Biology subjects

Kang, H.

Publications and source records attributed to Kang, H..

At least 73 records · Page 4Linked to original sources

bioRxiv2023

Cell state-dependent chromatin targeting in NUT carcinoma

Aberrant transcriptional programming and chromatin dysregulation are common to most cancers. Whether by deranged cell signaling or environmental insult, the resulting oncogenic phenotype is typically manifested in transcriptional changes characteristic of undifferentiated cell growth. Here we analyze targeting of an oncogenic fusion protein, BRD4-NUT, composed of two normally independent chromatin regulators. The fusion causes the formation of large hyperacetylated genomic regions or megadomains, mis-regulation of c-MYC, and an aggressive carcinoma of squamous cell origin. Our previous work revealed largely distinct megadomain locations in different NUT carcinoma patient cell lines. To assess whether this was due to variations in individual genome sequences or epigenetic cell state, we expressed BRD4-NUT in a human stem cell model and found that megadomains formed in dissimilar patterns when comparing cells in the pluripotent state with the same cell line following induction along a mesodermal lineage. Thus, our work implicates initial cell state as the critical factor in the locations of BRD4-NUT megadomains. These results, together with our analysis of c-MYC protein-protein interactions in a patient cell line, are consistent with a cascade of chromatin misregulation underlying NUT carcinoma.

genomics↗

bioRxiv2023

ER-to-lysosome Ca2+ refilling followed by K+ efflux-coupled store-operated Ca2+ entry in inflammasome activation and metabolic inflammation

We studied lysosomal Ca2+ in inflammasome. LPS+palmitic acid (PA) decreased lysosomal Ca2+ ([Ca2+]Lys) and increased [Ca2+]i through mitochondrial ROS, which was suppressed in Trpm2-KO macrophages. Inflammasome activation and metabolic inflammation in adipose tissue of high-fat diet (HFD)-fed mice were ameliorated by Trpm2 KO. ER[->]lysosome Ca2+ refilling occurred after lysosomal Ca2+ release whose blockade attenuated LPS+PA-induced inflammasome. Subsequently, store-operated Ca2+entry (SOCE) was activated whose inhibition suppressed inflammasome. SOCE was coupled with K+ efflux whose inhibition reduced ER Ca2+ content ([Ca2+]ER) and impaired [Ca2+]Lys recovery. LPS+PA activated KCa3.1 channel, a Ca2+-activated K+ channel. Inhibitors of KCa3.1 channel or Kcnn4 KO reduced [Ca2+]ER, attenuated increase of [Ca2+]i or inflammasome activation by LPS+PA, and ameliorated HFD-induced inflammasome or metabolic inflammation. Lysosomal Ca2+ release induced delayed JNK and ASC phosphorylation through CAMKII-ASK1. These results suggest a novel role of lysosomal Ca2+ release sustained by ER[->]lysosome Ca2+ refilling and K+ efflux through KCa3.1 channel in inflammasome activation and metabolic inflammation.

immunology↗

bioRxiv2023

Inhibition of Cellular MEK/ERK Signaling Suppresses Murine Papillomavirus Type 1 Replicative Activities and Promotes Tumor Regression

Human papillomaviruses (HPVs) are a significant public health concern due to their widespread transmission, morbidity, and oncogenic potential. Despite efficacious vaccines, millions of unvaccinated individuals and those with existing infections will develop HPV-related diseases for the next two decades. The continuing burden of HPV-related diseases is exacerbated by the lack of effective therapies or cures for most infections, highlighting the need to identify and develop antivirals. The experimental murine papillomavirus type 1 (MmuPV1) model provides opportunities to study papillomavirus pathogenesis in cutaneous epithelium, the oral cavity, and the anogenital tract. However, to date the MmuPV1 infection model has not been used to demonstrate the effectiveness of potential antivirals. We previously reported that inhibitors of cellular MEK/ERK signaling suppress oncogenic HPV early gene expression in vitro. Herein, we adapted the MmuPV1 infection model to determine whether MEK inhibitors have anti-papillomavirus properties in vivo. We demonstrate that oral delivery of a MEK1/2 inhibitor promotes papilloma regression in immunodeficient mice that otherwise would have developed persistent infections. Quantitative histological analyses revealed that inhibition of MEK/ERK signaling reduces E6/E7 mRNAs, MmuPV1 DNA, and L1 protein expression within MmuPV1-induced lesions. These data suggest that MEK1/2 signaling is essential for both early and late MmuPV1 replication events supporting our previous findings with oncogenic HPVs. We also provide evidence that MEK inhibitors protect mice from developing secondary tumors. Thus, our data suggest that MEK inhibitors have potent anti-viral and anti-tumor properties in a preclinical mouse model and merit further investigation as papillomavirus antiviral therapies. Significance StatementPersistent human papillomavirus (HPV) infections cause significant morbidity and oncogenic HPV infections can progress to anogenital and oropharyngeal cancers. Despite the availability of effective prophylactic HPV vaccines, millions of unvaccinated individuals, and those currently infected will develop HPV-related diseases over the next two decades and beyond. Thus, it remains critical to identify effective antivirals against papillomaviruses. Using a mouse papillomavirus model of HPV infection, this study reveals that cellular MEK1/2 signaling supports viral tumorigenesis. The MEK1/2 inhibitor, trametinib, demonstrates potent antiviral activities and promotes tumor regression. This work provides insight into the conserved regulation of papillomavirus gene expression by MEK1/2 signaling and reveals this cellular pathway as a promising therapeutic target for the treatment of papillomavirus diseases.

