Biology subjects

Choi, S.

Publications and source records attributed to Choi, S..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

Strain-specific differences in toxT expression and virulence gene activation in Vibrio cholerae

The transcriptional activator ToxT is a key regulator of Vibrio cholerae virulence, controlling the expression of cholera toxin (CT) and the toxin co-regulated pilus (TCP). Insights into the regulation and function of toxT have largely come from studies on the classical biotype strain O395, which exhibits robust toxT expression. However, toxT expression is not fully consistent across V. cholerae strains. Here, we show that toxT transcription and protein production differ significantly among strains, particularly in El Tor biotype, which exhibit allele-dependent regulatory constraints. Using qRT-PCR and Western blotting, we demonstrate that alternative toxT alleles confer distinct transcriptional activator functions across El Tor biotype strains. Notably, IB5230, a pandemic El Tor strain, exhibits enhanced toxT and virulence gene expression even at 37{degrees}C, suggesting a potential adaptation for increased pathogenicity. Our results suggest that toxT autoregulatory feedback plays a more critical role in virulence gene activation than previously recognized. This study underscores previously unrecognized complexity in toxT regulation, emphasizing the need to reassess virulence control mechanisms in epidemic and emerging V. cholerae strains. Understanding these strain-specific differences is essential for refining models of cholera pathogenesis. Author SummaryCholera is a severe diarrheal disease caused by the bacterium Vibrio cholerae, which continues to pose a major threat to global health. The ability of V. cholerae to cause disease depends on the expression of two key virulence factors--cholera toxin (CT) and the toxin-coregulated pilus(TCP)-- controlled by the transcriptional activator ToxT. While much of our understanding of ToxT regulation is based on classical biotype strains, most recent cholera outbreaks have been driven by El Tor biotype strains. In this study, we demonstrate that toxT expression and its ability to activate virulence genes vary markedly across V. cholerae strains, depending on both the specific toxT allele and the genetic background. Using isogenic strains engineered to express different toxT alleles, we show that some alleles are transcriptionally silent in certain El Tor strains while others are active, despite having similar functional capabilities when expressed. Notably, a hypervirulent strain linked to the Haitian cholera outbreak maintained high toxT expression even at human body temperature, hinting at possible adaptive mechanisms for enhanced pathogenicity. Our findings suggest that virulence regulation in V. cholerae may be more variable than previously recognized, highlighting strain- and allele-specific differences in toxT expression. Understanding these strain- and allele-specific differences in virulence gene regulation is crucial for improving models of cholera pathogenesis and could inform the development of more effective interventions and vaccines against this evolving pathogen.

microbiology↗

bioRxiv2025

PACAP Signaling Network in the Nucleus Accumbens Core Regulates Reinstatement Behavior in Rat

Cocaine use disorder (CUD) lacks FDA-approved treatments, partly due to the difficulty of creating therapeutics that target behavior-related neural circuits without disrupting signaling throughout the brain. Recent evidence highlights the therapeutic potential of targeting gut-brain axis components, such as GLP-1 receptors, to modulate neural circuits with minimal central nervous system disruption. Like GLP-1, pituitary adenylate cyclase polypeptide (PACAP) is a component of the gut-brain axis that regulates behavior through a network spanning the gut and brain. Here, we investigated the potential existence and function of an endogenous PACAP signaling network within the nucleus accumbens core (NAcc), which is a structure that integrates emotional, cognitive, and reward processes underlying behavior. We found that PACAP and its receptor, PAC1R, are endogenously expressed in the rat NAcc and that PACAP mRNA is present in medial prefrontal cortical projections to the NAcc. Behaviorally, intra-NAcc infusions of PACAP (100 pm) did not induce seeking behavior but blocked cocaine-primed reinstatement (10 mg/kg, IP). Intra-NAcc PACAP also inhibited reinstatement driven by co-infusion of the D1 receptor agonist (SKF 81297, 3 {micro}g) but not the D2 receptor agonist (sumanirole, 10 ng). These findings are significant since D1 and D2 receptor activities in the NAcc govern distinct behavioral mechanisms indicating precise actions of PACAP even within the NAcc. Future research should examine whether NAcc PACAP signaling can be selectively engaged by peripheral gut-brain axis mechanisms, potentially unveiling novel therapeutic approaches for CUD and related disorders.

