Biology subjects

Lee, S.-H.

Publications and source records attributed to Lee, S.-H..

At least 91 records · Page 5Linked to original sources

bioRxiv2023

Distinct neurochemical influences on fMRI response polarity in the striatum

The striatum is the primary input nucleus of the basal ganglia, widely studied for its complex roles in health and disease. Functional magnetic resonance imaging (fMRI) studies are essential for discerning striatal function, however the relationship between neuronal and hemodynamic activity, critical for interpreting fMRI signals, has not been rigorously examined in striatum. We find that optogenetic stimulation of striatal neurons or afferents evokes negative striatal fMRI responses in rats that can occur despite broad increases in local neuronal activity. Intra-striatal pharmacological manipulations suggest that opioidergic, but not dopaminergic transmission contributes to negative striatal fMRI signals (the latter instead associated with positive signals). Striatal neuronal activity peaks are also associated with negative hemodynamic signals in behaving rats. Negative fMRI responses are observed in human striatum under conditions of anticipated neuronal activity increases. Our results prompt consideration of local cellular and neurochemical environments along with neuronal activity in fMRI signal interpretation.

neuroscience↗

bioRxiv2023

Mismatch between human early visual cortex and perception in spatial extent representation: Radial bias shapes cortical representation while co-axial bias shapes perception

An object occupies an enclosed region in the visual field, which defines its spatial extent. Humans display exquisite finesse in spatial extent perception. Recent series of human neuroimaging and monkey single-cell studies suggest the spatial representation encoded in the early visual cortex (EVC) as the neural substrate of spatial extent estimation. Guided by this "EVC hypothesis" on spatial extent estimation, we predicted that human estimation of spatial extents would reflect the topographic biases known to exist in EVCs spatial representation, the co-axial and radial biases. To test this prediction, we concurrently assessed those two spatial biases in both EVCs and perceptual spatial representations by probing the anisotropy of EVCs population receptive fields, on the one hand, and that of humans spatial extent estimation, on the other hand. To our surprise, we found a marked topographic mismatch between EVCs and perceptual representations of oriented visual patterns, the radial bias in the former and the co-axial bias in the latter. Amid this topographic mismatch, the extent to which the anisotropy of spatial extents is modulated by stimulus orientation is correlated across individuals between EVC and perception. Our findings seem to require a revision of the current understanding of EVCs functional architecture and contribution to visual perception: EVCs spatial representation (i) is governed by the radial bias but only weakly modulated by the co-axial bias, and (ii) do contribute to spatial extent perception, but in a limited way where additional neural mechanisms are called in to counteract the radial bias in EVC. Significant statementPrevious anatomical and functional studies suggest both radial and co-axial biases as topographic factors governing the spatial representation of the early visual cortex (EVC). On the other hand, EVCs fine-grained spatial representation has been considered the most plausible neural substrate for exquisite human perception of spatial extents. Based on these suggestions, we reasoned that these two topographic biases are likely to be shared between EVCs and perceptual representations of spatial extents. However, our neuroimaging and psychophysics experiments implicate a need for revising those two suggestions. Firstly, the co-axial bias seems to exert only a modulatory influence on EVCs functional architecture. Secondly, human spatial extent perception requires further contribution from neural mechanisms that correct EVCs spatial representation for its radial bias.

neuroscience↗

bioRxiv2023

Systematic analysis of disease-linked rare germline variants reveals new classes of cancer predisposing genes

Despite recent insights into cancer predisposition genes (CPGs), the contribution of rare germline variants to carcinogenesis remains unclear. Here, we examine the enrichment of rare germline variants in Mendelian disease-associated genes using PCAWG and the 1,000 Genomes Project. Using an integrative approach that considers disease classes, cellular pathways, and tissue expression profiles, we find that subsets of Online Mendelian Inheritance in Man (OMIM) genes are strong candidate CPGs. These genes were classified into five clusters suggesting diverse mechanisms underlie tumor progression. We further analyzed PAH gene which shows the strongest prevalence of rare germline variants in cancers (2.2%) compared to controls (0.7%). This enrichment was validated in two independent cancer cohorts and present the possibility of tumorigenesis by contributing immune-associated pathways. Our data argue that rare germline variants of Mendelian disease-associated genes contribute to cancer progression and suggest new CPG classifications that may underlie diverse tumorigenesis mechanisms.

