Biology subjects

Kim, W. J.

Publications and source records attributed to Kim, W. J..

At least 19 recordsLinked to original sources

bioRxiv2026

A Conserved SIFamide Circuit Functions as the Insect Vagus Nerve

The insect functional homolog of the mammalian vagus nerve has remained elusive. Here, we identify the SIFamide (SIFa) peptidergic circuit as this homolog in Drosophila melanogaster. SIFa neurons project the longest axons from the brain to the hindgut ampulla, forming synapses with peripheral SIFa-receptor (SIFaR) neurons originating in the abdominal ganglion. This circuit is functionally plastic: sexual experience enhances synaptic strength at the hindgut, increasing excretion while reducing mating duration to to favor energy conservation and metabolic recovery. Mechanistically, this shift involves octopaminergic/tyraminergic gating and SIFa-mediated modulation of Adipokinetic Hormone (AKH) from the corpora cardiaca. We further uncover a feedback loop in which SIFaR/Allatostatin-A (AstA) neurons project back to the brain, signaling hindgut physiological status to SIFa neurons via AstA-R1. This hindgut projection is conserved across diverse insect orders. Thus, the SIFa-SIFaR circuit constitutes an evolutionarily conserved "insect vagus nerve" that integrates metabolic state and reproductive history to optimize survival strategies.

neuroscience↗

bioRxiv2026

Driver-independent lexAop-tdTomato.nls reporter signal in the adult Drosophila proventriculus

Reporters are widely used in Drosophila genetics to visualize gene expression and cell lineages. However, uncharacterized limitations in specific reporter lines can lead to data misinterpretation. Here, we identify a consistent, driver-independent tdTomato signal in the adult proventriculus from the widely used lexAop-tdTomato.nls reporter line. This signal was observed across multiple lexA driver combinations and was directly detectable in lexAop-tdTomato.nls responder-alone adult proventriculi lacking any lexA driver and without antibody staining. In contrast, no comparable native red fluorescence was detected in larval proventriculi under the same no-antibody imaging condition. Mouse and rabbit anti-RFP immunostaining further supported the presence of proventriculus-associated tdTomato/RFP antigen in adult responder-alone animals. In larval responder-alone proventriculi, antibody-amplified staining was antibody-source-dependent: a detectable signal was observed only with rabbit anti-RFP, whereas mouse and rat anti-RFP produced no reliable detectable signal under the same staining condition. A driver-matched comparison using lexAop-RFP.nls did not reproduce the proventricular signal, arguing against detectable ectopic activity of the tested lexA driver in this tissue. However, because lexAop-tdTomato.nls and lexAop-RFP.nls differ in reporter/transgene architecture and possibly genomic insertion context, the underlying cause cannot be assigned specifically to the lexAop sequence. Our findings highlight the necessity of including driver-negative and no-antibody controls when using this reporter line in adult Drosophila proventriculus and gut studies.

genetics↗

bioRxiv2026

Neuropeptide Receptors Harbor More Genomic Regulatory Elements in Their Loci Than the Loci of Their Ligands

The neuropeptide signaling pathway is vital for the physiology and behavior of multicellular organisms. This pathway is mediated by ligand-receptor binding, wherein neuropeptides (NPs) are often released from neurons, while their receptors (NPRs) are ubiquitously expressed in both neuronal and non-neuronal cell types. To elucidate the underlying mechanisms of this expression pattern divergence, here we dissect the genomic and epigenomic architectures of these two distinct gene classes. We first characterized the genomic architecture of NP and NPR genes to compare their total gene length, exon and intron lengths, exon counts, and number of alternatively spliced transcripts per gene. We also profiled their regulatory genomic elements including CpG islands, TATA boxes, and their overlapping antisense transcripts. These analyses were then expanded to non-human model organisms to evaluate the evolutionary conservation of the underlying mechanisms. We found that NPRs encompass larger genomic loci and encode longer transcripts than NPs. Furthermore, the increased length of NPR transcripts was driven by longer exons rather than higher exon counts. Consistently, the number of spliced variants per gene was similar between NPs and NPRs, suggesting that alternative splicing events are a minor contributor to their distinct expression patterns. At the RNA level, NPR mRNAs possess significantly longer 3'UTRs compared to NPs, indicating a greater potential for post-transcriptional gene regulation. This complexity is also mirrored at the chromatin level, where NPR loci exhibit a higher density of epigenetic marks than NPs. Together, these findings highlight the multi-layered nature of gene regulation prioritizing control at the receptor level.

