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Results for “Physiology”

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At least 703 records · Page 39Linked to original sources

bioRxiv2019

Common neurodegeneration-associated proteins are physiologically expressed by antigen-presenting cells and are interconnected via the inflammation/autophagy-related proteins TRAF6 and SQSTM1

There is circumstantial evidence that, under neurodegenerative conditions, peptides deriving from aggregated or misfolded specific proteins elicit adaptive immune responses. On another hand, several genes involved in familial forms of neurodegenerative diseases were found to exert key innate immune functions. However, whether or not such observations are causally linked remains unknown. To start addressing this issue, we followed a systems biology strategy based on the mining of large proteomics and immunopeptidomics databases. First, we retrieved the expression patterns of common neurodegeneration-associated proteins in two professional antigen-presenting cells, namely B-cells and dendritic cells. Surprisingly, we found that under physiological conditions, numerous neurodegeneration-associated proteins are abundantly expressed by human B-cells. A survey of the human proteome allowed us to map a unique protein-protein interaction network linking common neurodegeneration-associated proteins and their first shell interactors in human B-cells. Surprisingly, network connectivity analysis identified two major hubs that both relate with inflammation and autophagy, namely TRAF6 (TNF Receptor Associated Factor 6) and SQSTM1 (Sequestosome-1). Moreover, the mapped network in B-cells also comprised two other hub proteins involved in both inflammation and autoimmunity: HSPA8 (Heat Shock Protein Family A Member 8 also known as HSC70) and HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1). Based on these results, we then explored the Immune Epitope Database \"IEDB-AR\" and actually found that a large share of neurodegeneration-associated proteins were previously reported to provide endogenous MHC class II-binding peptides in human B-cells. Of note, peptides deriving from amyloid beta A4 protein, sequestosome-1 or profilin-1 were reported to bind multiple allele-specific MHC class II molecules. In contrast, peptides deriving from microtubule-associated protein tau, presenilin 2 and serine/threonine-protein kinase TBK1 were exclusively reported to bind MHC molecules encoded by the HLA-DRB1 1501 allele, a recently-identified susceptibility gene for late onset Alzheimers disease. Finally, we observed that the whole list of proteins reported to provide endogenous MHC class II-binding peptides in human B-cells is specifically enriched in neurodegeneration-associated proteins. Overall, our work indicates that immunization against neurodegeneration-associated proteins might be a physiological process which is shaped, at least in part, by B-cells.

immunology↗

bioRxiv2019

On Some Problems of Estimating Fundamental Niche from Physiological Data

Hutchinson proposed the idea of the fundamental niche, determined by physiological properties of a species, more than 50 years ago. The idea remains both central to ecological thinking and largely unexplored experimentally. In this note, we describe some problems of using physiological experiments databases to estimate fundamental niches, show some solutions, and the apply our solution to testing the prediction that fundamental niches contain realized niches, for some species of marine fishes and terrestrial beetles. Our results were concordant with Hutchinsons predictions.

ecology↗

bioRxiv2019

Interdependency of respiratory metabolism and phenazine-associated physiology in Pseudomonas aeruginosa PA14

Extracellular electron transfer (EET), the reduction of compounds that shuttle electrons to distal oxidants, can support bacterial survival when preferred oxidants are not directly accessible. EET has been shown to contribute to virulence in some pathogenic organisms and is required for current generation in mediator-based fuel cells. In several species, components of the electron transport chain (ETC) have been implicated in electron shuttle reduction, raising the question of how shuttling-based metabolism is integrated with primary routes of metabolic electron flow. The clinically relevant bacterium Pseudomonas aeruginosa can utilize carbon sources (i.e., electron donors) covering a broad range of reducing potentials and possesses a branched ETC that can be modulated to optimize respiratory efficiency. It also produces electron shuttles called phenazines that facilitate intracellular redox balancing, increasing the complexity of its metabolic potential. In this study, we investigated the reciprocal influence of respiratory metabolism and phenazine-associated physiology in Pseudomonas aeruginosa PA14. We found that phenazine production affects respiratory activity and terminal oxidase gene expression, and that carbon source identity influences the mechanisms enabling phenazine reduction. Furthermore, we found that growth in biofilms, a condition for which phenazine metabolism is critical to normal development and redox balancing, dramatically affects the composition of the P. aeruginosa phenazine pool. Together, these findings can aid interpretation of P. aeruginosa behavior during host infection and provide inroads to understanding the crosstalk between primary metabolism and shuttling-based physiology in the diverse bacteria that carry out EET.\n\nIMPORTANCEPseudomonas aeruginosa is a major cause of healthcare-associated infections and long-term lung infections in people with cystic fibrosis. It can use diverse organic compounds as electron donors and possesses multiple enzymes that can transfer electrons from central metabolism to O2. These pathways support a balanced intracellular redox state and the production of cellular energy. Under hypoxic conditions, P. aeruginosa can reduce phenazines, secondary metabolites that also promote redox homeostasis and that contribute to virulence. We asked how these primary and secondary routes of electron flow influence each other. We found that phenazines affect respiratory function, that the roles of respiratory enzymes in phenazine reduction are highly condition-dependent, and that the complement of phenazines produced is strongly affected by growth in assemblages called biofilms. These results provide a more nuanced understanding of P. aeruginosa redox metabolism and may inform strategies for treating persistent infections caused by this bacterium.