bioinformatics↗

bioRxiv2023

Transcranial direct current stimulation elevates the baseline activity while sharpening the spatial tuning of the human visual cortex

BackgroundAlthough transcranial direct current stimulation (tDCS) is widely used to affect various kinds of human cognition, behavioral studies on humans have produced highly inconsistent results. This requires a clear understanding of how tDCS impacts the system-level neural activity, a prerequisite for the principled application of tDCS to human cognition. ObjectiveHere, we aim to gain such understanding by probing the spatial and temporal cortical activity of the human early visual cortex (EVC) in diverse aspects while controlling the polarity and presence of tDCS. We target EVC to capitalize on its well-established anatomical and functional architecture that is readily accessible with non-invasive quantitative neuroimaging methods. MethodsTo create an electric field in EVC precisely and effectively, we tailored high-definition stimulation montages for 15 individual brains by running electric field simulations. We then conducted an fMRI (functional magnetic neuroimaging)-tDCS experiment on each brain with a sham-controlled crossover design over multiple days. We quantified tDCS effects with eight measures, tested their significance with mixed ANOVA, and further validated their robustness to across-voxel and across-subject variability. ResultsThe anodal application of tDCS gradually elevated EVCs baseline BOLD activity and sharpened its spatial tuning by augmenting surround suppression without affecting its evoked activity. ConclusionsComparisons of our and previous findings suggest the fundamental differences in tDCS effects between the visual and motor cortices, inhibitory and excitatory effects predominant in the former and latter, respectively. This calls for considering the differences in the excitatory-inhibitory recurrent network between brain regions in predicting or interpreting tDCS effects.

neuroscience↗

bioRxiv2023

L-type Ca2+ channels mediate regulation of glutamate release by subthreshold potential changes

Subthreshold depolarization enhances neurotransmitter release evoked by action potentials and plays a key role in modulating synaptic transmission by combining analog and digital signals. This process is known to be Ca2+-dependent. However, the underlying mechanism of how small changes in basal Ca2+ caused by subthreshold depolarization can regulate transmitter release triggered by a large increase in local Ca2+ is not well understood. This study aimed to investigate the source and signaling mechanisms of Ca2+ that couple subthreshold depolarization with the enhancement of glutamate release in hippocampal cultures and CA3 pyramidal neurons. Subthreshold depolarization increased presynaptic Ca2+ levels, the frequency of spontaneous release, and the amplitude of evoked release, all of which were abolished by blocking L-type Ca2+ channels. A high concentration of intracellular Ca2+ buffer or blockade of calmodulin and phospholipase C abolished depolarization induced increases in transmitter release. Estimation of the readily releasable pool size using hypertonic sucrose showed depolarization induced increases in readily releasable pool size, and this increase was abolished by blockade of calmodulin or phospholipase C. Our results provide mechanistic insights into the modulation of transmitter release by subthreshold potential change and highlight the role of L-type Ca2+ channels in coupling subthreshold depolarization to the activation of Ca2+-dependent signaling molecules that regulate transmitter release. SIGNIFICANCENeuronal activities are encoded by action potentials, but subthreshold changes in resting membrane potentials also play important roles in regulating neuronal functions including synaptic transmission. It is, however, poorly understood how small changes in basal Ca2+ induced by subthreshold depolarization regulate transmitter release triggered by a large increase in local Ca2+ in presynaptic terminals. We demonstrate that L-type Ca2+ channels are the major source of presynaptic Ca2+ influx at basal state and during subthreshold depolarization, resulting in the activation of signaling molecules such as calmodulin and phospholipase C, which facilitate transmitter release by increasing both release probability and the readily releasable pool size. Our results provide mechanistic insight into how subthreshold potential changes contribute to regulating transmitter release.