genomics↗

bioRxiv2025

Simple Methods to Acutely Measure Multiple Timing Metrics among Sexual Repertoire of Male Drosophila

Male Drosophila courtship behavior is a key model for studying temporal decision-making. While courtship index (CI) is widely used to quantify mating activity, other timing metrics like courtship latency, copulation latency (CL), and mating duration (MD) remain understudied. Traditional methods for quantifying these behaviors are often labor-intensive and prone to human error. In this study, we present a protocol combining a modular chamber system and automated software (DrosoMating) to quantify 6 key timing metrics during male courtship. Our image-based video analysis enables precise identification of courtship and copulation events, as well as quantification of their timing and duration under controlled conditions. Validation shows <0.05% error rates and 98-99% agreement with manual scoring for CL, CI, and MD. The protocol supports genetic and neural circuit manipulations, detecting subtle genetic, social, and environmental behavioral variations. By minimizing manual effort and standardizing data collection, this approach facilitates scalable, reproducible studies on adaptive trade-offs, learning, and neural mechanisms in mating behavior. This method streamlines timing analysis in male courtship, offering reproducible metrics for behavioral genetics. HighlightA high-throughput software pipeline for automated temporal profiling of Drosophila melanogaster mating behavior after brief user-guided calibration. An accompanying, open-hardware platform that can be assembled at minimal cost while maintaining experimental rigor. The system attains near-manual accuracy and outputs Temporal Measurement Parameters data that are readily adaptable to--and quantifiable within--diverse behavioral paradigms.

developmental biology↗

bioRxiv2025

CLOCK-dependent pathway in a single pair of LNd neurons instruct circadian-independent interval timing behavior.

Interval timing is a cognitive ability essential for behaviors such as mating, foraging, and decision-making, and it is distinct from circadian rhythm regulation. Despite the involvement of circadian clock genes in both interval timing and circadian rhythms, the mechanisms differentiating these functions remain unclear. Using Drosophila as a model, we demonstrate that the CLK/CYC heterodimer, but not PER/TIM, is essential for interval timing. Neuronal CLK/CYC expression is necessary and sufficient for sexual experience-dependent shorter mating duration (SMD) behavior. We identified that CLK/CYC expression in a single pair of ITP-positive LNd neurons is pivotal for SMD. These neurons are glutamatergic with output circuits to central brain regions. CLK variants lacking DNA binding motifs dissociate circadian rhythms from interval timing and sleep behaviors in these neurons. Our study uncovers a specialized circuit for interval timing and highlights the non-circadian functions of circadian clock genes. Statement of SignificanceThis study in Drosophila demonstrates that the CLK/CYC heterodimer is crucial for interval timing, distinct from circadian rhythm regulation. The research pinpoints a specific pair of neurons that are critical for shortened mating duration behavior, and it suggests that CLK variants can influence interval timing dissociation from circadian rhythm and sleep behaviors. HighlightsO_LICLK/CYC heterodimer are essential for interval timing. C_LIO_LISpecialized mechanism of interval timing behavior revealed. C_LIO_LIIdentified a pair of glutamatergic ITP-LNd neurons that independently regulate both interval timing and sleep. C_LIO_LIRevealed a novel mechanism by which CLK variants regulate sleep and interval timing. C_LI Graphical AbstractDifferent CLK/CYC mediate separate regulatory mechanism between circadian rhythm, sleep and interval timing in Drosophila melanogaster.

animal behavior and cognition↗

bioRxiv2025

The role of miR-9a in modulating sensory neuron morphology and mating behavior in Drosophila melanogaster.

Following mating, female Drosophila melanogaster display profound behavioral changes, including sensory sensitivity and rejection of courting males. The molecular mechanisms governing this plasticity remain incompletely understood. Here, we identify the conserved microRNA, miR-9a, as a critical regulator of this process. We show that miR-9a mutant females exhibit a premature rejection phenotype, mimicking mated-female behavior, which is correlated with an aberrant overgrowth of adult body wall sensory neurons. We demonstrate that this neuronal phenotype is governed by a dual regulatory system. First, in a non-cell autonomous mechanism, miR-9a expression in the epidermis is required to constrain sensory neuron dendrite growth, indicating that an epithelial-derived signal patterns the underlying neuron. Second, within the neuron itself, miR-9a interacts genetically with the transcription factor senseless (sens) and the novel RNA-binding protein bruno2 (bru2). Reducing the dosage of either sens or bru2 rescues both the neuronal and behavioral defects of miR-9a mutants. Our findings reveal an integrated, inter-tissue signaling axis where epithelial miR-9a orchestrates a non-cell autonomous cue that modulates a cell-intrinsic network to ensure the precise development of sensory neurons, thereby calibrating behavioral responses critical for reproductive success.