cancer biology↗

bioRxiv2023

Auditory feedback-independent maintenance of song performance through daily singing in adult songbirds

Many songbirds learn to produce songs through vocal practice early in life and continue to sing numerous renditions of their learned songs daily throughout their lifetime. While it is well-known that adult songbirds sing as part of a mating ritual, the functions of singing behavior outside of reproductive contexts are not fully understood. Here, we demonstrate that adult singing outside of reproductive contexts serves to prevent passive changes in song performance. We suppressed the daily singing behavior of adult zebra finches produced in the solo context for two weeks using a reversible behavioral manipulation and examined the effect on song performance. Our results indicated that suppressing daily singing significantly decreased the pitch of song elements and both the amplitude and duration of song motifs. These findings suggest that adult song is not acoustically stable without singing, and that adult birds maintain their song performance by daily singing. Moreover, we found that the changes in song structure caused by singing suppression were substantially recovered within two weeks of free singing, even in deafened birds. Thus, the recovery of song performance does not necessarily require auditory feedback but is predominantly caused by singing behavior per se (i.e., the physical act of singing). Finally, unlike the auditory feedback-dependent song plasticity reported previously, the passive song changes caused by singing suppression were not significantly dependent on age. Taken together, our findings demonstrate that adult songbirds maintain song performance by preventing passive song changes through the physical act of daily singing throughout their life. Such daily singing likely functions as vocal training to maintain the neural and/or muscular system in optimal conditions for song performance in reproductive contexts, similar to how human singers and athletes practice daily to maintain their performance.

animal behavior and cognition↗

bioRxiv2023

Modernizing the original influenza vaccine to enhance protective antibody responses against neuraminidase antigens

Most seasonal influenza vaccines are produced using hemagglutinin (HA) surface antigens from inactivated virions. However, virions are thought to be a suboptimal source for the less abundant NA surface antigen, which is also protective against severe disease. Here, we demonstrate that inactivated influenza virions are compatible with two modern approaches for improving protective NA antibody responses. Using a DBA/2J mouse model, we confirmed that the strong infection-induced NA inhibitory (NAI) antibody responses are only achieved by high dose immunizations of inactivated virions, likely due to low viral NA content. Based on this observation, we first produced virions with higher NA content by using reverse genetics to exchange the viral internal gene segments. Single immunizations with these inactivated virions enhanced NAI antibody responses, improved NA-based protection from a lethal viral challenge and allowed the development of natural immunity to the heterotypic challenge virus HA. Second, we combined inactivated virions with recombinant NA proteins. These mixtures increased NA-based protection following viral challenge and elicited stronger NA antibody responses than either component alone, especially when the NAs were homologous. Together, these results indicate that viral- and protein-based vaccines can be combined in a single syringe to improve protective antibody responses to influenza antigens.

microbiology↗

bioRxiv2023

Auditory memory of complex sounds in sparsely distributed, highly correlated neurons in the auditory cortex