neuroscience↗

bioRxiv2023

What humans learn from corrective feedback for perceptual decision-making

Corrective feedback received on perceptual decisions is crucial for adjusting decision-making strategies to improve future choices. However, its complex interaction with other decision components, such as previous stimuli and choices, challenges a principled account of how it shapes subsequent decisions. One popular approach, based on animal behavior and extended to human perceptual decision-making, employs reinforcement learning, a principle proven successful in reward-based decision-making. The core idea behind this approach is that decision-makers, although engaged in a perceptual task, treat corrective feedback as rewards from which they learn choice values. Here, we explore an alternative idea, which is that humans consider corrective feedback on perceptual decisions as evidence of the actual state of the world rather than as rewards for their choices. By implementing these feedback-as-reward and feedback-as-evidence hypotheses on a shared learning platform, we show that the latter outperforms the former in explaining how corrective feedback adjusts the decision-making strategy along with past stimuli and choices. Our work suggests that humans learn about what has happened in their environment rather than the values of their own choices through corrective feedback during perceptual decision-making.

neuroscience↗

bioRxiv2023

Neural evidence for boundary updating as the source of the repulsive bias in classification

Binary classification, an act of sorting items into two classes by setting a boundary, is biased by recent history. One common form of such biases is repulsive bias, a tendency to sort an item into the class opposite to its preceding items. Sensory-adaptation and boundary-updating are considered as two contending sources of the repulsive bias, yet no neural support has been provided for either source. Here we explored human brains, using fMRI, to find such supports by relating the brain signals of sensory-adaptation and boundary-updating to human classification behavior. We found that the stimulus-encoding signal in the early visual cortex adapted to previous stimuli, yet its adaptation-related changes were dissociated from current choices. Contrastingly, the boundary-representing signals in the inferior-parietal and superior-temporal cortices shifted to previous stimuli and covaried with current choices. Our exploration points to boundary-updating, rather than sensory-adaptation, as the origin of the repulsive bias in binary classification.

neuroscience↗

bioRxiv2022

Burst firing is required for induction of Hebbian LTP at lateral perforant path to hippocampal granule cell synapses

High frequency burst firing is critical in summation of back-propagating action potentials (APs) in dendrites, which may greatly depolarize dendritic membrane potential. The physiological significance of burst firings of hippocampal dentate GCs in synaptic plasticity remains unknown. We found that GCs with low input resistance could be categorized into regular-spiking (RS) and burst-spiking (BS) cells based on their initial firing frequency (Finit) upon somatic rheobase current injection, and investigated how two types of GCs differ in long-term potentiation (LTP) induced by high-frequency lateral perforant pathway (LPP) inputs. Induction of Hebbian LTP at LPP synapses required at least three postsynaptic APs at Finit higher than 100 Hz, which was met in BS but not in RS cells. The synaptically evoked burst firing was critically dependent on persistent Na+ current, which was larger in BS than RS cells. The Ca2+ source for Hebbian LTP at LPP synapses was primarily provided by L-type calcium channels. In contrast, Hebbian LTP at medial PP synapses was mediated by T-type calcium channels, and could be induced regardless of cell types or Finit of postsynaptic APs. These results suggest that intrinsic firing properties affect synaptically driven firing patterns, and that bursting behavior differentially affects Hebbian LTP mechanisms depending on the synaptic input pathway.

neuroscience↗

bioRxiv2022

Anti-integrin αvβ6 autoantibodies are a novel predictive biomarker in ulcerative colitis