neuroscience↗

bioRxiv2025

SYSTEM XC- AS A MOLECULAR MECHANISM FOR EVOLUTIONARY NEW FORMS OF ADVANCED COGNITION

Human cognitive abilities are deeply rooted in evolutionary building blocks that maximize computation while maintaining efficiency. These abilities are not without evolutionary signatures; conserved processes like vision have undergone continual phylogenetic adjustments to better serve ecological niches. Conversely, more sophisticated forms of cognition may have required evolutionary innovations to transform existing neuronal processing to expand computational abilities. One such innovation is system xc- (Sxc), a cystine-glutamate antiporter predominantly localized to astrocytes that emerged in deuterostomes (e.g., vertebrates) after their divergence from protostomes over 550 million years ago. Previous evidence suggests that genetically modified rats that lack functional Sxc (MSxc) exhibit enhanced cocaine-seeking behavior. In this study, we deconstructed drug-seeking into its component behaviors, categorizing them as reliant on evolutionary conserved or newly evolved cognitive processes. Our results reveal that Sxc function is dispensable for conserved processes like visual, emotional, and hedonic processing, but critical for advanced, evolutionary new cognitive functions, particularly impulse control and decision making. Notably, we demonstrate a temporally specific reliance on Sxc during the learning phase of optimal decision-making, but not in maintaining established strategies. This is an important addition to our current understanding of astrocytes in non-homeostatic functions, indicating their critical role in computationally demanding phases of learning and memory. Unraveling evolutionary innovations like Sxc not only deepens our understanding of cognitive evolution but also paves the way for revolutionary, precision- targeted therapies in neuropsychiatric disorders, potentially transforming treatment paradigms and patient outcomes.

neuroscience↗

bioRxiv2025

3D Bioprinting of Kidney Tissue Using a Photocrosslinkable Hydrogel Derived from Decellularized Extracellular Matrix

Three-dimensional bioprinting has emerged as a promising strategy in tissue engineering, aiming to fabricate functional tissue constructs for organ regeneration. A critical challenge in this field is the development of organ-specific bioinks that can provide a microenvironment conducive to cellular growth and differentiation. In this study, we successfully developed a photocrosslinkable bioink by methacrylating decellularized porcine kidney extracellular matrix. The decellularization process effectively removed all cellular components while preserving the native kidney extracellular matrix composition. The resulting methacrylated decellularized extracellular matrix bioink exhibited optimal rheological properties, making it well-suited for digital light processing based stereolithography and piston-driven extrusion bioprinting. Human embryonic kidney cells encapsulated in the bioink showed high viability and a strong proliferative capacity, indicating potential for tissue-specific maturation over time. This work demonstrates the feasibility of utilizing kidney-specific decellularized extracellular matrix-based bioinks, providing a platform for engineering renal tissue constructs for therapeutic applications.

bioengineering↗

bioRxiv2025

Astrocytic MAOB-GABA axis as a molecular brake on repair following spinal cord injury

Neuroregeneration and remyelination rarely occur in the adult mammalian brain and spinal cord following central nervous system (CNS) injury. The glial scar has been proposed as a major contributor to this failure in the regenerative process. However, its underlying molecular and cellular mechanisms remain unclear. Here, we report that monoamine oxidase B (MAOB)-dependent excessive GABA release from reactive astrocytes suppresses CNS repair system by reducing BDNF and TrkB expression in severe spinal cord injury (SCI) animal models. Genetic deletion of MAOB in a mouse SCI model promotes both functional and tissue recovery. Notably, the selective MAOB inhibitor, KDS2010, facilitates recovery and regeneration by disinhibiting the BDNF-TrkB axis in a rat SCI model. Its dose-dependent effects were further validated in a monkey SCI model. Moreover, KDS2010 demonstrates a tolerable safety profile and dose-proportional pharmacokinetics in healthy humans during a phase 1 clinical trial. Our findings identify the astrocytic MAOB-GABA axis as a crucial molecular and cellular brake on CNS repair system following SCI and highlight translational potential of KDS2010 as a promising therapeutic candidate for SCI treatment.

