Biology subjects

Nagai, Y.

Publications and source records attributed to Nagai, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Ile35 residue of SOD1 plays a key role in aggregate formation and eye degeneration in a Drosophila model of ALS

{middle dot}The pathophysiology of ALS caused by mutant SOD1 remains unclear. {middle dot}We previously demonstrated, using the BioID2-EGFP sandwich expression system in cultured cells, that the Ile35 residue of ALS-linked mutant SOD1 promotes its aggregate formation. {middle dot}However, the precise role of the SOD1 Ile35 residue in aggregate formation and neurodegeneration in vivo remained unclear. {middle dot}Drosophila expressing BioID2-G93A-EGFP demonstrated aggregate formation and eye degeneration with reduced eye size, whereas those expressing BioID2-G93A/I35S-EGFP showed less of these phenotypes. {middle dot}These findings highlight the crucial role of the Ile35 residue of ALS-linked SOD1 in aggregate formation and neurodegeneration in vivo.

neuroscience↗

bioRxiv2026

Autonomic challenge uncovers hidden link between diastolic blood pressure and mental imagery vividness

Mental imagery is viewed as a fundamental component of human cognition, supporting memory, emotional processing, future simulation, and conscious experience. Although mental imagery vividness has traditionally been attributed to differences in sensory processing, emerging evidence suggests that internally generated images are also shaped by ongoing bodily and interoceptive signals. Here, we investigated whether cardiovascular physiology contributes to individual differences in mental imagery vividness using a virtual reality paradigm in which participants encoded and reconstructed emotional and neutral scenes during a tilt-table-induced autonomic challenge. Acute autonomic changes induced by a tilt table did not alter imagery vividness. However, elevated diastolic blood pressure during the tilt-up condition predicted reduced mental imagery vividness, with the strongest effects observed for disgust and neutral imagery. Our findings provide direct evidence that the vividness of the "minds eye" is linked to cardiovascular physiology and support interoceptive accounts of consciousness in which mental imagery emerges from dynamic interactions between neural and bodily systems. More broadly, these results identify cardiovascular function as a potential physiological contributor to altered imagery experiences, including those observed in aphantasia and related clinical conditions. Significance statementVisual mental imagery has traditionally been explained as a top-down process driven by the brain. We investigated whether bottom-up physiological signals from the cardiovascular system also contribute to imagery vividness. An autonomic challenge revealed a hidden relationship between diastolic blood pressure and the vividness of emotional mental imagery, indicating that ongoing cardiovascular signals influence internally generated visual experiences. These findings identify bottom-up autonomic physiology as a previously unrecognized contributor to mental imagery and broaden current understanding of how top-down and bottom-up processes interact to shape conscious mental imagery experience.

neuroscience↗

bioRxiv2026

How the Body Shapes the Mind's Eye: Cardiac vagal reactivity predicts visual imagery vividness

Mental imagery is known to be accompanied by autonomic responses, traditionally viewed as merely downstream consequences of imagery. Recent theoretical work has challenged this view, proposing that mental imagery requires the integration of cortical sensory representations with ascending interoceptive signals supplied by the autonomic nervous system. These two views make opposite predictions: if autonomic activity is only a consequence of imagery, then the responsiveness of the autonomic nervous system should not predict imagery vividness. If instead autonomic input shapes the generation of mental images, individuals with greater autonomic responsiveness should experience more vivid imagery. The present study tested these competing predictions by examining whether individual differences in cardiac vagal reactivity predict self-reported visual imagery vividness, with imagery assessed at a separate time point from the paced breathing protocol. Cardiac vagal reactivity significantly predicted VVIQ scores after controlling for factors such as resting HRV, respiratory amplitude, age and negative affect (b = 13.75, p = .022; model R2 = 0.12), whereas neither baseline HRV nor fast-breathing evoked HRV change were linked to imagery, suggesting the effect is specific to the capacity to enter a high parasympathetic state rather than reflecting general autonomic capacity. Self-reported interoceptive noticing (MAIA Noticing) was significantly associated with both delta HRV and VVIQ, suggesting that cardiac vagal reactivity and imagery vividness are linked through a broader individual difference in interoceptive function. These findings indicate that the vividness of mental imagery is not exclusively central in origin but also appears to be shaped by the capacity of the autonomic nervous system to enter a high parasympathetic state. Imagery thus likely involves bidirectional interaction between cortical and autonomic processes, with descending efferent pathways activating autonomic responses while ascending interoceptive signals contributing to the construction of mental images.

