tumor-derived DNA on their surface, forming a distinct circulating pool of RBC-bound tumor DNA (rtDNA). Desialylation increased DNA capture in a Toll-like receptor 9 (TLR9)-dependent manner, identifying RBC surface sialylation and TLR9 as a regulator of DNA binding. In mice bearing lung cancer xenografts, rtDNA was detected in all animals and its abundance correlated with tumor burden, whereas tumor DNA was undetectable in matched plasma samples. In patients with lung cancer, the majority of detected mutant tumor DNA was associated with RBCs rather than plasma, and RBC-derived mutations were concordant with molecular alterations identified in matched tumor tissue. Collectively, these findings establish the RBC surface as a tunable site of tumor-DNA capture and retention and challenge the plasma-centric paradigm of liquid biopsy by identifying a distinct cellular reservoir of tumor-derived genetic material.

cancer biology↗

bioRxiv2026

Molecular and cell type-specific determinants of inferior colliculus development and auditory function

Sound perception requires sensory information processing through brain regions where alterations to cellular composition or function may impact auditory-relevant behaviors. The inferior colliculus (IC) is a central midbrain hub for integrating and transforming auditory information prior to relay to the forebrain. However, the molecular logic that underlies the cell type specification of the IC remains unknown. Here, using a multiomic approach, we define the transcriptional and chromatin landscapes that underlie IC cell type diversity. We identify distinct glutamatergic neuronal subclasses and the gene regulatory programs that drive their specification, maturation, and survival. We show that perturbation to the transcription factor FOXP2, previously implicated in speech and language as well as brain disorders with altered sensory processing, selectively disrupts the specification and survival of three newly defined glutamatergic neuronal subclasses. We link these molecular and cellular disruptions to functional deficits in auditory processing including altered brainstem and forebrain responses and impaired behavioral sensitivity to acoustic stimuli. Together, these results link gene regulatory mechanisms to cell type-specification in the IC, providing insight into how molecular control of neuronal identity in midbrain sensory centers contributes to systems-level processing of sound.

neuroscience↗

bioRxiv2026

The genetic signature of memory encoding along the human hippocampal axis

Episodic memory formation engages hippocampal oscillations that vary along the anterior-posterior axis, but the molecular programs supporting this physiological specialization remain unclear. Here, we leveraged a rare neurosurgical dataset in which patients performed verbal episodic memory tasks during intrahippocampal intracranial EEG recordings prior to en bloc hippocampal resection, enabling integration of encoding-related oscillatory signatures with matched cell-type-resolved transcriptomics from the same individuals. Subsequent memory effects (SMEs) spanned delta/theta, gamma, and hippocampal ripple activity across anterior and posterior hippocampus. Single-nucleus RNA sequencing from anatomically matched anterior and posterior tissue revealed longitudinal transcriptional gradients, most prominent in excitatory neurons. Spatial transcriptomic maps validated axis-enriched transcripts and their localization. Linking subject-specific SMEs to gene expression identified distinct molecular programs: anterior low frequency SMEs associated with synaptic and chromatin-regulatory pathways, and posterior high-frequency SMEs associated with metabolic and protein synthesis processes. Gene regulatory network inference further revealed axis-specific hub architectures. Together, these results define a cell-type-specific genetic architecture linking longitudinal molecular specialization to the human hippocampal encoding dynamics.

neuroscience↗

bioRxiv2026

Older adults amplify passive gait stability during obstacle crossing without weakening the stabilizing synergy

Older adults sustain disproportionately severe injuries from trip-induced falls during obstacle crossing. Such falls depend partly on forward momentum when the foot crosses the obstacle. MOSAP, an index of passive dynamic gait stability, reflects this momentum. We quantified MOSAP and a synergy index from uncontrolled manifold analysis of step length and extrapolated center of mass in 25 young (21.6 {+/-} 3.5 yr) and 23 older adults (68 {+/-} 4.3 yr) during unobstructed and obstructed walking, to test whether MOSAP increases during obstacle crossing and whether it is actively stabilized at each step. Both groups increased MOSAP progressively over two approach steps by reducing forward momentum and shifting the center of mass posteriorly. Older adults showed greater increases at the crossing steps. The synergy index was positive for all steps, showing that deviations in step length and extrapolated center of mass covaried to stabilize MOSAP at step-specific values. The synergy index was not influenced by age. We conclude that adults actively recruit passive body mechanics while approaching and crossing obstacles to reduce the risk of a trip becoming a fall. Older adults amplify this strategy to compensate for diminished neuromuscular corrective capabilities.