Background and AimsBetter biomarkers for prediction of ulcerative colitis (UC) development and prognostication are needed. Anti-integrin v{beta}6 autoantibodies (anti-v{beta}6) have been described in UC patients. Here, we tested for the presence of anti-v{beta}6 antibodies in the pre-clinical phase of UC and studied their association with disease-related outcomes after diagnosis. MethodsAnti-v{beta}6 were measured in 4 longitudinal serum samples collected from 82 subjects who later developed UC and 82 matched controls from a Department of Defense pre-clinical cohort (PREDICTS). In a distinct, external validation cohort (GEM), we tested 12 pre-UC subjects and 49 matched controls. Further, anti-v{beta}6 were measured in 2 incident UC cohorts (COMPASS n=55 and OSCCAR n=104) and associations between anti-v{beta}6 and UC-related outcomes were defined using Cox proportional-hazards model. ResultsAnti-v{beta}6 were significantly higher among individuals who developed UC compared to controls up to 10 years before diagnosis in PREDICTS. The anti-v{beta}6 seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 timepoints. Anti-v{beta}6 predicted UC development with an AUC of at least 0.8 up to 10 years before diagnosis. The presence of anti-v{beta}6 in pre-clinical UC samples was validated in the GEM cohort. Finally, high anti-v{beta}6 was associated with a composite of adverse UC-outcomes including hospitalization, disease extension, colectomy, systemic steroid use and/or escalation to biologic therapy in recently diagnosed UC. ConclusionAnti-integrin v{beta}6 auto-antibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes.

immunology↗

bioRxiv2022

Identifying brain areas for tactile perception through natural finger touch with MR-compatible tactile stimulus delivery system

Primates actively touch objects with their hands to collect information. In investigations of the tactile information processes, participants should experience tactile stimuli through active touch while brain activities are monitored. Here, we developed a pneumatic tactile stimulus delivery system (pTDS) that delivers various tactile stimuli on a programmed schedule and allows tactile perception through voluntary finger touches during MRI scanning. A pneumatic actuator moved tactile blocks and placed one in a finger hole. The time when an index finger touched a tactile stimulus was detected with a photosensor, allowing analysis of the touch-elicited brain responses. The brain responses were examined while the participants actively touched braille objects presented by the pTDS. BOLD responses during tactile perception were significantly stronger in a finger touch area of the contralateral somatosensory cortex compared with that of visual perception. This pTDS enables MR study of brain mechanisms for tactile processes through natural finger touch.

neuroscience↗

bioRxiv2022

Imaging through Windansee electrode arrays reveals a small fraction of local neurons following surface MUA

Prior studies have shown that neuronal spikes can be recorded with microelectrode arrays placed on the cortical surface. However, the etiology of these spikes remains unclear. Because the top cortical layer (layer 1) contains very few neuronal cell bodies, it has been proposed that these spikes originate from neurons with cell bodies in layer 2. To address this question, we combined two-photon calcium imaging with electrophysiological recordings from the cortical surface in awake mice using chronically implanted PEDOT:PSS electrode arrays on transparent parylene C substrate. Our electrode arrays (termed Windansee) were integrated with cortical windows offering see-through optical access while also providing measurements of local field potentials (LFP) and multiunit activity (MUA) from the cortical surface. To enable longitudinal data acquisition, we have developed a mechanical solution for installation, connectorization, and protection of Windansee devices aiming for an unhindered access for high numerical aperture microscope objectives and a lifetime of several months while worn by a mouse. Contrary to the common notion, our measurements revealed that only a small fraction of layer 2 neurons from the sampled pool (~13%) faithfully followed MUA recorded from the surface above the imaging field-of-view. Surprised by this result, we turned to computational modeling for an alternative explanation of the MUA signal. Using realistic modeling of neurons with back-propagating dendritic properties, we computed the extracellular action potential at the cortical surface due to firing of local cortical neurons and compared the result to that due to axonal inputs to layer 1. Assuming the literature values for the cell/axon density and firing rates, our modeling results show that surface MUA due to axonal inputs is over an order of magnitude larger than that due to firing of layer 2 pyramidal neurons. Thus, a combination of surface MUA recordings with two-photon calcium imaging can provide complementary information about the input to a cortical column and the local circuit response. Cortical layer I plays an important role in integration of a broad range of cortico-cortical, thalamocortical and neuromodulatory inputs. Therefore, detecting their activity as MUA while combining electrode recording with two-photon imaging using optically transparent surface electrode arrays would facilitate studies of the input/output relationship in cortical circuits, inform computational circuit models, and improve the accuracy of the next generation brain-machine interfaces.