microbiology↗

bioRxiv2019

Systems-level physiology of the human red blood cell is computed from metabolic and macromolecular mechanisms

The human red blood cell has served as a starting point for the application and development of systems biology approaches due to its simplicity, intrinsic experimental accessibility, and importance in human health applications. Here, we present a multi-scale computational model of the human red blood cell that accounts for the full metabolic network, key proteins (>95% of proteome mass fraction), and several macromolecular mechanisms. Proteomics data are used to place quantitative constraints on individual protein complexes that catalyze metabolic reactions, as well as a total proteome capacity constraint. We explicitly describe molecular mechanisms--such as hemoglobin binding and the formation and detoxification of reactive oxygen species--and takes standard hematological variables (e.g., hematocrit, hemoglobin concentration) as input, allowing for personalized physiological predictions. This model is built from first principles and allows for direct computation of physiologically meaningful quantities such as the oxygen dissociation curve and an accurate computation of the flux state of the metabolic network. More broadly, this work represents an important step toward including the proteome and its function in whole-cell models of human cells.

systems biology↗

bioRxiv2019

Succession of physiological stages hallmarks the transcriptomic response of fungus Aspergillus niger to lignocellulose

BackgroundUnderstanding how fungi degrade lignocellulose is a cornerstone of improving renewables-based biotechnology, in particular for the production of hydrolytic enzymes. Considerable progress has been made in investigating fungal degradation during time-points where CAZyme expression peaks. However, a robust understanding of the fungal survival strategies over its life time on lignocellulose is thereby missed. Here we aimed to uncover the physiological responses of the biotechnological workhorse and enzyme producer Aspergilllus niger over its life time to six substrates important for biofuel production.\n\nResultsWe analysed the response of A. niger to the feedstock Miscanthus and compared it with our previous study on wheat straw, alone or in combination with hydrothermal or ionic liquid feedstock pretreatments. Conserved (substrate-independent) metabolic responses as well as those affected by pretreatment and feedstock were identified via multivariate analysis of genome-wide transcriptomics combined with targeted transcript and protein analyses and mapping to a metabolic model. Initial exposure to all substrates increased fatty acid beta-oxidation and lipid metabolism transcripts. In a strain carrying a deletion of the ortholog of the Aspergillus nidulans fatty acid beta-oxidation transcriptional regulator farA, there was a reduction in expression of selected lignocellulose degradative CAZyme-encoding genes suggesting that beta-oxidation contributes to adaptation to lignocellulose. Mannan degradation expression was wheat straw feedstock-dependent and pectin degradation was higher on the untreated substrates. In the later life stages, known and novel secondary metabolite gene clusters were activated, which are of high interest due to their potential to synthesize bioactive compounds.\n\nConclusionIn this study, which includes the first transcriptional response of Aspergilli to Miscanthus, we highlighted that life time as well as substrate composition and structure (via variations in pretreatment and feedstock) influence the fungal responses to lignocellulose. We also demonstrated that the fungal response contains physiological stages that are conserved across substrates and are typically found outside of the conditions with high CAZyme expression, as exemplified by the stages that are dominated by lipid and secondary metabolism.

microbiology↗

bioRxiv2019

Effects of physiological parameter evolution on the dynamics of tonic-clonic seizures