neuroscience↗

bioRxiv2025

Membrane Tethering of Honeybee Antimicrobial Peptides in Drosophila Enhances Pathogen Defense at the Cost of Stress-Induced Host Vulnerability

Antimicrobial peptides (AMPs) represent a promising alternative to conventional antibiotics in combating multidrug-resistant pathogens, yet their clinical translation is hindered by proteolytic instability, cytotoxicity, and poor bioavailability. Here, we demonstrate that glycosylphosphatidylinositol (GPI)-mediated membrane tethering of honeybee defensin1 (Def1) in Drosophila melanogaster enhances its antimicrobial efficacy by [~]100-fold compared to secreted or untethered forms, while preserving physiological and behavioral integrity under baseline conditions. Using a genetically engineered Drosophila model, we expressed three Def1 variants: native (Def1), secreted (s-Def1), and membrane-tethered (t-Def1). Flies expressing t-Def1 exhibited superior bacterial clearance of Pseudomonas aeruginosa and improved survival post-infection, with no adverse effects on locomotion, courtship, or sleep architecture. However, under stress paradigms--including sleep deprivation and dextran sulfate sodium (DSS)-induced gut injury--t-Def1 exacerbated intestinal barrier dysfunction, as evidenced by elevated Smurf phenotype incidence, highlighting a trade-off between antimicrobial potency and epithelial vulnerability. Our work establishes Drosophila as a powerful platform for dissecting AMP mechanisms and engineering spatially targeted therapies, offering translational insights for pollinator health and human infectious disease management. These results advocate for iterative refinement of membrane-anchoring strategies to balance therapeutic efficacy with host safety, advancing the development of next-generation AMPs with minimized off-target effects.

biochemistry↗

bioRxiv2024

Leveraging Drosophila Models to Explore AI-generated Synthetic Peptide's Potential in Boosting Honeybee Health and Resilience

The integration of artificial intelligence (AI) and machine learning (ML) in peptide design has revolutionized the development of antimicrobial peptides (AMPs), which are essential components of innate immunity. In this study, we identified a novel synthetic peptide, PAN4 (GAYTFKIRRK), through genetic screening of AI-generated candidates in Drosophila melanogaster. PAN4 demonstrated robust antimicrobial activity, stress tolerance, and antitumor effects, significantly enhancing survival rates following bacterial infections and improving locomotor behaviors without adversely affecting lifespan. Furthermore, PAN4 expression in intestinal stem cells completely suppressed RasV12-induced tumor progression, indicating its potential role in cancer prevention. The peptide also mitigated gut barrier dysfunction associated with sleep deprivation and reduced inflammation in a dextran sulfate sodium (DSS)-induced colitis model. Mechanistically, PAN4s antimicrobial activity was linked to its interaction with specific peptidoglycan recognition proteins (PGRPs), particularly PGRP-SC1a, while the Tak1-mediated immune signaling pathway was found to be non-essential for its efficacy. PAN4 showed promising effects on honeybee health, enhancing survival rates under bacterial stress. Furthermore, PAN4 expression demonstrated significant anti-tumor activity in the Drosophila gut tumor model. Our findings suggest that PAN4 serves as a versatile agent with significant implications for enhancing immune responses and combating diseases in honeybee populations, paving the way for future applications in agriculture and medicine.

genetics↗

bioRxiv2024

Transcriptional Regulation of Neuropeptide Receptors Decodes Complexity of Peptidergic Modulation of Behavior and Physiology.