neuroscience↗

bioRxiv2024

Ipflufenoquin, Novel Dihydroorotate Dehydrogenase Inhibitor: Efficacy Against Strawberry Diseases and Docking Simulations via AlphaFold2 and Autodock Vina

In 2023, fungal diseases, including Botrytis cinerea (gray mold), were isolated from various strawberry fields in Korea. Ipflufenoquin, a novel class 2 dihydroorotate dehydrogenase (DHODH) inhibitor, was applied to plant pathogenic fungal species. EC50 values indicated that ipflufenoquin achieved high sensitivity in B. cinerea while maintaining broad-spectrum activity against other fungi. Fruit and greenhouse trials confirmed its robust efficacy in gray mold diseases, including those resistant to conventional fungicides like pyraclostrobin, fluxapyroxad, and benomyl. However, the ipflufenoquin application was less effective against fungal pathogens like blossom blight and Rhizopus rot, causing shifts in the fungal community and allowing less sensitive species to emerge. Structural prediction using Alphafold2 and molecular docking simulation showed ipflufenoquin was bound to the quinone binding tunnel in DHODH and highlighted the correlation between protein-ligand binding affinity and fungicide susceptibility, with species showing higher affinities being more sensitive. This study is the first to report sensitivity of strawberry fungal species to ipflufenoquin, and this fungicide is recommended in strawberry farms against gray mold disease. Additionally, we conducted in silico predictions of fungicide sensitivity across various plant pathogenic fungi using Alphafod2 and Autodock Vina. This establishes a foundation for future computational analyses to predict the effectiveness of fungicides, offering important baseline data to enhance fungicide management strategies.

microbiology↗

bioRxiv2024

Resolving the design principles that control postnatal vascular growth and scaling

After birth, tissues grow continuously until reaching adult size, with each organ exhibiting unique cellular dynamics, growth patterns, and (stem or non-stem) cell sources. Using a suite of experimental and computational multiscale approaches, we found that aortic expansion is guided by specific biological principles and scales with the vertebral column rather than animal body weight. Expansion proceeds via two distinct waves of arterial cell proliferation along blood flow that are spatially stochastic, yet temporally coordinated. Each wave exhibits unique cell cycle kinetics and properties, with the first wave exhibiting cell cycle durations as fast as 6 hours. Single-cell RNA sequencing showed changes in fatty acid metabolism concomitant with an increase in cell size. Mathematical modeling and experiments indicated endothelial cell extrusion is essential for homeostatic aortic growth and balancing excess proliferation. In a genetic model of achondroplasia, the aorta achieves proper scaling through enhanced cell extrusion while maintaining normal proliferation dynamics. Collectively, these results provide a blueprint of the principles that orchestrate aortic growth which depends entirely on differentiated cell proliferation rather than resident stem cells.

developmental biology↗

bioRxiv2024

Comparing alpha-synuclein-interactomes between multiple systems atrophy and Parkinsons disease reveals unique and shared pathological features.