neuroscience↗

bioRxiv2022

Cardiomyocyte alpha-1A adrenergic receptors mitigate post-infarct remodeling and mortality by constraining necroptosis

Activation of alpha-1-adrenergic receptors (1-ARs), particularly the 1A subtype, protects the murine heart against injury, whereas human studies show that 1-AR antagonists (-blockers) may increase the risk of heart failure. We created a cardiomyocyte-specific 1A-AR knockout mouse (cmAKO) to define the mechanisms underlying these effects and to elucidate whether they arise from cardiomyocyte 1A-ARs or systemic factors. Myocardial infarction (MI) resulted in 70% 7-day mortality in cmAKO compared to 10% in wild type (WT) mice. cmAKO mice exhibited exaggerated ventricular remodeling and increased cell death compared to WT mice 3 days post-MI, coupled to upregulation of canonical mediators of necroptosis: receptor-interacting protein (RIP) kinases RIP1 and RIP3 and mixed lineage kinase domain-like protein. An 1A-AR agonist mitigated ischemia-induced cardiomyocyte death and necroptotic signaling in vitro. A RIP1 antagonist abrogated the protective effects of 1A activation in vivo and in vitro. We found that patients at our center who were taking -blockers at the time of MI experienced a higher risk of mortality (hazard ratio 1.53, p=0.029) during 5-year follow-up, providing clinical correlation for our experimental data. Collectively our findings indicate that cardiomyocyte 1A-ARs constrain ischemia-induced necroptosis and suggest caution in the use of -blockers in patients at risk for MI.

pathology↗

bioRxiv2022

Inhibiting 5-lipoxygenase prevents skeletal muscle atrophy by targeting organogenesis signaling and insulin-like growth factor-1

BackgroundSkeletal muscle atrophy can occur in response to numerous factors, such as aging and certain medications, and produces a major socioeconomic burden. At present, there are no approved drugs for treating skeletal muscle atrophy. Arachidonate 5-lipoxygenase (Aox5) is a drug target for a number of diseases. However, pharmacological targeting of Alox5, and its role in skeletal muscle atrophy, is unclear. MethodsThe potential effects of gene knockdown and pharmacological targeting of Alox5 on skeletal muscle atrophy was investigated using cell-based models, animal models, and human skeletal muscle tissue cultures. Malotilate, a clinically safe drug developed for enhancing liver regeneration and Alox5 inhibitor, was investigated as a repurposing candidate. Mechanism(s) of action in skeletal muscle atrophy were assessed by measuring the expression level or activation status of key regulatory pathways, and validated using gene knockdown and RNA sequencing. ResultsMyotubes treated with the atrophy-inducing glucocorticoid, dexamethasone, were protected from catabolic responses by treatment with malotilate (+41.29%, P < 0.01). Similar anti-atrophy effects were achieved by gene knockdown of Alox5 (+30.4%, P < 0.05). Malotilate produced anti-atrophy effects without affecting the myogenic differentiation program. In an in vivo model of skeletal muscle atrophy, malotilate treatment enhanced muscle performance (Grip strength: +35.72%, Latency to fall: +553.1%, P < 0.05), increased mass and fiber cross sectional area (Quadriceps: +23.72%, Soleus: +33.3%, P < 0.01), and down-regulated atrogene expression (Atrogin-1: -61.58%, Murf-1: -66.06%, P < 0.01). Similar, beneficial effects of malotilate treatment were observed in an aging muscle, which also showed the preservation of fast twitch fibers (Type 2a: +56.48%, Type 2b: +37.32%, P < 0.01). Leukotrine B4, a product of Alox5 activity with inflammatory and catabolic functions, was found to be elevated in skeletal muscle undergoing atrophy (Quadriceps: +224.4%, P < 0.001). Cellular transcriptome analysis showed that targeting Alox5 upregulated biological processes regulating organogenesis and increased the expression of insulin-like growth factor-1, a key anti-atrophy hormone (+226.5%, P < 0.05). Interestingly, these effects were restricted to the atrophy condition and not observed in normal skeletal muscle cultures with Alox5 inhibition. Human skeletal muscle tissue was also protected from atrophy by pharmacological targeting of Alox5 (+23.68%, P < 0.05). ConclusionThese results shed new light on novel drug targets and mechanisms underpinning skeletal muscle atrophy. Alox5 is a regulator and drug target for muscle atrophy, and malotilate is an attractive compound for repurposing studies to treat this disease.