The temporal and spectral characteristics of tonic-clonic seizures are investigated using a neural field model of the corticothalamic system in the presence of a temporally varying connection strength between the cerebral cortex and thalamus. Increasing connection strength drives the system into [~] 10 Hz seizure oscillations once a threshold is passed and a subcritical Hopf bifurcation occurs. In this study, the spectral and temporal characteristics of tonic-clonic seizures are explored as functions of the relevant properties of physiological connection strengths, such as maximum strength, time above threshold, and the ramp rate at which the strength increases or decreases. Analysis shows that the seizure onset time decreases with the maximum connection strength and time above threshold, but increases with the ramp rate. Seizure duration and offset time increase with maximum connection strength, time above threshold, and rate of change. Spectral analysis reveals that the power of nonlinear harmonics and the duration of the oscillations increase as the maximum connection strength and the time above threshold increase. A secondary limit cycle at [~] 18 Hz, termed a saddle-cycle, is also seen during seizure onset and becomes more prominent and robust with increasing ramp rate. If the time above the threshold is too small, the system does not reach the 10 Hz limit cycle, and only exhibits 18 Hz saddle-cycle oscillations. It is also seen that the times to reach the saturated large amplitude limit-cycle seizure oscillation from both the instability threshold and from the end of the saddle-cycle oscillations are inversely proportional to the square root of the ramp rate.\n\nAuthor SummaryEpilepsy, which is characterized by recurrent seizures, affects around 1% of the world population at some point in their lives. Tonic-clonic seizures are the most commonly encountered primary generalized seizures and it is widely considered that they can be induced by an increase in the connection strength between the cerebral cortex and the thalamus. In this paper, we analyze the detailed dynamics of tonic-clonic seizures along with their dependence on the parameters of the changing connection strength. We study the relationship of the seizure onset, offset, oscillation strength, and oscillation frequency to the duration, amplitude, and rate of change of the connection strength. A detailed understanding of the dynamics and their dependence on the physiological parameters of the brain may explain the variability of seizure dynamics among patients. It may also help to constitute successful seizure prediction.

neuroscience↗

bioRxiv2019

Advantages of acute brain slices prepared at physiological temperature in characterization of synaptic functions

Acute brain slice preparation is a powerful experimental model for investigating the characteristics of synaptic function in the brain. Although brain tissue is usually cut at ice-cold temperature (CT) to facilitate slicing and avoid neuronal damage, exposure to CT causes molecular and architectural changes of synapses. To address these issues, we investigated ultrastructural and electrophysiological features of synapses in mouse acute cerebellar slices prepared at ice-cold and physiological temperature (PT). In the slices prepared at CT, we found significant spine loss and reconstruction, synaptic vesicle rearrangement and decrease in synaptic proteins, all of which were not detected in slices prepared at PT. Consistent with these structural findings, slices prepared at PT showed higher release probability and higher detectability of long-term depression after motor learning compared with slices prepared at CT. These results indicate substantial advantages of the slice preparation at PT for investigating synaptic functions in different physiological conditions.

neuroscience↗

bioRxiv2019

Human-specific regulatory features of brain development manifest staggering breadth of associations with physiological processes and pathological conditions of H. sapiens

Recent advances in identification and characterization of human-specific regulatory DNA sequences set the stage for the assessment of their global impact on physiology and pathology of Modern Humans. Gene set enrichment analyses (GSEA) of 8,405 genes linked with 35,074 human-specific neuro-regulatory single-nucleotide changes (hsSNCs) revealed a staggering breadth of significant associations with morphological structures, physiological processes, and pathological conditions of Modern Humans. Significantly enriched traits include more than 1,000 anatomically-distinct regions of the adult human brain, many different types of cells and tissues, more than 200 common human disorders and more than 1,000 records of rare diseases. Thousands of genes connected with neuro-regulatory hsSNCs have been identified, which represent essential genetic elements of the autosomal inheritance and offspring survival phenotypes. A total of 1,494 hsSNC- linked genes are associated with either autosomal dominant or recessive inheritance and 2,273 hsSNC-linked genes have been associated with premature death, embryonic lethality, as well as pre-, peri-, neo-, and post-natal lethality phenotypes of both complete and incomplete penetrance. Differential GSEA implemented on hsSNC-linked loci and associated genes identify 7,990 genes linked to evolutionary distinct classes of human-specific regulatory sequences (HSRS), expression of a majority of which (5,389 genes; 67%) is regulated by stem cell-associated retroviral sequences (SCARS). Interrogations of the MGI database revealed readily available mouse models tailored for precise experimental definitions of functional effects of hsSNCs and SCARS on genes causally affecting thousands of mammalian phenotypes and implicated in hundreds of common and rare human disorders. These observations suggest that a preponderance of human-specific traits evolved under a combinatorial regulatory control of HSRS and neuro-regulatory loci harboring hsSNCs that are fixed in humans, distinct from other primates, and located in differentially-accessible chromatin regions during brain development.