physiology↗

bioRxiv2026

Integrative multi-omic analysis identifies tumor-intrinsic p38 as a driver of immune exclusion in human epithelial cancers

Patients with tumors not responding to immune-checkpoint inhibition (ICI) often harbor a non-T cell-inflamed tumor microenvironment, characterized by the absence of IFN-{gamma}-associated CD8+ T cells and dendritic cell activation. While the role of p38 mitogen-activated protein kinases (MAPKs) in regulating dendritic and myeloid cells is established, the tumor-intrinsic immunomodulatory function of p38 remains underexplored. Here, we identify tumor cell-intrinsic p38 signaling as a target candidate associated with immune exclusion and reduced immunotherapy response. In human papillomavirus-negative head and neck squamous carcinoma (HNSCC), molecular analysis of 395 tumor tissues revealed a p38-centered network enriched in non-T cell-inflamed tumors. Multi-cancer single-cell RNA sequencing analysis of over 200,000 cells further identifies p38 activation as a potential immune-exclusion program across multiple epithelial tumor types, including HNSCC and lung squamous cell carcinoma (LUSC), supported by tissue validation in [~]250 human biospecimens using multispectral imaging and digital spatial profiling. Functional studies demonstrate that p38 knockdown or pharmacologic inhibition in HNSCC and LUSC cell lines increases T cell migration, with CXCL16 identified as a chemokine mediator in vitro; neutralization of CXCL16 attenuated this effect. Together, these findings identify tumor-intrinsic p38 activation as a driver of immune exclusion in epithelial cancers and support its potential as a therapeutic target to overcome immunotherapy resistance.

Cancer Biology↗

bioRxiv2026

Inducible lipid storage and steatosis in the human choroid plexus associated with age and adiposity

Cells that store lipids for other cells or organs can contain "giant" or large lipid droplets (LLDs) greater than 2 {micro}m in diameter. In this study, human postmortem choroid plexus was evaluated for lipid droplets. Staining with hematoxylin and eosin (H&E), the lipophilic dye Oil red O, and anti-adipophilin antibodies established the presence of LLDs exceeding 10 {micro}m in diameter in choroid plexus epithelial cells (CPECs). Manual annotation of H&E stains from 105 cases revealed a significant association between age and the percentage of CPECs containing LLDs (reaching up to 69%) and involving LLDs in our largest annotated category (>5 {micro}m in diameter). The LLD association with age was replicated and extended to a total of 245 cases using a trained convolutional neural network, which further showed significant associations with body mass index at time of death (increasing with BMI), sex (higher in females >65 years old), and a near-significant association with Alzheimers Disease (lower in AD). Like HepG2 and derived hepatocytes, excess fatty acids in culture media readily induced LLDs and steatosis in human embryonic stem cell-derived CPECs. Akin to hepatocytes for the human body, we propose that CPECs store lipids for the human brain and become steatotic in the setting of excess adiposity.