cell biology↗

bioRxiv2022

Post-weaning parvalbumin expression in left orbitofrontal cortex shapes sociability in female mice

The adolescent social experience is essential for the maturation of the prefrontal cortex in mammalian species. However, it still needs to be determined which cortical circuits mature with such experience and how it shapes adult social behaviors in a sex-specific manner. Here, we examined social approaching behaviors in male and female mice after post-weaning social isolation (PWSI), which deprives social experience during adolescence. We found that the PWSI, particularly isolation during late adolescence, caused an abnormal increase in social approaches (hypersociability) only in female mice. We further found that the PWSI female mice showed reduced parvalbumin (PV) expression in the left orbitofrontal cortex (OFCL). When we measured neural activity in the female OFCL, a substantial number of neurons showed higher activity when mice sniffed other mice (social sniffing) than when they sniffed an object (object sniffing). Interestingly, the PWSI significantly reduced both the number of activated neurons and the activity level during social sniffing in female mice. Similarly, the CRISPR/Cas9-mediated knock-down of PV in the OFCL during late adolescence enhanced sociability and reduced the social sniffing-induced activity in adult female mice via decreased excitability of PV+ neurons and reduced synaptic inhibition in the OFCL. Moreover, optogenetic activation of excitatory neurons or optogenetic inhibition of PV+ neurons in the OFCL enhanced sociability in female mice. Our data demonstrate that the adolescent social experience is critical for the maturation of PV+ inhibitory circuits in the OFCL; this maturation shapes female social behavior via enhancing social representation in the OFCL. Significance StatementAdolescent social isolation often changes adult social behaviors in mammals. Yet, we do not fully understand the sex-specific effects of social isolation and the brain areas and circuits that mediate such changes. Here, we found that adolescent social isolation causes three abnormal phenotypes in female but not male mice: hypersociability, decreased PV+ neurons in the OFCL, and decreased socially evoked activity in the OFCL. Moreover, PV deletion in the OFCL in vivo caused the same phenotypes in female mice by increasing excitation compared with inhibition within the OFCL. Our data suggest that adolescent social experience is required for PV maturation in the OFCL, which is critical for evoking OFCL activity that shapes social behaviors in female mice.

animal behavior and cognition↗

bioRxiv2022

Integrative in situ mapping of single-cell transcriptional states and tissue histopathology in an Alzheimer's disease model