physiology↗

bioRxiv2026

RPL38 controls 60S ribosomal subunit homeostasis to regulate start-codon stringency and frame selection during C9ORF72 RAN translation

Translation initiation depends on stringent start-codon recognition, yet how ribosomal states modulate initiation stringency remains incompletely defined. Repeat-associated non-AUG (RAN) translation is a non-canonical initiation pathway that generates toxic dipeptide repeat proteins in C9ORF72-associated frontotemporal dementia and amyotrophic lateral sclerosis (FTD/ALS). Here, we performed a dual-luciferase reporter-based siRNA screen to identify factors that differentially regulate canonical AUG-initiated and C9ORF72 RAN translation. We identified the 60S ribosomal protein RPL38 as a key determinant of translational output. RPL38 depletion selectively suppressed AUG-dependent translation while relatively preserving near-cognate-initiated RAN translation, resulting in a dose-dependent increase in the RAN-to-AUG translation ratio. Polysome profiling showed a selective reduction in large ribosomal subunit abundance without impaired subunit joining, consistent with defective 60S subunit homeostasis. Substitution of a near-cognate CUG start codon with AUG rendered translation sensitive to RPL38 depletion, supporting a role for ribosomal subunit availability in modulating initiation stringency. Graded RPL38 depletion altered frame usage within C9ORF72 repeat RNA. Consistent with these findings, RPL38 knockdown in the Drosophila eye enhanced GR-frame RAN translation while suppressing canonical AUG-dependent translation. Collectively, these findings identify 60S ribosomal subunit availability as a key determinant of start-codon stringency and frame selection in pathological C9ORF72 RAN translation.

molecular biology↗

bioRxiv2026

Interoceptive autonomic regulation in typical development and autism spectrum disorder: A computational model integrating multiple physiological systems

BackgroundInteroceptive cardiovascular signals, including heart rate (HR) and blood pressure (BP), arise from coordinated sympathetic (SNS) and parasympathetic (PSNS) regulation and contribute to affective and cognitive processes. Although atypical autonomic nervous system (ANS) modulation has been reported in autism spectrum disorder (ASD), the dynamical structure underlying branch-specific coordination remains insufficiently characterized. ObjectiveTo estimate latent ANS regulatory structure in typically developing (TD) and ASD individuals using a computational modeling framework. MethodsA closed-loop computational model integrating cardiovascular, respiratory, and autonomic dynamics was developed. ANS regulation was formalized using three autonomic control modes (coupled reciprocal, coupled nonreciprocal, and uncoupled) and parameterized by the relative activity of SNS and PSNS branches. HR and BP responses to the head-up tilt (HUT) test were simulated, and regulatory surfaces were compared with empirical HR and BP data from TD and ASD groups. Additional simulations under normal respiration, deep respiration, and absence of respiration evaluated mean arterial pressure (MAP) regulation across varying SNS-PSNS activity combinations. ResultsTD individuals exhibited differentiated SNS-PSNS coordination patterns across control modes, whereas ASD individuals showed convergence of relative SNS-PSNS activity. In TD, HR and BP distributions under coupled reciprocal mode were most consistent with expected physiological responses, characterized by high SNS and low PSNS activity during postural challenge. In ASD, empirical data extended toward regions of relatively higher PSNS weighting. Incorporation of deep respiration enhanced MAP reduction during BP recovery, particularly under over-elevated SNS activity. ConclusionThis study provides a mechanistic, state-space characterization of autonomic coordination in TD and ASD populations, enabling inference of latent autonomic regulation from measurable interoceptive phenotypes and identifying respiration as a model-based regulatory lever that augments cardiovascular stabilization.

neuroscience↗

bioRxiv2026

Mechanism of ATXN8OS CTA/CTG repeat-associated non-AUG translation revealed by approaches ranging from cell-free translation to live-cell imaging.