The modulation of complex behaviors in response to environmental and physiological contexts is a fundamental aspect of animal biology, with neuropeptides (NPs) playing a crucial role in this process. This study investigates the transcriptional regulation of neuropeptide receptors (NPRs) as a mechanism for context-dependent neuropeptidergic modulation of physiology and behavior. We hypothesize that the transcriptional control of NPR genes, rather than the NPs themselves, is a critical determinant in the context-dependent modulation of behavior and physiology. Using a multi-faceted approach, including comparative genomics, transcription factor network analysis, and empirical validation in model organisms such as Drosophila melanogaster, we reveal a complex regulatory landscape where NPR expression is tightly controlled. Our findings demonstrate that NPR genes exhibit a higher number of enhancers, CTCF-binding sites, and open chromatin regions compared to NP genes, suggesting a greater susceptibility to transcriptional modulation. This regulatory architecture allows for precise control over neuropeptidergic signaling, enabling dynamic and context-specific behavioral and physiological responses. Our results highlight the importance of NPR-expressing cells by transcriptional regulation in mediating the effects of NPs on behavior and physiology. We show that this regulation is conserved across species, indicating an evolutionarily significant mechanism for fine-tuning neuropeptidergic signaling. Furthermore, our study provides insights into the distinct regulatory mechanisms underlying the multifunctionality of NPs and their receptors, offering a novel perspective on the transcriptional control of complex behaviors. In conclusion, this study advances our understanding of neuropeptidergic signaling by focusing on the transcriptional regulation of NPRs. Our findings have broad implications for the development of therapeutic strategies targeting neuropeptidergic systems in various neurological and behavioral disorders.

neuroscience↗

bioRxiv2024

Male-specific sNPF peptidergic circuits control energy balance for mating duration through neuron-glia interactions.

ABSTRACTThis study reveals a sexually dimorphic sNPF-sNPF-R circuit in the Drosophila brain that regulates energy balance behavior, specifically the shorter-mating-duration (SMD) response to sexual experience. sNPF is predominantly expressed in neurons, while sNPF-R is expressed in both neurons and glial cells, particularly astrocyte-like glia (ALG) in a subset of cells outside the mushroom body (MB) termed "Rishi cells" (RS cells). Sexual experience induces global alterations in calcium signaling and synaptic plasticity within this circuit, with sNPF-R expressing neurons and glia in RS cells playing a critical role in encoding sexual experience-related information into energy balance behavior related to mating duration. Neuronal glucose metabolism, specifically the Tret1l transporter, is essential for maintaining the high calcium levels and proper function of sNPF neurons near RS cells. This novel and intricate neuron-glia sNPF-sNPF-R network acts as critical circuits within the Drosophila brain for processing interval timing behaviors, highlighting the dynamic interplay between metabolism, neural circuits, and behavior in regulating energy balance.

neuroscience↗

bioRxiv2024

Molecular and Neural Circuit Mechanisms Underlying Sexual Experience-dependent Long-Term Memory in Drosophila.

The neural and molecular underpinnings of sexual experience-dependent long-term memory (SELTM) in male Drosophila melanogaster remain poorly understood, despite its significance for reproductive success. Here, we dissect the role of a specific class of neurons, termed Yuelao (YL) neurons, in the formation of SELTM and the associated molecular pathways. We employed a combination of genetic manipulations, immunohistochemistry, and behavioral assays in Drosophila to investigate the function of YL neurons and their molecular interactors in SELTM. Utilizing the RNA sequencing data and transgenic tools, we delineated the neural circuits involved in taste and pheromone processing relevant to SELTM. Our findings reveal that the YL neurons, expressing the Orb2 scaffolding protein, are indispensable for the formation of SELTM following sexual experience. These neurons are regulated by the neuromodulator short neuropeptide F (sNPF) and its receptor (sNPF-R), which modulate glutamate release via NMDAR2. We demonstrate that sexual experience triggers synaptic plasticity in YL neurons, characterized by an increase in dendritic and presynaptic terminal areas, and a decrease in intracellular calcium levels. Furthermore, we show that YL neurons are specialized for the generation of appetitive sexual experience-dependent memory and project to brain regions implicated in memory formation. Our study uncovers the YL neurons as a key neural substrate for SELTM in Drosophila, shedding light on the molecular and circuit mechanisms that mediate the formation of long-term memories following sexual experience. These findings provide novel insights into the neural basis of taste-related memory and have broader implications for understanding the interplay between experience, memory formation, and behavior.

neuroscience↗

bioRxiv2024

Investigating the role of axonal localization of sex peptide receptor in post-mating responses of female Drosophila melanogaster