IntroductionPrimary synucleinopathies, such as Parkinsons disease (PD), Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are neurodegenerative disorders with some shared clinical and pathological features. Aggregates of alpha-synuclein (syn) phosphorylated at serine 129 (PSER129) are the hallmark of synucleinopathies, which for PD/DLB are found predominantly in neurons (Neuronal cytoplasmic inclusions "NCIs"), but for MSA, aggregates are primarily found in oligodendroglia (Glial cytoplasmic inclusions "GCIs"). It remains unclear if the distinct pathological presentation of PD/DLB and MSA are manifestations of distinct or shared pathological processes. We hypothesize that the distinct synucleinopathies MSA and PD/DLB share common molecular features. MethodsUsing the in-situ proximity labeling technique biotinylation by antibody recognition (BAR), we compare aggregated syn-interactomes (BAR-PSER129) and total syn-interactomes (BAR-MJFR1) between MSA (n=5) and PD/DLB (n=10) in forebrain and midbrain structures. ResultsFor BAR-PSER129 and BAR-MJFR1 captures, syn was the most significantly enriched protein in PD/DLB and MSA. In PD/DLB, BAR-PSER129 identified 194 syn-aggregate-interacting proteins, while BAR-MJFR1 identified 245 syn interacting proteins. In contrast, in the MSA brain, only 38 and 175 proteins were identified for each capture, respectively. When comparing MSA and PD/DLB, a high overlap (59.5%) was observed between BAR-MJFR1 captured proteins, whereas less overlap (14.4%) was observed for BAR-PSER129. Direct comparison between MSA and PD/DLB revealed 79 PD/DLB-associated proteins and only three MSA-associated proteins (CBR1, CRYAB, and GFAP). Pathway enrichment analysis revealed PD/DLB interactions were dominated by vesicle/SNARE-associated pathways, in contrast to MSA, which strongly enriched for metabolic/catabolic, iron, and cellular oxidant detoxification pathways. A subnetwork of cytosolic antioxidant enzymes called peroxiredoxins drove cellular detoxification pathways in MSA. A common network of 26 proteins, including neuronal-specific proteins (e.g., SNYGR3) with HSPA8 at the core, was shared between MSA and DLB/PD. Extracellular exosome pathways were universally enriched regardless of disease or BAR target protein. ConclusionSynucleinopathies have divergent and convergent syn-aggregate interactions, indicating unique and shared pathogenic mechanisms. MSA uniquely involves oxidant detoxification processes in glial cells, while vesicular processes in neurons dominate PD/DLB. Shared interactions, specifically SNYGR3 (i.e., a neuronal protein), between MSA and PD/DLB suggest neuronal axons origin for both diseases. In conclusion, we provide syn aggregates protein interaction maps for two distinct synucleinopathies.

neuroscience↗

bioRxiv2024

Elongation factor P controls ribosomal frameshift of a Salmonella antimicrobial resistance gene

Ribosomes translate mRNAs by matching every 3-nucleotide sequence in mRNA, producing the corresponding proteins. As the amino acid sequence directly dictates the activity of the protein, frameshifts often lead to unexpected effects. Here, ribosome profiling reveals that the intracellular pathogen Salmonella Typhimurium suppresses frameshift in the ugtL antimicrobial resistance gene during translation. This suppression of frameshift is mediated by a ribosome pause occurring in a newly-identified overlapping gene, serving as a non-slip bump. Given that the pause site contains a poly-proline motif and can be resolved by elongation factor P, the removal of the ribosome pause by substituting the motif induces ribosome slippage in ugtL, resulting in UgtL frameshifted protein production. This renders Salmonella sensitive to antimicrobial peptides but, in turn, protects the MgtC virulence factor from the FtsH-mediated proteolysis, indicating that elongation factor P-dependent ribosome pause is required for controlling both full antimicrobial resistance and mouse virulence. These findings reveal a new regulatory mechanism in which ribosome pause controls the production of two different protein isoforms by suppressing ribosome slippage-mediated frameshift.

microbiology↗

bioRxiv2024

Ongoing genome doubling promotes evolvability and immune dysregulation in ovarian cancer