genomics↗

bioRxiv2019

mTOR-RhoA signalling impairments in direct striatal projection neurons induce altered behaviours and striatal physiology in mice

As an integrator of molecular pathways, mTOR has been associated with diseases including neurodevelopmental, psychiatric and neurodegenerative disorders as autism, schizophrenia, and Huntingtons disease. An important brain area involved in all these diseases is the striatum. However, the mechanisms behind how mTOR is involved in striatal physiology and its relative role in distinct neuronal populations in these striatal-related diseases still remain to be clarified. Taking advantage of the D1-mTOR KO mice (males), we combined behavioural, biochemical, electrophysiological and morphological analysis aiming to untangle the role of mTOR in direct pathway striatal projection neurons (dMSNs) and how this would impact on striatal physiology. Our results indicate deep behavioural changes in absence of mTOR in dMSNs such as decreased spontaneous locomotion, impaired social interaction and repetitive behaviour. These were accompanied by a Kv1.1-induced increase in the fast phase of afterhyperpolarization and decreased distal spines density that were mechanistically independent of protein synthesis but dependent of RhoA activity. These results identify mTOR RhoA signaling as an important regulator of striatal functions through an intricate mechanism involving RhoA and culminating in Kv1.1 overfunction, which could be targeted to treat striatal-related mTORopathies.

neuroscience↗

bioRxiv2019

CD300lf is the primary physiologic receptor of murine norovirus but not human norovirus

Murine norovirus (MNoV) is an important model of human norovirus (HNoV) and mucosal virus infection more broadly. Viral receptor utilization is a major determinant of cell tropism, host range, and pathogenesis. The bona fide receptor for HNoV is unknown. Recently, we identified CD300lf as a proteinaceous receptor for MNoV. Interestingly, its paralogue CD300ld was also sufficient for MNoV infection in vitro. Here we explored whether CD300lf is the sole physiologic receptor in vivo and whether HNoV can use a CD300 ortholog as an entry receptor. We report that both CD300ld and CD300lf are sufficient for infection by diverse MNoV strains in vitro. We further demonstrate that CD300lf is essential for both oral and parenteral MNoV infection and to elicit anti-MNoV humoral responses in vivo. In mice deficient in STAT1 signaling, CD300lf is required for MNoV-induced lethality. However, after high dose intraperitoneal challenge with MNoV in Cd300lf-/-Stat1-/- mice a single amino acid mutation in the MNoV capsid protein emerged. This substitution did not alter receptor utilization in vitro. Finally, we demonstrate that human CD300lf (huCD300lf) is not essential for HNoV infection, nor does huCD300lf inhibit binding of HNoV virus-like particles to glycans. Thus, we report huCD300lf is not a receptor for HNoV. Author SummaryHuman norovirus is the leading cause of non-bacterial gastroenteritis causing up to 200,000 deaths each year. How human norovirus enters cells is unknown. Because human norovirus is difficult to grow in the laboratory and in small animals, we use mouse or murine norovirus as a model system. We recently discovered that murine norovirus can use the either CD300ld or CD300lf as a receptor in vitro. We also showed that CD300lf deficient mice were resistant to oral challenge with a single virus strain. Here we determined that CD300lf is essential for infection of diverse murine norovirus strains in cell lines and in mice with normal immune systems demonstrating its the primary physiologic receptor for diverse murine norovirus strains independent of infection route. However, in immunodeficient mice injected with high dose virus directly into the abdominal cavity, we observed a norovirus mutant that enabled CD300lf-independent infection. Finally, we demonstrated that human CD300lf is not the elusive receptor for human norovirus.

microbiology↗

bioRxiv2025

Behavioural and Physiological Signatures of Chronic Unpredictable Mild Stress Models in Mice