pathology↗

bioRxiv2026

T-cell Receptor (TCR) targeting with Multivalent T-cell Engagers

T-cell engagers (TCEs) for cancer immunotherapy have traditionally relied on high affinity single chain fragment variable (scFv) domains to target CD3, specifically the {varepsilon} chain, for the activation of T-cells. Despite their clinical success, there have been reports of TCEs driving systemic toxicity, non-specific T-cell activation, on-target off-tumor effects, and severe inflammation due to cytokine release. To address these limitations, we designed multivalent TCEs using Chemically Self-Assembled Nanorings (CSANs) that target the /{beta} constant region of the T-cell receptor (TCR) in the TCR/CD3 complex using a moderate affinity TCR nanobody (TCRVHH). Nanobodies offer superior physical and chemical properties over scFvs-including higher solubility, stability and lower production cost-making them increasingly popular as structural units of TCEs. We compared the efficacy and safety profile of this moderate affinity, nanobody-based TCR binder against high affinity CD3scFv based CSANs across EGFR and PSMA expressing solid tumor models. While the CD3scFv CSANs offered potent cytotoxicity, they also induced antigen independent T-cell activation bypassing the requirement of tumor crosslinking for cytotoxicity. In contrast the TCRVHH CSANs required strict antigen engagement to trigger cytotoxicity, significantly reducing non-specific T-cell activation and thus enhancing the safety profile. Although the initiation of cytotoxicity was kinetically slower than the CD3scFv counterpart, TCRVHH CSANs achieved comparable end point cytotoxicity across multiple antigen densities, as well as in 3D tumor spheroids. Through this study we demonstrate the applicability of nanobodies as T-cell targeting domains, enhanced specificity and safety of moderate affinity T-cells binders and the diversification of T-cell targeting epitopes without compromising the efficacy of TCEs. Abstract Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/725710v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@9bcb83org.highwire.dtl.DTLVardef@4e30daorg.highwire.dtl.DTLVardef@1695931org.highwire.dtl.DTLVardef@15ec7ab_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Natural aging drives a subclinical cardiovascular phenotype in a non-human primate

Aging is an inevitable risk factor for cardiovascular disease. Profound understanding of mechanisms underlying the early stages of cardiovascular aging is essential for the development of novel therapeutics. Therefore, animal models which closely reflect the human condition are highly sought after. Here, we investigated natural cardiovascular aging in a non-human primate, comparing healthy young-adult and aged common marmosets (Callithrix jacchus). Despite preservation of most cardiac functional parameters in aged animals, significant histological alterations were found including fibrosis and microvascular rarefaction. Molecular phenotyping by single-nuclei RNA-sequencing revealed activation of cardiac stress, pro-inflammatory and fibrotic gene programs in aged hearts. Importantly, proteomic analysis of cardiac extracellular vesicles revealed a cardioprotective cargo in young animals while functionally demonstrating pro-angiogenic properties on human cardiac microvascular endothelial cells. Finally, large vessel atherosclerosis was strikingly evident in aged animals and elucidated by bulk RNA-sequencing. Overall, the aging marmoset offers a great potential for translational cardiovascular research.

physiology↗

bioRxiv2026

Explicit representation of germline and non-germline residues improves antibody language modeling

Antibodies originate from germline templates and are diversified by somatic hypermutation, producing sequences in which conserved germline residues scaffold structure while rare non-germline (NGL) substitutions refine antigen binding. Current antibody language models (ALMs) treat all residues equivalently and inherit a germline bias that systematically down-weights functionally critical NGL mutations as statistical noise. We introduce PRISM, a germline-aware ALM that explicitly represents germline and nongermline residues as distinct token types over a factorized 53-token vocabulary. PRISM achieves state-of-the-art pseudo-perplexity in hypervariable CDRs and is uniquely positively correlated with experimental binding affinity across three deep mutational scanning landscapes on which all compared ALMs anti-correlate. The dual-vocabulary further enables property-specific controllable generation previously unattainable with entangled ALMs. NGL-directed sampling improves physics-based binding scores while GL-directed sampling preserves stability and solubility. These results establish disentangled germline/non-germline representation as a substantive advance in antibody language modeling.

immunology↗

bioRxiv2026

Understanding heterogeneous responses to T cell engagers: Binding characteristics and dosing thresholds determine cytotoxic efficacy