Whole-genome doubling (WGD) is a critical driver of tumor development and is linked to drug resistance and metastasis in solid malignancies. Here, we demonstrate that WGD is an ongoing mutational process in tumor evolution. Using single-cell whole-genome sequencing, we measured and modeled how WGD events are distributed across cellular populations within tumors and associated WGD dynamics with properties of genome diversification and phenotypic consequences of innate immunity. We studied WGD evolution in 65 high-grade serous ovarian cancer (HGSOC) tissue samples from 40 patients, yielding 29,481 tumor cell genomes. We found near-ubiquitous evidence of WGD as an ongoing mutational process promoting cell-cell diversity, high rates of chromosomal missegregation, and consequent micronucleation. Using a novel mutation-based WGD timing method, doubleTime, we delineated specific modes by which WGD can drive tumor evolution: (i) unitary evolutionary origin followed by significant diversification, (ii) independent WGD events on a pre-existing background of copy number diversity, and (iii) evolutionarily late clonal expansions of WGD populations. Additionally, through integrated single-cell RNA sequencing and high-resolution immunofluorescence microscopy, we found that inflammatory signaling and cGAS-STING pathway activation result from ongoing chromosomal instability and are restricted to tumors that remain predominantly diploid. This contrasted with predominantly WGD tumors, which exhibited significant quiescent and immunosuppressive phenotypic states. Together, these findings establish WGD as an evolutionarily active mutational process that promotes evolvability and dysregulated immunity in late stage ovarian cancer.

cancer biology↗

bioRxiv2024

A HigB-like toxin promotes non-replicating Salmonella inside macrophages by inhibiting ribonuclease III

Many bacteria are often resistant to antibiotic treatment because they can slow down their growth rate, thereby attenuating the drugs effectiveness. A similar growth-rate control is observed in pathogens that infect and persist inside their hosts. The bacterial toxin-antitoxin (TA) system serves as a non-heritable phenotypic switch by slowing down growth through the expression of a toxin component. Here, we investigated a HigB-like type II toxin from the intracellular bacterial pathogen Salmonella Typhimurium. Unlike other HigB-like toxins that cleave ribosome-bound mRNAs, it does not exhibit endoribonuclease activity. Instead, it inhibits ribonuclease III, which mediates the initial cleavage for rRNA processing, by directly binding to the dsRNA-binding domain of RNase III, thereby decreasing ribosome assembly and bacterial growth. Given that the formation of HigB-like toxin-mediated non-replicating Salmonella within macrophages is RNase III-dependent, persister formation by inhibiting RNase III is a newly identified strategy for pathogens to survive within host cells.

microbiology↗

bioRxiv2024

C-LTMRs mediate wet dog shakes via the spinoparabrachial pathway

Mammals perform rapid oscillations of their body- "wet dog shakes" -to remove water and irritants from their back hairy skin. The somatosensory mechanisms underlying this stereotypical behavior are unknown. We report that Piezo2-dependent mechanosensation mediates wet dog shakes evoked by water or oil droplets applied to hairy skin of mice. Unmyelinated low-threshold mechanoreceptors (C-LTMRs) were strongly activated by oil droplets and their optogenetic activation elicited wet dog shakes. Ablation of C-LTMRs attenuated this behavior. Moreover, C-LTMRs synaptically couple to spinoparabrachial (SPB) neurons, and optogenetically inhibiting SPB neuron synapses and excitatory neurons in the parabrachial nucleus impaired both oil droplet- and C-LTMR-evoked wet dog shakes. Thus, a C-LTMR- spinoparabrachial pathway mediates wet dog shakes for rapid and effective removal of foreign particles from back hairy skin.

neuroscience↗

bioRxiv2024

Regulation of dopamine release by tonic activity patterns in the striatal brain slice