Microsatellite repeat expansions contribute to the pathogenesis of many neurodegenerative disorders. In spinocerebellar ataxia type 8 (SCA8), abnormal expansion of CTA/CTG repeats in the 3' untranslated region of the ATXN8OS (ATXN8 Opposite Strand) gene has been implicated in disease pathology. Although the occurrence of repeat-associated non-AUG (RAN) translation from the ATXN8 transcript has been reported, whether and how RAN translation occurs from the ATXN8OS transcript has remained unexplored. Here, using a cell-free translation system and cultured cells, we showed that ATXN8OS undergoes robust AUG-independent translation in a repeat length-dependent manner. Mechanistic analyses revealed that translation of the poly L (0) frame initiates at a non-AUG codon located upstream of the repeats. Moreover, using live-cell imaging at a single mRNA level, we directly visualized ribosomal -1 frameshifting from the poly L (0) frame to the poly T-poly A (+2) frame during translation elongation. We further showed that ATXN8OS translation was enhanced upon activation of the integrated stress response. Together, these findings establish both the occurrence and the molecular mechanisms of ATXN8OS translation from expanded CTA/CTG repeats and provide insights into the pathogenic processes underlying SCA8. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/700793v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1f836fborg.highwire.dtl.DTLVardef@e1b77forg.highwire.dtl.DTLVardef@d605c3org.highwire.dtl.DTLVardef@11475d9_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Cardio-respiratory coordination during memory encoding predicts performance

Cardiorespiratory coupling (i.e., the phase synchronization between cardiac and respiratory rhythms) varies with physiological state, but whether coupling strength functionally predicts cognitive performance remains unknown. Here we demonstrate that cardiorespiratory coupling predicts trial-level accuracy during the initial formation of mental representations but not during their subsequent retention, revealing temporal specificity in the relationship between bodily rhythms and cognition. We experimentally manipulated coupling via paced breathing (slow: 6 bpm vs. fast: 20 bpm) while participants performed mental imagery and working memory tasks with continuous physiological monitoring. Slow breathing enhanced parasympathetic activity (respiratory sinus arrhythmia), which strengthened baseline cardiorespiratory coupling. This coordinated autonomic state persisted into subsequent cognitive trials, predicting trial-by-trial accuracy specifically during the initial encoding phase when internal representations were actively constructed, but not during subsequent maintenance when representations were sustained. This temporal dissociation indicates that cardiorespiratory coordination selectively predicts performance when the brain constructs internal representations under elevated processing demands. Experimental manipulation of breathing improved behavioral accuracy, validating couplings functional relevance. These findings establish cardiorespiratory coupling as a physiological state marker that reliably predicts encoding success, providing a measurable target for interventions targeting memory and mental representation.

physiology↗

bioRxiv2026

Opposing Autonomic Pathways Link Childhood Trauma to Mental Imagery Deficits

Although childhood trauma alters neurobiological systems supporting emotion regulation and autonomic function, mechanisms linking trauma to mental imagery deficits remain unexplored. Here we examined whether autonomic nervous system symptoms mediate trauma-imagery associations in a general population sample (n = 433). All trauma types showed associations with reduced imagery vividness (r = -.12 to -.23), with emotional neglect and emotional abuse demonstrating the strongest effects. Physical trauma types and emotional abuse correlated with increased autonomic symptoms (r = .35-.38). Parallel mediation analyses revealed that autonomic symptom burden (BPQ ANS subscale), but not anxiety, significantly mediated trauma-imagery relationships through opposing mechanisms. Physical trauma types and emotional abuse showed negative indirect effects through heightened autonomic reactivity, with complete mediation for emotional abuse and physical neglect. In contrast, emotional neglect showed a positive indirect effect through reduced autonomic reactivity (a pattern that emerged when controlling for other trauma types) alongside the strongest direct effect on imagery. These findings demonstrate that childhood trauma impacts mental imagery through distinct autonomic mechanisms--hyperreactive dysregulation for physical/emotional abuse versus hyporeactive blunting for emotional neglect--suggesting autonomic-targeted interventions should be tailored to trauma type.

neuroscience↗

bioRxiv2025

Canonical translation factors eIF1A and eIF5B modulate the initiation step of repeat-associated non-AUG translation.