Therapeutic efficacy of multivalent T cell engagers varies widely across individuals, but the basis for this heterogeneity remains poorly understood. Here, we integrate in vitro experiments of antitumor immune responses with a mechanistic modeling framework to investigate sources of response variability across T cell donors and TE constructs, focusing on a novel multivalent bispecific T cell engager currently in development. We identify parameter regimes that accurately recapitulate dose-response behaviors across T cell donors and doses, and perform cross-validation studies that demonstrate the models predictive accuracy. We find that variability in therapy efficacy is governed by the relationship between binding affinity and dose. When dose exceeds the binding affinity, responses are relatively robust across donors; when dose is below the binding affinity, responses are more donor dependent. At smaller doses, the TE-specific shape characteristics of the tumor-binding dose response, its steepness in particular, is a key marker of therapy efficacy. More generally, our integrated modeling and experimental framework offers insights and tools that are applicable to other bispecific T-cell engagers, and provides a quantitative foundation for the systematic, in silico optimization of TE design and dosing strategies.

immunology↗

bioRxiv2026

Stress-Survival Pathway Profiling Reveals MCM10 as a Candidate Biomarker of Hispanic Colorectal Cancer Disparities

BackgroundColorectal cancer (CRC) remains the second leading cause of cancer mortality in the U.S., with significant racial and ethnic disparities in incidence, survival, and mortality rates. The rising incidence of early-onset CRC and the frequent presentation at advanced stages of CRC among the Hispanics makes this an important ethnic group to study. A deeper understanding of the complex interplay between molecular, genetic, and environmental factors is critical for developing targeted therapies to reduce the prevalence in specific racial and ethnic groups, such as Hispanics. This study explores the role of stress-survival pathway (SSP) genes in early-onset and late-stage CRC, primarily focusing on disparities between Hispanics and Non-Hispanic Whites (NHWs). Additionally, this study investigates the role of MCM10, in contributing to CRC disparities among the Hispanic populations with an emphasis of early-onset and late-stage CRC Hispanics. MethodsOne of our previous studies had identified some SSP protein coding genes associated with CRC. The transcript and protein level expressions of these genes were validated in CRC cell lines, cDNA arrays, and tissue microarrays, using qRT-PCR and immunohistochemistry, respectively. The transcript level expressions of differentially expressed SSP genes were further evaluated in Hispanic and NHWs tumor tissues, including early onset and late-stage cohorts. Additionally, we performed cellular, physiological, and functional assays to explore the role of MCM10 in tumor progression, before and after siRNA mediated knockdown of MCM10. High-throughput transcriptomic and proteomic analyses were performed to reveal the underlying molecular mechanism. ResultsWe observed the differential expressions of twelve SSP genes in CRC cell lines, at the transcript level; that of ten genes in early and late stages using cDNA arrays, and nine genes at the protein levels using tissue microarrays and immunohistochemistry. Hispanic CRC samples showed differential expression of all nine SSP genes compared to NHWs, in early-onset, and late-stage CRC, with all genes being upregulated other than CDK4 and PRDX4 in late-stage CRC and CDK4 in early-onset CRC. Our functional study demonstrated that MCM10 knockdown in CRC cell lines significantly reduced cell proliferation, growth, invasion, and migration by inducing cell cycle arrest, apoptosis, and reactive oxygen species pathways. The integrative RNA-sequencing and proteomics study identified that PPFIA1 could be associated with MCM10 mediated cancer progression. The role of MCM10 and PPFIA1 in cancer progression has also been validated by CRISPR-Cas9 mediated MCM10 knock out, using a Hispanic CRC patient derived organoid. ConclusionThe differential expression of SSP genes suggest a potential molecular contribution to CRC disparities in the Hispanic population. The essential oncogenic role of MCM10 and its axis with PPFIA1 was identified; this could lead to a new avenue for therapeutics targeting the MCM10-PPFIA1 axis, thereby, combating early-onset and advanced-stage CRC in this high-risk ethnic group. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/698057v2_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@11528c8org.highwire.dtl.DTLVardef@288d15org.highwire.dtl.DTLVardef@466703org.highwire.dtl.DTLVardef@150890_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Behavioral divergence between a generalist and a specialist mosquito despite minimal differentiation across chemosensory receptor gene families