Voluntary movement, motivation, and reinforcement learning depend on the activity of ventral midbrain neurons that extend axons to release dopamine (DA) in the striatum. These neurons exhibit two patterns of action potential activity: a low-frequency tonic activity that is intrinsically generated and superimposed high-frequency phasic bursts that are driven by synaptic inputs. Ex vivo acute striatal brain preparations are widely employed to study the regulation of evoked DA release but exhibit very different DA release kinetics than in vivo recordings. To investigate the relationship between phasic and tonic neuronal activity, we stimulated the slice in patterns intended to mimic tonic activity, which were interrupted by a series of burst stimuli. Conditioning the striatal slice with low-frequency activity altered DA release triggered by high-frequency bursts and produced kinetic parameters that resemble those in vivo. In the absence of applied tonic activity, nicotinic acetylcholine receptor and D2 dopamine receptor antagonists had no significant effect on neurotransmitter release driven by repeated burst activity in the striatal brain slice. In contrast, in tonically stimulated slices, D2 receptor blockade decreased the amount of DA released during a single burst and facilitated DA release in subsequent bursts. This experimental system provides a means to reconcile the difference in the kinetics of DA release ex vivo and in vivo and provides a novel approach to more accurately emulate pre- and post-synaptic mechanisms that control axonal DA release in vivo. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/595411v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@e9412corg.highwire.dtl.DTLVardef@1b5cce4org.highwire.dtl.DTLVardef@9ebabforg.highwire.dtl.DTLVardef@f66982_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

The cochlear hook region detects harmonics beyond the canonical hearing range

Ultrasound, or sound at frequencies exceeding the conventional range of human hearing, is not only audible to mice, microbats, and dolphins, but also creates an auditory sensation when delivered through bone conduction in humans. Although ultrasound is utilized for brain activation and in hearing aids, the physiological mechanism of ultrasonic hearing remains unknown. In guinea pigs, we found that ultrasound above the hearing range delivered through ossicles of the middle ear evokes an auditory brainstem response and a mechano-electrical transduction current through hair cells, as shown by the local field potential called the cochlear microphonic potential (CM). The CM synchronizes with ultrasound, and like the response to audible sounds is actively and nonlinearly amplified. In vivo optical nano-vibration analysis revealed that the sensory epithelium in the hook region, the basal extreme of the cochlear turns, resonates in response both to ultrasound within the hearing range and to harmonics beyond the hearing range. The results indicate that hair cells can respond to stimulation at the optimal frequency and its harmonics, and the hook region detects ultrasound stimuli with frequencies more than two octaves higher than the upper limit of the ordinary hearing range.

physiology↗

bioRxiv2024

Assessing Long-Term Stored Tissues for Multi-Omics Data Quality and Proteogenomics Suitability

As research into the complexities of cancer biology deepens, the integration of multi-omics analyses has emerged as a powerful approach to unravel the complex molecular basis of cancers. However, challenges related to sample availability, including size, collection procedures, and storage duration, hinder the broad application of this methodology. Despite these limitations, there is a growing interest in exploring the potential of archived samples to expand the scope of multi-omics research. Our study aims to investigate the impact of storage duration on the measurment in genomic, transcriptomic, and proteomic profiles of archived samples, demonstrating their viability for advancing our understanding of cancer biology. To comprehensively address these trends and limitations, we systematically examined archived samples collected over a decade, focusing on their transcriptomic, proteomic, and phosphoproteomic attributes. Analysis revealed intricate patterns and dynamic shifts, especially in long-term transcriptomic data, with observed declines in read counts related to protein coding and gene coverage. However, these changes did not compromise the fundamental gene expression landscape. Proteomic result also demonstrated that storage period did not significantly influence proteomic measurement. Comparisons of housekeeping gene (HKG) and housekeeping protein (HKP) expressions unveiled consistent transcriptomic levels across samples, while distinctive proteomic disparities between tumor and normal tissues. In conclusion, the challenges posed by limited sample availability in multi-omics studies can be partially overcome through the strategic integration of archived samples. While technical shifts were evident in certain aspects of transcriptomic data, core gene expression patterns remained robust, and the functionality of essential transcription factors (TFs) and kinases remained unaffected. These findings underscore the potential of archived samples as valuable resources for multi-omics research, providing a broader landscape for investigating cancer biology and paving the way for more comprehensive insights into this intricate field.