This study elucidates the molecular mechanisms underlying the axonal localization of the sex peptide receptor, a pivotal G-protein coupled receptor in the Drosophila melanogaster post-mating response cascade. Utilizing transgenic expression, neuronal labeling, and bioinformatics analyses, we demonstrate that the N-terminal domain of SPR is indispensable for its axonal targeting in both Drosophila larval ventral nerve cord neurons and mouse hippocampal neurons. Deletion of the N-terminal domain abolished axonal localization, highlighting its critical role in this process. Intriguingly, the C-terminal domain of SPR appears to play a subordinate role in axonal targeting. Bioinformatical analysis revealed a striking homology between the N-terminus of SPR and the Broad-complex, Tramtrack, and Bric-a-brac/poxvirus and zinc finger family of proteins. The BTB domain, a conserved protein-protein interaction domain within this family, is implicated in diverse cellular processes and axonal targeting. Further investigation into the role of the BTB domain-like region in SPR could provide valuable insights into the molecular underpinnings of axonal targeting and post-mating responses in Drosophila. This research contributes to our understanding of the intricate mechanisms governing GPCR localization and function in the context of reproductive biology and neuronal signaling.

neuroscience↗

bioRxiv2024

Hypersensitivity controlled by mir-9a modulates female receptivity of Drosophila melanogaster.

Female Drosophila melanogaster undergo a complex behavioral transformation following mating, characterized by increased sensory sensitivity and altered reproductive behaviors. In this study, we investigated the role of miR-9a, a conserved microRNA, in regulating these post-mating changes. We found that miR-9a mutant females exhibited a hypersensitivity phenotype, with increased rejection of courting males, delayed onset of sexual receptivity, and abnormal mating termination behavior. This phenotype was associated with aberrant overgrowth of adult body wall sensory neurons, suggesting a link between neuronal hypersensitivity and reproductive behavior. To further elucidate the underlying mechanisms, we performed genetic interaction studies with sens and bru2, genes known to interact with miR-9a. We found that removing one copy of sens or bru2 in miR-9a mutant backgrounds rescued the female rejection phenotype and normalized neuronal morphology. This suggests that miR-9a regulates sensory neuron development and female receptivity by modulating the expression of target genes like sens and bru2. Our findings reveal a novel role for miR-9a in regulating sensory hypersensitivity and reproductive behaviors in Drosophila. This research provides valuable insights into the molecular mechanisms underlying post-mating behavioral adaptations and neural development. Additionally, our findings highlight the potential of Drosophila as a model organism for investigating the role of miR-9 family members in neuronal specification and function, with implications for understanding sensory processing and neural plasticity in other organisms.

neuroscience↗

bioRxiv2024

Investigating the antimicrobial and immunomodulatory effects of honeybee venom peptide apamin in the Drosophila genetic platform.

Apamin, an 18-amino acid peptide neurotoxin, constitutes a significant portion of honeybee venom. Although traditionally recognized for its neurotoxic effects, our research demonstrates that apamin exhibits potent antimicrobial properties when genetically expressed in Drosophila. The antimicrobial efficacy of apamin is independent of its disulfide bonds and is enhanced when the peptide is membrane-tethered. This expression selectively targets and inhibits specific harmful bacterial species, such as Pseudomonas aeruginosa, Enterococcus faecalis, and Escherichia coli, while promoting beneficial bacteria like Lactobacillus plantarum thereby improving the gut microbiome. The antimicrobial activity of apamin is localized to the gut and is associated with increased proliferation of intestinal stem cells, acidification of the midgut pH, and activation of enteroendocrine cell calcium signaling. Furthermore, apamins antimicrobial function is dependent on specific peptidoglycan recognition proteins, with PGRP-LA and PGRP-SCs being essential. Apamin expression alone is sufficient to restore the integrity of the gut barrier compromised by stressed conditions. Ultimately, apamin supplementation enhances honeybee gut health, particularly in the presence of ingested bacteria. The expression of other honeybee antimicrobial peptides also significantly reduces bacterial infection in flies. Overall, our study provides a comprehensive understanding of the molecular function and regulation of honeybee venom peptides and antimicrobial peptides, utilizing the Drosophila model system to unravel their mechanisms of action and therapeutic potential.

immunology↗

bioRxiv2024

Insights into the foraging Gene's Influence on Mating Investments of Male Drosophila