The chronic unpredictable mild stress (CUMS) paradigm is one of the most widely used preclinical models to investigate the role of stress in the neurobiology of depression and to evaluate potential antidepressant therapies, owing to its strong translational relevance. However, despite its extensive use, substantial discrepancies and concerns regarding the reproducibility of CUMS outcomes persist in the literature, with many studies reporting inconsistent or unreliable results. In the present comparative study, we implemented several CUMS protocols in mice that differed in the intensity and duration of stress exposure, and systematically evaluated the resulting pathophysiological and behavioural alterations associated with depressive- and anxiety-like phenotypes. We found that progressive escalation in stress intensity and frequency, as well as prolonged exposure, induced increasingly robust disease-related behavioural and physiological changes, including depression- and anxiety-like behaviours, adrenal hypertrophy, and reduced body weight gain.. Moreover, social isolation emerged as a major contributing factor exacerbating stress-induced deficits. Altogether, data suggest that a multidimensional assessment of the behavioural impairments is critical to reinforce the physiological changes indicative of a hyperactive hypothalamic-pituitary-adrenal axis (HPA). Differences in individual stress susceptibility, stressor intensity, frequency, and housing conditions are key determinants of CUMS outcomes. Therefore, precise, detailed, and transparent reporting of protocol parameters is critical to enhance reproducibility and enable meaningful comparisons across studies.

neuroscience↗

bioRxiv2025

The yellow-in-the-dark chIL Chlamydomonas mutant as a model for time-resolved chloroplast biogenesis and physiological responses to lincomycin

Understanding chloroplast biogenesis is key given the importance of photosynthesis and chloroplast metabolism. Chloroplast assembly has been extensively studied in angiosperms, where the main hallmarks have been established, including the need for nuclear and plastid genome coordination through anterograde and retrograde signals. However, recent works in other photosynthetic lineages have revealed both divergent and conserved regulators. These differences likely represent adaptive strategies that emerged during the evolution of the green lineage, and highlight the need for evolutionary studies to fully elucidate the mechanisms controlling chloroplast biogenesis, a light-promoted process. Here, we characterize the yellow-in-the-dark chIL mutant of Chlamydomonas reinhardtii, which carries a mutation in the CHLL subunit of the dark-operative POR enzyme. Dark-adapted chIL cells cannot synthesize chlorophylls and display a de-differentiated chloroplast, and our results show that upon exposure to light, chloroplast biogenesis is initiated very rapidly based on starch reserves. We demonstrate that accumulation of pigments, photosynthesis-related proteins, and functional chloroplast activity is detected within 1-3 hours of illumination. Additionally, we show that lincomycin, an inhibitor of plastid translation, specifically affects chloroplast physiology, and blocks light-induced chloroplast biogenesis and cell growth, establishing lincomycin as a valuable tool for investigating chloroplast physiology and plastid-to-nucleus signals in Chlamydomonas. Together, this study introduces the chIL mutant as a powerful model system to dissect light-induced, time-resolved chloroplast biogenesis, as well as the responses and signaling triggered by lincomycin. By promoting broader adoption of this model, we aim to help inform strategies to enhance photosynthesis and stress tolerance, and optimize bioproduct production.

plant biology↗

bioRxiv2025

Universal genomic constraints in the evolvability of thermal physiology

Thermal physiological traits such as body temperature often show surprisingly slow evolutionary rates over macroevolutionary time, despite apparent lability at microevolutionary time scales. While long-term stabilizing selection may slow rates of thermal evolution, we propose an alternative hypothesis from a bottom-up, population genomic perspective: the nature of body temperature (Tb) as an organism-level trait that must accommodate diverse protein thermal performances leads to evolutionary constraints at the organismal level. We support this hypothesis using a simulation framework in which we modeled and compared the rates of evolution for Tb alongside one or more proteins. Protein performances and organismal Tb were modeled as evolving, QTL-encoded traits, and organismal fitness was determined based on Tb given the performance curves of each protein. As predicted, a greater number of proteins led to drastic decrease in the rate of Tb evolution. When a shift in environmental temperature was simulated, Tb evolved with an initial rapid pulse toward the new optimum, followed by a phase of gradual evolution as the cumulative fitness costs of mismatching Tb and protein optima constrained thermal adaptation. That is, lability and stasis are predictable features of body temperature evolution: rapid, yet bounded microevolutionary bursts followed by long phases of sluggish evolution are both expected outcomes of directional selection operating on hierarchically structured traits like Tb. We suggest that protein thermal coordination might contribute to intrinsic, universal macroevolutionary patterns of stasis in organismal physiology across endotherms and ectotherms.