cancer biology↗

bioRxiv2024

Mechanisms of genomic instability dictate cytosolic DNA composition and dendritic cell mediated anti-tumor immunity

Patients with microsatellite instable (MSI) colorectal cancers (CRC) face better prognosis than those with the more common chromosomal instable (CIN) subtype due to improved anti-tumor immune responses characterized by high cytotoxic T cell infiltration. Previous investigation identified the cytosolic DNA (cyDNA) sensor STING as necessary for chemokine-mediated T cell recruitment in MSI CRCs. Here, we find cyDNA from MSI CRC cells is inherently more capable of inducing STING activation and induces improved cytotoxic T cell activation by dendritic cells (DCs). Sequencing indicates MSI cyDNA is enriched for microsatellites, which upon DC uptake induce anti-tumor immunity in a manner consistent with clinical MSI CRCs. Radiation also modulates cyDNA stimulation capacity through larger cyDNA size and increased mitochondrial DNA content. Identifying highly stimulatory cyDNA arising from genomic instability such as in MSI CRCs allows for optimized development of DNA-based STING agonist therapies to improve responses of CIN CRC patients to immunotherapies.

cancer biology↗

bioRxiv2024

AIBP controls amyloid beta induced TLR4 inflammarafts and mitochondrial dysfunction in microglia

Microglia-driven neuroinflammation plays an important role in the development of Alzheimers disease (AD). Microglia activation is accompanied by the formation and chronic maintenance of TLR4 inflammarafts, defined as enlarged and cholesterol-rich lipid rafts serving as an assembly platform for TLR4 dimers and complexes of other inflammatory receptors. The secreted apoA-I binding protein (APOA1BP or AIBP) binds TLR4 and selectively targets cholesterol depletion machinery to TLR4 inflammaraft expressing inflammatory, but not homeostatic microglia. Here we demonstrated that amyloid-beta (A{beta}) induced formation of TLR4 inflammarafts in microglia in vitro and in the brain of APP/PS1 mice. Mitochondria in Apoa1bp-/- APP/PS1 microglia were hyperbranched and cupped, which was accompanied by increased ROS and the dilated ER. The size and number of A{beta} plaques and neuronal cell death were significantly increased, and the animal survival was decreased in Apoa1bp-/- APP/PS1 compared to APP/PS1 female mice. These results suggest that AIBP exerts control of TLR4 inflammarafts and mitochondrial dynamics in microglia and plays a protective role in AD associated oxidative stress and neurodegeneration.

neuroscience↗

bioRxiv2024

Reverse engineering placebo analgesia

Placebo analgesia is a widely observed clinical phenomenon. Establishing a robust mouse model of placebo analgesia is needed for careful dissection of the underpinning circuit mechanisms. However, previous studies failed to observe consistent placebo effects in rodent models of chronic pain. We wondered whether strong placebo analgesia can be reverse engineered using general anesthesia-activated neurons in the central amygdala (CeAGA) that can potently suppress pain. Indeed, in both acute and chronic pain models, pairing a context with CeAGA-mediated pain relief produced robust context-dependent analgesia, exceeding that induced by morphine in the same paradigm. We reasoned that if the analgesic effect was dependent on reactivation of CeAGA neurons by conditioned contextual cues, the analgesia would still be an active treatment, rather than a placebo effect. CeAGA neurons indeed receive monosynaptic inputs from temporal lobe areas that could potentially relay contextual cues directly to CeAGA. However, in vivo imaging showed that CeAGA neurons were not re-activated in the conditioned context, despite mice displaying a strong analgesic phenotype, supporting the notion that the cue-induced pain relief is true placebo analgesia. Our results show that conditioning with activation of a central pain-suppressing circuit is sufficient to engineer placebo analgesia, and that purposefully linking a context with an active treatment could be a means to harness the power of placebo for pain relief.

neuroscience↗