Nucleotide repeat expansions, such as the GGGGCC repeats in C9orf72, associated with C9-ALS, are linked to neurodegenerative diseases. These repeat sequences undergo a non-canonical translation known as repeat-associated non-AUG (RAN) translation. Unlike canonical translation, RAN translation initiates from non-AUG codons and occurs in all reading frames. To identify potential regulators of RAN translation, we employed a bottom-up approach using a human factor-based reconstituted cell-free translation system to recapitulate RAN translation. This approach revealed that omission of either eIF1A or eIF5B enhanced the translation in all reading frames of C9orf72-mediated RAN translation (C9-RAN), suggesting that eIF1A and eIF5B act as repressors of RAN translation. eIF1A and eIF5B are known to contribute to the fidelity of translation initiation. In HEK293T cells, double knockdown of eIF1A and eIF5B further promoted C9-RAN compared to single knockdowns, indicating that these factors regulate C9-RAN through distinct initiation steps. Furthermore, under eIF1A knockdown conditions, the enhancement of RAN translation via the integrated stress response (ISR) was not observed in HEK293T cells, indicating that eIF1A is involved in the ISR-mediated non-AUG translation. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/654993v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@160e2adorg.highwire.dtl.DTLVardef@1c1cc8forg.highwire.dtl.DTLVardef@5d01d0org.highwire.dtl.DTLVardef@220507_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Establishment of a second-generation transgenic marmoset model of polyglutamine disease recapitulating neurological symptoms and pathology

Neurodegenerative diseases, including polyglutamine diseases, remain a major clinical challenge, partly because of limited animal models that recapitulate human disease. Here, we describe a second-generation transgenic marmoset model of spinocerebellar ataxia 3 (SCA3), a polyglutamine disease, which stably expresses expanded CAG repeats in ATXN3. All five offspring of the founder marmoset harbored the transgene with reduced transgene integration sites and without repeat instability or genetic mosaicism, offering improved construct validity. Three of the five marmosets developed progressive motor impairments that segregated into two distinct phenotypes: early onset with rapid progression and late onset with mild progression, accompanied by corresponding patterns in body weight gain and grip strength. Pathological analysis revealed cerebellar Purkinje cell loss, spinal cord neurodegeneration, and widespread intranuclear inclusions. The severity of motor phenotypes correlated with transgene expression levels in disease-relevant brain regions, including the cerebellum, spinal cord, and striatum. By overcoming the common translational limitations of rodent systems, our second-generation model offers a powerful platform for investigating disease mechanisms and testing potential therapeutic interventions. Our results advance the utility of transgenic marmosets as clinically relevant models of neurodegenerative diseases. Summary StatementSecond-generation transgenic marmoset models of spinocerebellar ataxia 3 replicated the progressive motor deficits and neuropathology of the founder marmoset, providing a powerful platform for studying disease mechanisms and developing therapies.

neuroscience↗

bioRxiv2025

Mother-child autonomic nervous system interaction as an indication of parental stress: 24-hour cross recurrence plot analysis

Mothers and children interact through behaviors and mutual physiological signals. Recent research has suggested that physiological interactions are sensitive biomarkers for parenting challenges such as childcare stress. Most studies have focused on short-term, activity-based interactions. However, few studies have examined longer timescale data, such as interactions containing circadian rhythms, which are closely associated with stress. This study aimed to explore the link between childcare stress and mother-child autonomic nervous system activities in daily interactions using 24-hour at-home data. Cross-recurrence plots were used to quantify interactive patterns to reflect the rich nonlinear dynamics of autonomic nervous system signals and the complex interplay between mothers and children. The relationships between quantified low-dimensional cross-recurrence plot representations and parenting stress were evaluated through multiple regression analysis. The day-to-night mother-child autonomic nervous system patterns, quantified through cross-recurrence plots, significantly predict maternal parenting stress, surpassing the predictions achieved by separately analyzing individual autonomic nervous system activity using recurrence plots.