evolutionary biology↗

bioRxiv2025

Biochemical and Physiological Evidence of Maternal Care in Plants: A Case Study of Chlorophytum comosum

Plants exhibit a wide array of well-characterized survival and reproductive strategies, yet definitive evidence for maternal care has remained absent. Here, we report evidence of maternal care in the plant kingdom using Chlorophytum comosum as a model system. Biochemical and physiological analyses were conducted on mother (MRs) and daughter ramets (DRs) of C. comosum across four distinct developmental stages of the DRs (S1-S4), ranging from the juvenile stage (S1) to the fully photoautotrophic stage (S4). It was observed that, during the progressive development stages, DRs first develop their photosynthetic potential, followed by the subsequent development of water and mineral uptake capacity. Biochemical and anatomical studies highlighted that stolon acts as a vital life-support conduit, analogous to a placenta, facilitating the translocation of nutrients and water from MRs to DRs. In the present study, the dynamics of sucrose-phosphate synthase, acid invertase, and starch concentrations in MRs and DRs clearly reveal metabolic communication between MRs and DRs and demonstrated the biochemical basis of maternal care in C. comosum. The findings further supported by the stolon severance experiment, in which detached DRs at stage S1 exhibited a 0% survival rate, which increased progressively with developmental stage and reached 100% survival at stage S4. At this stage, when DRs attain full independence, all biological communication between MRs and DRs was terminated. Although DRs achieved full autonomy by Stage S4, MRs maintain stolon-mediated physical connections for approximately two additional weeks, with gradual deterioration at Stage S5 and complete disconnection occurring naturally at Stage S6, indicating post-establishment maternal care. Chlorophyll fluorescence and stolon anatomical analyses during root-prevention and drought-induction experiments revealed that stolon connectivity is maintained when DRs fail to establish roots at Stage S3 or experience drought stress at Stage S4. Under these conditions, MRs continued to provide physiological support via the stolon until successful establishment. Together, these findings demonstrated that C. comosum exhibits maternal care until establishment is assured, thereby enhancing survival under environmental stress, and open new avenues for investigating the plant neurobiology and molecular communication underlying maternal care.

plant biology↗

bioRxiv2025

Defining bottlenecks and physiological impact of an orthogonal translation initiation system

Reengineering translation initiation provides a powerful route to develop new translation systems that enable precise control of protein synthesis. While many engineered translation systems show promise, their orthogonality and impact on host physiology is largely uncharacterized, limiting broader application. Here, we develop an initiator-tRNA with an AAC anticodon mutation (i-tRNA-AAC), enabling translation initiation at a GUU start codon. Using fluorescence assays, proteomics, and tRNA sequencing, we assess the i-tRNA-AAC initiation orthogonality and effects on the host, guiding the optimization of its translational efficiency. We find the i-tRNA-AAC mutant initiates translation exclusively from its GUU start codon and is improved by overexpression of valyl-tRNA synthetase and methionyl-tRNA formyltransferase. However, this intervention perturbs aminoacylation and base modifications of endogenous tRNAs along with proteome-wide changes likely due to increased valine demand. Our findings demonstrate how an orthogonal translation initiation system reshapes host physiology and reveals the adaptive responses that accompany translational reprogramming.

synthetic biology↗

bioRxiv2026

Expectation of aversive outcomes drives multimodal integration of behavioural, physiological and neural activations during human fear retrieval and generalisation