Oviposition site choice is a major determinant of habitat selection in insects, yet its behavioral and genetic bases remain poorly understood. Although model organisms such as Drosophila melanogaster provide well-established systems for studying oviposition, disentangling foraging from egg-laying decisions remains challenging because females use the same substrates for feeding and reproduction. Here, we identify a pair of sister mosquito species that exhibit contrasting oviposition strategies and provide a promising system for investigating how divergence in sensory information processing shapes behavioral shifts between generalist and specialist taxa. Using binary-choice assays, we tested oviposition preferences in 1,046 gravid females from both field and laboratory populations. Anopheles gambiae females were highly selective and deposited nearly all eggs in a single water source, consistent with specialist behavior. In contrast, females of its sibling species, An. coluzzii, adopted a generalist strategy marked by a more even distribution of eggs across available substrates. To identify chemosensory receptor genes that diverge between the cryptic species and may underlie these behavioral differences, we analyzed amino acid substitutions across odorant, ionotropic, and gustatory receptor families using whole-genome sequencing data. Although differentiation was limited at the gene-family level, several individual divergent loci associated with carboxylic acid, amine, and other volatile detection pathways emerged as candidate drivers of species-specific oviposition behavior. These findings suggest that shifts in sensory perception during egg laying may facilitate behavioral and ecological specialization, and that phenotypic divergence in environmental sensing can arise before substantial genome-wide differentiation.

evolutionary biology↗

bioRxiv2025

A sensory system for mating in octopus

Sensory systems for mate recognition maintain species boundaries and influence diversification. Therefore, uncovering how molecules and receptors evolve to mediate this critical function is essential to understanding biodiversity. Male octopuses use a specialized arm called the hectocotylus to identify females and navigate their internal organs to reach the oviduct and deliver sperm. Here, we discovered that the hectocotylus is a dual sensory and mating organ that uses contactdependent chemosensation of progesterone, a conserved ovarian hormone. We identify chemotactile receptors for progesterone and resolve the structural basis for their evolution from ancestral neurotransmitter receptors and subsequent expansion and tuning across cephalopods. These findings reveal principles by which sensory innovations shape reproductive behavior and suggest mechanisms for how sensory evolution contributes to the diversification of life.

cell biology↗

bioRxiv2025

The G Protein-Coupled Receptor GPR31 Promotes Pro-inflammatory Responses in Pancreatic Islets and Macrophages

In type 1 diabetes (T1D), the innate and adaptive immune systems attack and eventually destroy the insulin-secreting pancreatic {beta} cells. During this process, {beta} cells activate inflammatory signaling pathways that augment the dysfunction and destruction imposed by cellular autoimmunity. The 12-lipoxygenase (12-LOX) pathway produces the pro-inflammatory eicosanoid 12-HETE, which induces oxidative and endoplasmic reticulum stress and results in diminished insulin secretion and apoptosis. The G protein-coupled receptor GPR31 has been identified as a putative receptor for 12-HETE. In this study, we generated conventional GPR31 knockout (KO) mice on the C57BL/6J background. To interrogate the role of GPR31 in {beta} cells, we treated islets from wildtype and Gpr31b KO mice with pro-inflammatory cytokines and subjected the islets to RNA sequencing. Differentially expressed pathways in Gpr31b KO islets included those pertaining to inflammation and oxidative stress, consistent with functional studies that demonstrated reduced cytokine-induced oxidative stress in Gpr31b KO islets compared to wildtype controls. Bone marrow-derived macrophages from Gpr31b KO mice showed reduced macrophage migration and decreased inflammatory IFN- and IFN-{gamma} signaling by RNA sequencing. To mimic islet and macrophage inflammation as seen in T1D, wildtype and Gpr31b KO mice were treated with the diabetogenic toxin streptozotocin. Compared to wildtype, Gpr31b KO mice had improved glucose tolerance and preserved {beta}-cell mass. siRNA knockdown of Gpr31b in non-obese diabetic (NOD) mice reduced insulitis, macrophage infiltration, and oxidative stress. Collectively, these findings are consistent with previously published data using 12/15-LOX KO mice and suggest that GPR31 mediates the pro-inflammatory responses of 12-HETE in both {beta} cells and macrophages.