physiology↗

bioRxiv2025

An anti-amyloidogenic approach to specifically block memory consolidation in mice for therapeutic intervention

Post-traumatic stress disorder (PTSD) is a mental health disorder triggered by the exposure to a traumatic event, which manifests with anguish, intrusive memories, and negative mood changes. So far, there is no efficient treatment for PTSD other than symptomatic palliative care. However, the cytoplasmic polyadenylation element binding protein-3 (CPEB3) has been recently associated to a potential risk gene for PTSD. Considering that CPEB3 protein is a functional amyloid whose importance for long-term memory consolidation in mammals is well established, we propose the active (amyloid) state of CPEB3 as a promising therapeutic target to block the consolidation of traumatic memories through by the anti-amyloidogenic polyglutamine binding peptide 1 (QBP1). Here we report a preclinical development in mice of this pharmacological treatment for PTSD based on the action of the QBP1 peptide. We first characterized the human CPEB3 (hCPEB3) protein in vitro, showing how its amyloid aggregation is inhibited by the active core of QBP1 (QBP1-M8) without affecting other self-assembly processes such as phase separation. Then, we generated and characterized a novel transgenic mouse that constitutively expresses QBP1 in tandem (TgQBP1). TgQBP1 mice have shown that the consolidation of simple learning is impaired after 24 h for both hippocampal-dependent and aversive memories and that it is limited to new learned memories and has no effect on short-term memory. Furthermore, fear induced anxiety was reduced in comparison to WT mice, suggesting that PTSD-like symptoms are also being ameliorated. Intriguingly, we found that aversive memories seem to be more strongly affected in younger mice. Finally, the analysis of CPEB3 amyloid presence in hippocampal extracted samples showed a correlative decrease in murine CPEB3 oligomerization in the TgQBP1 mice. Taking together, these results strongly suggest that the amyloidogenic blockage of CPEB3 by QBP1 peptide is a potential drug for the prevention and treatment of PTSD.

neuroscience↗

bioRxiv2024

Longitudinal assessment of DREADD expression and efficacy in the monkey brain

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) offer a powerful means for reversible control of neuronal activity through systemic administration of inert actuators. Because chemogenetic control relies on DREADD expression levels, understanding and quantifying the temporal dynamics of their expression is crucial for planning long-term experiments in monkeys. In this study, we longitudinally quantified in vivo DREADD expression in macaque monkeys using positron emission tomography with the DREADD-selective tracer [11C]deschloroclozapine (DCZ), complemented by functional studies. Twenty macaque monkeys were evaluated after being injected with adeno-associated virus vectors expressing the DREADDs hM4Di or hM3Dq, whose expression was quantified as changes in [11C]DCZ binding potential from baseline levels. Expression levels of both hM4Di and hM3Dq peaked around 60 days post-injection, remained stable for about 1.5 years, and declined gradually after two years. Significant chemogenetic control of neural activity and behavior persisted for about two years. The presence of protein tags significantly influenced expression levels, with co-expressed protein tags reducing overall expression levels. These findings provide valuable insights and guidelines for optimizing the use of DREADDs in long-term primate studies and potential therapeutic applications.

neuroscience↗

bioRxiv2024

Advancing Clinical Response Against Glioblastoma: Evaluating SHP1705 CRY2 Activator Efficacy in Preclinical Models and Safety in Phase I Trials