Classical fear conditioning describes how neutral cues acquire a threat value, yet how learned associations are retrieved and generalised across similar stimuli specifically is an ongoing debate. We combined behavioural ratings, physiological measures, and fMRI in a two-day classical fear conditioning paradigm to characterize acquisition, retrieval, and generalisation across modalities. Twenty-five healthy participants completed acquisition trials on Day 1 and retrieval and generalisation trials on Day 2 using conditioned (CS+, CS-) and graded generalisation stimuli (GS). Outcomes included trial-wise US expectancy ratings, pre/post fear and arousal ratings, skin conductance responses (SCR), pupil dilation, and ROI-based fMRI (amygdala, hippocampus, insula, periaqueductal gray (PAG), locus coeruleus). Acquisition yielded robust CS+/CS-discrimination in behavioural ratings and increased BOLD responses in bilateral insula and PAG. During retrieval, US-expectancy ratings indicated early retrieval of CS contingency. The fMRI results showed greater BOLD activity during CS+ presentations than during CS-presentations in bilateral hippocampus, left insula and right PAG. Additionally, hippocampus-insula coupling increased. Critically, parametric modulation during retrieval revealed that trial-wise mean US-expectancy modulated BOLD responses in left insula and right PAG, with a trend in left hippocampus. Across generalisation, US-expectancy and pupil dilation responses followed graded profiles, which could be explained by a Gaussian model, whereas SCR generalised, but was not captured by a Gaussian model. Parametric modulation by US-expectancy correlated with BOLD activity in left PAG, with a trend in right hippocampus. Stimulus identity explained variance in bilateral insula and left PAG. Findings converge on a hippocampus-insula-PAG network that retrieves learned predictions, and scales defensive output according to similarity-based threat probability, linking subjective, physiological, and neural outcomes.

neuroscience↗

bioRxiv2026

Proteome analysis reveals common players between the physiological neurodegeneration of the ascidian Ciona intestinalis and the pathological neurodegeneration in humans

Tunicates, including ascidians, are recognized as the true sister group of vertebrates and are emerging as models to study the development and degeneration of central nervous system (CNS). Ascidian larvae have the typical chordate body plan that includes a dorsal neural tube. During their metamorphosis, a deep tissue reorganization takes place, with some tissues that degenerate while others develop to become functional during the adult life. The larval CNS also degenerates and most neurons disappear, making room for the formation of adult CNS. The genome of the ascidian Ciona intestinalis has been sequenced and annotated, with several CNS specific genes that have been characterized, revealing specification mechanisms shared with humans. These features make ascidian metamorphosis a good model to study the mechanisms underlying physiological CNS degeneration and to compare them to the pathological conditions typical of neurodegenerative diseases. In order to shed light on the molecular determinants of C. intestinalis metamorphosis and neurodegeneration, we analyzed the proteome at three stages of development: swimming larva (SwL, Hotta stage 28), settled larva (SetL, Hotta stage 32) and metamorphosing larva (MetL, Hotta stage 34). A total of 405 modulated proteins were identified by mass spectrometry by comparing the three stages. Enrichment and network analysis showed the involvement of several processes/pathways, including autophagy and mTOR pathway, and actin cytoskeleton organization and remodeling among the most significant ones. This study elucidates molecular pathways underlying ascidian metamorphosis and highlights shared mechanisms between physiological neurodegeneration in ascidians and pathological neurodegeneration in humans.

neuroscience↗

bioRxiv2026

Pharmacological intervention targeting neuroimmune axis in the aging hypothalamus prevents age-associated physiological decline

Systemic physiological aging is largely driven by disrupted metabolic homeostasis, yet the central mechanisms of this metabolic dysfunction remain poorly defined. Here, we identify the hypothalamus as a critical hub driving systemic aging through neuroimmune-mediated mechanisms. Single-cell transcriptomic and immunohistochemical analyses revealed that aged hypothalami exhibit significant infiltration of CD8 T lymphocytes, beginning in middle age, with signatures of activation and tissue residency. These T cells intimately interact with tanycytes and microglia, promoting neuroinflammation and progressive tanycyte loss, a defining hallmark of hypothalamic aging. T cell receptor profiling revealed a substantial presence of invariant natural killer T (iNKT) and mucosal-associated invariant T (MAIT) cells, likely activated through cytokine-driven, antigen-independent mechanisms. In aged hypothalamus, microglia secrete chemokines CCL3 and CCL4, whose ectopic expression in young mice was sufficient to trigger persistent hypothalamic T cell infiltration and accelerated systemic aging. Circulating oxidized LDLs (OxLDLs) were identified as upstream inducers of this chemokine response. Notably, pharmacological blockade of the CCL3/4-CCR5 axis with Maraviroc and Cenicriviroc prevented T cell recruitment and ameliorated metabolic and physiological impairments. Given the clinical safety of CCR5 antagonists and individuals lacking functional CCR5 remain generally healthy throughout life, our findings highlight midlife CCL3/4-CCR5 inhibition as a translatable therapeutic target for delaying age-related decline and promoting healthspan.

neuroscience↗