Amyloid-{beta} plaques and neurofibrillary tau tangles are the neuropathologic hallmarks of Alzheimers disease (AD), but the spatiotemporal cellular responses and molecular mechanisms underlying AD pathophysiology remain poorly understood. Here we introduce STARmap PLUS to simultaneously map single-cell transcriptional states and disease marker proteins in brain tissues of AD mouse models at subcellular resolution (200 nm). This high-resolution spatial transcriptomics map revealed a core-shell structure where disease-associated microglia (DAM) closely contact amyloid-{beta} plaques, whereas disease-associated astrocytes (DAA) and oligodendrocyte precursor cells (OPC) are enriched in the outer shells surrounding the plaque- DAM complex. Hyperphosphorylated tau emerged mainly in excitatory neurons in the CA1 region accompanied by the infiltration of oligodendrocyte subtypes into the axon bundles of hippocampal alveus. The integrative STARmap PLUS method bridges single-cell gene expression profiles with tissue histopathology at subcellular resolution, providing an unprecedented roadmap to pinpoint the molecular and cellular mechanisms of AD pathology and neurodegeneration.

genomics↗

bioRxiv2021

Structural basis for the peptidoglycan editing activity of YfiH

Bacterial cells are encased in peptidoglycan (PG), a polymer of disaccharide N-acetyl-glucosamine (GlcNAc) and N-acetyl-muramic acid (MurNAc) cross-linked by peptide stems. PG is synthesized in the cytoplasm as UDP-MurNAc-peptide precursors, of which the amino-acid composition of the peptide is unique, with L-Ala added at the first position in most bacteria but L-Ser or Gly in some bacteria. YfiH is a PG-editing factor whose absence causes misincorporation of L-Ser instead of L-Ala into peptide stems; but its mechanistic function is unknown. Here we report the crystal structures of substrate-bound and product-bound YfiH, showing that YfiH is a cytoplasmic amidase that controls the incorporation of the correct amino acid to the nucleotide precursors by preferentially cleaving the nucleotide precursor byproduct UDP-MurNAc-L-Ser. This work reveals an editing mechanism in the cytoplasmic steps of peptidoglycan biosynthesis.

molecular biology↗

bioRxiv2021

Senescent stroma induces nuclear deformations in cancer cells via the inhibition of RhoA/ROCK/myosin II-based cytoskeletal tension

The presence of senescent cells within tissues has been functionally linked to malignant transformations. Here, using tension-gauge tethers technology, particle-tracking microrheology, and quantitative microscopy, we demonstrate that senescent associated secretory phenotype (SASP) derived from senescent fibroblasts impose nuclear lobulations and volume shrinkage on malignant cells, which stems from the loss of RhoA/ROCK/myosin II-based cortical tension. This loss in cytoskeletal tension induces decreased cellular contractility, adhesion, and increased mechanical compliance. These SASP-induced morphological changes are in part mediated by lamin A/C. These findings suggest that SASP induces a defective outside-in mechanotransduction, from actomyosin fibers in the cytoplasm to the nuclear lamina, thereby triggering a cascade of biophysical and biomolecular changes in cells that associate with malignant transformations.

cancer biology↗

bioRxiv2021

Chemogenetic activation of Locus Coeruleus Noradrenergic Neurons Modulates the Default Mode Network

The default mode network (DMN) of the brain is involved in cognition, emotion regulation, impulsivity, and balancing between internally and externally focused states. DMN dysregulation has been implicated in several neurological and neuropsychiatric disorders. In this study, we used functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and spectral fiber-photometry to investigate the selective neuromodulatory effect of norepinephrine (NE)-releasing noradrenergic neurons in the locus coeruleus (LC) on the DMN in mice. Chemogenetic-induced tonic LC-NE activity decreased cerebral blood volume (CBV) and glucose uptake, and increased synchronous low frequency fMRI activity within the frontal cortices of the DMN. Fiber-photometry results corroborated these findings, showing that LC-NE activation induced NE release, enhanced calcium-weighted neuronal spiking, and reduced CBV in the anterior cingulate cortex. These data suggest that LC-NE alters conventional stimulus-evoked coupling between neuronal activity and CBV in the frontal DMN. We also demonstrated that chemogenetic activation of LC-NE neurons strengthened functional connectivity within the frontal DMN, and this effect was causally mediated by reduced modulatory inputs from retrosplenial and hippocampal regions to the association cortices of the DMN.

neuroscience↗