BackgroundIt has been reported that circadian clock components, Brain and Muscle ARNT-Like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK), are uniquely essential for glioblastoma (GBM) stem cell (GSC) biology and survival. Consequently, we developed a novel Cryptochrome (CRY) activator SHP1705, which inhibits BMAL1-CLOCK transcriptional activity. MethodsWe analyzed buffy coats isolated from Phase 1 clinical trial subjects blood to assess any changes to circadian, housekeeping, and blood transcriptome-based biomarkers following SHP1705 treatment. We utilized GlioVis to determine which circadian genes are differentially expressed in non-tumor versus GBM tissues. We employed in vitro and in vivo methods to test the efficacy of SHP1705 against patient-derived GSCs and xenografts in comparison to earlier CRY activator scaffolds. Additionally, we applied a novel-REV-ERB agonist SR29065, which inhibits BMAL1 transcription, to determine whether targeting both negative limbs of the circadian transcription-translation feedback loop (TTFL) would yield synergistic effects against various GBM cells. ResultsSHP1705 is safe and well-tolerated in Phase I clinical trials. SHP1705 has increased selectivity for the CRY2 isoform and potency against GSC viability compared to previously published CRY activators. SHP1705 prolonged survival in mice bearing GBM tumors established with GSCs. When combined with the novel REV-ERB agonist SR29065, SHP1705 displayed synergy against multiple GSC lines and differentiated GSCs (DGCs). ConclusionsThese demonstrate the efficacy of SHP1705 against GSCs, which pose for GBM patient outcomes. They highlight the potential of novel circadian clock compounds in targeting GBM as single agents or in combination with each other or current standard-of-care. KEY POINTSO_LISHP1705 is a novel CRY2 activator that has shown success in Phase 1 safety trials C_LIO_LISHP1705 has a significantly improved efficacy against GSCs and GBM PDX tumors C_LIO_LINovel REV-ERB agonist SR29065 and SHP1705 display synergistic effects against GSCs C_LI IMPORTANCE OF THE STUDYCRY2 is decreased in GBM tissues compared to CRY1 suggesting that promoting CRY2 activity will be an efficacious GBM treatment paradigm. SHP1705, a CRY2 activator that has shown success in Phase 1 safety trials, has significantly improved preclinical efficacy. Novel REV-ERB agonist SR29065 displays synergistic effects against diverse GBM cells.

cancer biology↗

bioRxiv2023

Neural correlates of category learning in monkey inferior temporal cortex

We trained two monkeys implanted with multi-electrode arrays to categorize natural images of cats and dogs, in order to observe changes in neural activity related to category learning. We recorded neural activity from area TE, which is required for normal learning of visual categories based on perceptual similarity. Neural activity during a passive viewing task was compared pre- and post-training. After the category training, the accuracy of abstract category decoding improved. Specifically, the proportion of single units with category selectivity increased, and units sustained their category-specific responses for longer. Visual category learning thus appears to enhance category separability in area TE by driving changes in the stimulus selectivity of individual neurons and by recruiting more units to the active network.

neuroscience↗

bioRxiv2023

Distinct roles of monkey OFC-subcortical pathways in adaptive behavior

To be the most successful, primates must adapt to changing environments and optimize their behavior by making the most beneficial choices. At the core of adaptive behavior is the orbitofrontal cortex (OFC) of the brain, which updates choice value through direct experience or knowledge-based inference. Here, we identify distinct neural circuitry underlying these two separate abilities. We designed two behavioral tasks in which macaque monkeys updated the values of certain items, either by directly experiencing changes in stimulus-reward associations, or by inferring the value of unexperienced items based on the tasks rules. Chemogenetic silencing of bilateral OFC combined with mathematical model-fitting analysis revealed that monkey OFC is involved in updating item value based on both experience and inference. In vivo imaging of chemogenetic receptors by positron emission tomography allowed us to map projections from the OFC to the rostromedial caudate nucleus (rmCD) and the medial part of the mediodorsal thalamus (MDm). Chemogenetic silencing of the OFC-rmCD pathway impaired experience-based value updating, while silencing the OFC-MDm pathway impaired inference-based value updating. Our results thus demonstrate a dissociable contribution of distinct OFC projections to different behavioral strategies, and provide new insights into the neural basis of value-based adaptive decision-making in primates.

neuroscience↗

bioRxiv2023

Multimodal imaging for validation and optimization of ion channel-based chemogenetics in nonhuman primates