molecular biology↗

bioRxiv2025

Multivalent Tri-Functional T-cell Engagers by Chemically Induced Protein Self-Assembly

T-cell engagers (TCEs) show promise in cancer immunotherapy but face challenges in solid tumors due to heterogeneity, antigen escape, and limited T-cell infiltration. To address this, we developed a modular platform using chemically self-assembled nanorings (CSANs). We engineered a bifunctional fusion protein, E1-DHFR2-CD3, with an EGFR-binding fibronectin (E1) and an anti-CD3 scFv on a DHFR2 scaffold. With bis-methotrexate, the monomers formed multivalent cis-CSANs. Both monomers and CSANs bound EGFR+ tumor cells and T-cells, were internalized, and induced dose-dependent, EGFR- and T-cell-dependent cytotoxicity in co-culture assays. The system was reproducible across T-cell donors. To expand targeting, E1-DHFR2-CD3 co-assembled with other DHFR2 monomers targeting GFP or EpCAM, forming trispecific CSANs capable of binding multiple antigens and mediating cytotoxicity. This platform enables the discovery of potent multispecific TCEs to address antigen escape and solid tumor heterogeneity. Future work will focus on optimizing antigen combinations to enhance efficacy across breast cancer subtypes.

immunology↗

bioRxiv2025

12-Hydroxystearic acid induces epidermal keratinocytes to secrete antimicrobial peptides that are potent inhibitors of viral infection.

Epidermal keratinocytes produce antimicrobial peptides (AMPs) that serve as a crucial component of the skins innate immune barrier. These peptides effectively target a broad spectrum of pathogenic microorganisms while preserving commensal microbiota essential for skin barrier homeostasis and overall skin health. Regulating the release of these AMPs presents a promising approach to enhancing the skin barriers defense mechanisms with minimal side effects. We have identified 12-hydroxystearic acid (12-HSA) as a potent stimulator of AMP secretion from primary epidermal keratinocytes. Mechanistic investigations revealed that, akin to bacterial stimulation, 12-HSA induces AMP release through the downregulation of caspase-8, which subsequently activates the inflammasome. Notably, we discovered that 12-HSA mediates caspase-8 downregulation via the acute activation of DNA methyltransferase 3A (DNMT3A), leading to transcriptional silencing of the caspase-8 locus. Importantly, 12-HSA is widely utilized in the cosmetic industry for its several skin beneficial properties including hydration and emolliency. Our findings suggest that this compound can be leveraged to enhance innate immune defenses in the skin, effectively mobilizing stored AMPs from keratinocytes to counteract microbial threats. This discovery highlights the potential for 12-HSA as a novel agent in dermatological applications aimed at fortifying skin barrier immunity.

cell biology↗

bioRxiv2025

Stimulation modulates cell assemblies linked with gene networks in the human temporal cortex ex vivo

Deep brain stimulation of the temporal cortex can enhance learning and memory in the face of cognitive impairment. Despite the potential of such therapies, the neural and genetic mechanisms underlying the effect of stimulation on human brain circuits are not understood. To explicate direct mechanisms of neural modulation elicited by brain stimulation, we developed an ex vivo approach utilizing microelectrode array stimulation and recording of resected temporal cortex from neurosurgical patients. We find that stimulation preferentially increases firing rates in pyramidal cells compared to interneurons and also strengthens cell assemblies. Using single cell multiomics, we link the observed physiological changes to cell type-specific gene expression patterns. We detail gene regulatory networks that indicate preferential involvement of specific excitatory neuron subtypes and the response of non-neurons. We conclude that the overall impact of stimulation on the human temporal cortex is activation of specific excitatory neurons and enhanced cell assembly activity, and that these changes are supported by gene networks involving immediate early, synaptic, and ion channel genes. Our findings establish a foundation to identify targetable cell type-specific genetic signatures that may be harnessed for therapeutic benefit in future neuromodulation strategies.

neuroscience↗