The foraging gene is a key genetic factor that modulates social behavior in insects, primarily by governing the trade-off between individual foraging and group-related activities. It has been associated with various behaviors associated with food search and resource exploitation, thereby playing a crucial role in determining the efficiency of foraging and the overall success of the collective. In this study, we investigate the critical role of the foraging gene in mediating complex interval timing behaviors, particularly mating duration, in the fruit fly Drosophila melanogaster. By examining two distinct variant phenotypes, rover and sitter, we observe specific deficiencies in longer (LMD) and shorter mating duration (SMD) behaviors, respectively, suggesting the genes crucial influence on these interval timing mechanisms. Utilizing single-cell RNA sequencing and knockdown experiments, we identify the genes significant expression in key neurons involved in learning and memory. However, its impact on mating duration is not observed in these brain regions. Instead, our data reveal the genes crucial role in specific neurons expressing Pdfr, a critical regulator of circadian rhythms. Furthermore, the study uncovers sexually dimorphic expression patterns in the brain and highlights the necessity of the genes dosage in specific cell populations within the ellipsoid body for normal mating duration. These findings underscore the foraging genes pivotal role in mediating complex interval timing behaviors in Drosophila, providing valuable insights into the intricate interplay between genetics, environment, and behavior. This research contributes to a deeper understanding of the genetic and neural mechanisms underlying complex interval timing behaviors, with broader implications for unraveling the function of foraging gene.

neuroscience↗

bioRxiv2024

Peptidergic neurons with extensive branching orchestrate the internal states and energy balance of male Drosophila melanogaster.

Neuropeptide SIFamide (SIFa) neurons in Drosophila melanogaster have been characterized by their exceptionally elaborate arborization patterns, which extend from the brain into the ventral nerve cord (VNC). SIFa neurons are equipped to receive signals that integrate both internal physiological cues and external environmental stimuli. These signals enable the neurons to regulate energy balance, sleep patterns, metabolic status, and circadian timing. These peptidergic neurons are instrumental in orchestrating the animals internal states and refining its behavioral responses, yet the precise molecular underpinnings of this process remain elusive. Here we demonstrate that SIFa neurons coordinate a range of behavioral responses by selectively integrating inputs and outputs in a context-dependent manner. These neurons engage in a feedback loop with sNPF neurons in the ventral nerve cord, modifying behaviors such as long mating duration (LMD) and shorter mating duration (SMD). Furthermore, SIFa neurons receive essential inputs from neuropeptides Dsk, sNPF, and dilp2, which regulate interval timing behaviors. Activating SIFa neurons leads to reduced mating duration and increased food intake, while deactivating them reduces food intake. Overall, these findings demonstrate the importance of SIFa neurons in absorbing inputs and turning them into behavioral outputs, shedding light on animals intricate behavioral orchestration.

neuroscience↗

bioRxiv2024

Long-range neuropeptide relay as a central-peripheral communication mechanism for the context-dependent modulation of interval timing behaviors.

Neuropeptides play crucial roles in regulating context-dependent behaviors, but the underlying mechanisms remain elusive. We investigate the role of the neuropeptide SIFa and its receptor SIFaR in regulating two distinct mating duration behaviors in male Drosophila: Longer-Mating-Duration (LMD) and Shorter-Mating-Duration (SMD). We found that SIFaR expression in specific neurons is required for both LMD and SMD behaviors. Social context and sexual experience lead to synaptic reorganization between SIFa and SIFaR neurons, altering internal states of brain. We revealed that the SIFa-SIFaR/Crz-CrzR neuropeptide relay pathway is essential for generating distinct interval timing behaviors, with Crz neurons being responsive to the activity of SIFa neurons. Additionally, CrzR expression in non-neuronal cells is critical for regulating LMD and SMD behaviors. Our study provides insights into how neuropeptides and their receptors modulate context-dependent behaviors through synaptic plasticity and calcium signaling, with implications for understanding the neural circuitry underlying interval timing and neuropeptidergic system modulation of behavioral adaptations.

neuroscience↗

bioRxiv2024

Immunotherapy-related cognitive impairment after CAR T cell therapy in mice

Persistent central nervous system (CNS) immune dysregulation and consequent dysfunction of multiple neural cell types is central to the neurobiological underpinnings of a cognitive impairment syndrome that can occur following traditional cancer therapies or certain infections. Immunotherapies have revolutionized cancer care for many tumor types, but the potential long-term cognitive sequelae are incompletely understood. Here, we demonstrate in mouse models that chimeric antigen receptor (CAR) T cell therapy for both CNS and non-CNS cancers can impair cognitive function and induce a persistent CNS immune response characterized by white matter microglial reactivity and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis are disrupted. Microglial depletion rescues oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function. Taken together, these findings illustrate similar mechanisms underlying immunotherapy-related cognitive impairment (IRCI) and cognitive impairment following traditional cancer therapies and other immune challenges.

neuroscience↗