Chemogenetic tools provide an opportunity to manipulate neuronal activity and behavior selectively and repeatedly in nonhuman primates (NHPs) with minimal invasiveness. Designer Receptors Exclusively Activated by Designer Drugs are one example that is based on mutated muscarinic acetylcholine receptors. Another channel-based chemogenetic system available for neuronal modulation in NHPs uses Pharmacologically Selective Actuator Modules (PSAMs), which are selectively activated by Pharmacologically Selective Effector Molecules (PSEMs). To facilitate the use of the PSAM/PSEM system, the selection and dosage of PSEMs should be validated and optimized for NHPs. To this end, we used a multimodal imaging approach. We virally expressed excitatory PSAM (PSAM4-5HT3) in the striatum and the primary motor cortex of two macaque monkeys, and visualized its location through positron emission tomography (PET) with the reporter ligand [18F]ASEM. Chemogenetic excitability of neurons triggered by two PSEMs (uPSEM817 and uPSEM792) was evaluated using [18F]fluorodeoxyglucose-PET imaging, with uPSEM817 being more efficient than uPSEM792. Pharmacological magnetic resonance imaging showed that increased brain activity in the PSAM4-expressing region began approximately 13 min after uPSEM817 administration and continued for at least 60 min. Our multimodal imaging data provide valuable information regarding the manipulation of neuronal activity using the PSAM/PSEM system in NHPs, facilitating future applications. Significance statementLike other chemogenetic tools, the ion channel-based system called Pharmacologically Selective Actuator Module/Pharmacologically Selective Effector Molecule (PSAM/PSEM) allows remote manipulation of neuronal activity and behavior in living animals. Nevertheless, its application in non-human primates (NHPs) is still limited. Here, we used multi-tracer positron emission tomography (PET) imaging and pharmacological magnetic resonance imaging (MRI) to visualize an excitatory chemogenetic ion channel (PSAM4-5HT3) and validate its chemometric function in macaque monkeys. Our results provide the optimal agonist, dose, and timing for chemogenetic neuronal manipulation, facilitating the use of the PSAM/PSEM system and expanding the flexibility and reliability of circuit manipulation in NHPs in a variety of situations.

neuroscience↗

bioRxiv2023

Isoxanthohumol improves obesity and glucose metabolism via inhibiting intestinal lipid absorption with a bloom of Akkermansia muciniphila in mice

AimsDysbiosis is an important factor that leads to metabolic disorders by disrupting energy balance and insulin sensitivity. A decrease in Akkermansia muciniphila is a phenotype of obesity-induced dysbiosis. Although interventions to increase A. muciniphila are expected to improve glucose metabolism, the underlying mechanism has not been fully understood. MethodsIsoxanthohumol (IX), a prenylated flavonoid found in beer hops was administered to high fat diet-fed mice. We analyzed glucose metabolism, gene expression profiles and histology of liver, epididymal adipose tissue and colon. Lipase activity, fecal lipid profiles and plasma metabolomic analysis were assessed. Fecal 16s rRNA sequencing was obtained and selected bacterial species were used for in vitro studies. Fecal microbiota transplantation and monocolonization were conducted to antibiotic-treated or germ-free (GF) mice. ResultsThe administration of IX lowered weight gain, decreased steatohepatitis and improved glucose metabolism. Mechanistically, IX inhibited pancreatic lipase activity and lipid absorption by decreasing the expression of the fatty acid transporter CD36 in the small intestine, which was confirmed by increased lipid excretion in feces. IX administration improved the gut barrier function and reduced metabolic endotoxemia. In contrast, the effects of IX were nullified by antibiotics. As revealed using 16S rRNA sequencing, the microbial community structure changed with a significant increase in the abundance of A. muciniphila in the IX-treated group. An anaerobic chamber study showed that IX selectively promoted the growth of A. muciniphila while exhibiting antimicrobial activity against some Bacteroides and Clostridium species. To further explore the direct effect of A. muciniphila on lipid and glucose metabolism, we monocolonized either A. muciniphila or Bacteroides thetaiotaomicron to GF mice. A. muciniphila monocolonization decreased CD36 expression in the jejunum and improved glucose metabolism, with decreased levels of multiple classes of fatty acids determined using plasma metabolomic analysis. ConclusionOur study confirmed a direct role of A. muciniphila in energy metabolism, which was induced by microbial actions of IX. These highlight new treatment strategies for preventing metabolic syndrome by boosting the gut microbiota with food components.

microbiology↗