Listening in complex sound environments requires rapid segregation of different sound sources e.g., speakers from each other, speakers from other sounds, or different instruments in an orchestra, and also adjust auditory processing on the prevailing sound conditions. Thus, fast encoding of inputs and identifying and adapting to reoccurring sounds are necessary for efficient and agile sound perception. This adaptation process represents an early phase of developing implicit learning of sound statistics and thus represents a form of auditory memory. The auditory cortex (ACtx) is known to play a key role in this encoding process but the underlying circuits and if hierarchical processing exists are not known. To identify ACtx regions and cells involved in this process, we simultaneously imaged population of neurons in different ACtx subfields using in vivo 2-photon imaging in awake mice. We used an experimental stimulus paradigm adapted from human studies that triggers rapid and robust implicit learning to passively present complex sounds and imaged A1 Layer 4 (L4), A1 L2/3, and A2 L2/3. In this paradigm, a frozen spectro-temporally complex Target sound would be randomly re-occurring within a stream of random other complex sounds. We find distinct groups of cells that are specifically responsive to complex acoustic sequences across all subregions indicating that even the initial thalamocortical input layers (A1 L4) respond to complex sounds. Cells in all imaged regions showed decreased response amplitude for reoccurring Target sounds indicating that a memory signature is present even in the thalamocortical input layers. On the population level we find increased synchronized activity across cells to the Target sound and that this synchronized activity was more consistent across cells regardless of the duration of frozen token within Target sounds in A2, compared to A1. These findings suggest that ACtx and its input layers play a role in auditory memory for complex sounds and suggest a hierarchical structure of processes for auditory memory.

neuroscience↗

bioRxiv2023

GolpHCat (TMEM87A): a unique voltage-gated and pH-sensitive cation channel in the Golgi

The Golgi apparatus is a critical intracellular organelle that is responsible for modifying, packaging, and transporting proteins to their destinations. Golgi homeostasis involving the acidic pH, ion concentration, and membrane potential, is critical for proper functions and morphology of the Golgi. Although transporters and anion channels that contribute to Golgi homeostasis have been identified, the molecular identity of cation channels remains unknown. Here we identify TMEM87A as a novel Golgi-resident cation channel that contributes to pH homeostasis and rename it as GolpHCat (Golgi pH-sensitive Cation channel). The genetic ablation of GolpHCat exhibits an impaired resting pH in the Golgi. Heterologously expressed GolpHCat displays voltage- and pH-dependent, non-selective cationic, and inwardly rectifying currents, with potent inhibition by gluconate. Furthermore, reconstitution of purified GolpHCat in liposomes generates functional channel activities with unique voltage-dependent gating and ion permeation. GolpHCat is expressed in various cell types such as neurons and astrocytes in the brain. In the hippocampus, GolpHCat-knockout mice show dilated Golgi morphology and altered glycosylation and protein trafficking, leading to impaired spatial memory with significantly reduced long-term potentiation. We elucidate that GolpHCat, by maintaining Golgi membrane potential, regulates ionic and osmotic homeostasis, protein glycosylation/trafficking, and brain functions. Our results propose a new molecular target for Golgi-related diseases and cognitive impairment.

molecular biology↗

bioRxiv2023

Structural insights into ion conduction by novel cation channel, TMEM87A, in Golgi apparatus

TMEM87 family is evolutionarily conserved eukaryotic transmembrane proteins residing in the Golgi1. TMEM87 members play a role in retrograde transport in Golgi and are also proposed mechanosensitive ion channel implicated in cancer and heart disease2-7. In an accompanying study, TMEM87A is described as a voltage-gated, pH-sensitive, non-selective cation channel whose genetic ablation in mice disrupts Golgi morphology, alters glycosylation and protein trafficking, and impairs hippocampal memory. Despite the pivotal functions of TMEM87s in Golgi, underlying molecular mechanisms of channel gating and ion conduction have remained unknown. Here, we present a high-resolution cryo-electron microscopy structure of human TMEM87A (hTMEM87A). Compared with typical ion channels, the architecture of hTMEM87A is unique: a monomeric cation channel consisting of a globular extracellular/luminal domain and a seven-transmembrane domain (TMD) with close structural homology to channelrhodopsin. The central cavity within TMD is occupied by endogenous phosphatidylethanolamine, which seals a lateral gap between two TMs exposed to the lipid bilayer. By combining electrophysiology and molecular dynamics analysis, we identify a funnel-shaped electro-negative luminal vestibule that effectively attracts cations, and phosphatidylethanolamine occludes ion conduction. Our findings suggest that a conformational switch of highly conserved positively-charged residues on TM3 and displacement of phosphatidylethanolamine are opening mechanisms for hTMEM87A, providing an unprecedented insight into the molecular basis for voltage-gated ion conduction in Golgi.

biophysics↗

bioRxiv2022

Mapping the convergence of genes for coronary artery disease onto endothelial cell programs

Genome-wide association studies (GWAS) have discovered thousands of risk loci for common, complex diseases, each of which could point to genes and gene programs that influence disease. For some diseases, it has been observed that GWAS signals converge on a smaller number of biological programs, and that this convergence can help to identify causal genes1-6. However, identifying such convergence remains challenging: each GWAS locus can have many candidate genes, each gene might act in one or more possible programs, and it remains unclear which programs might influence disease risk. Here, we developed a new approach to address this challenge, by creating unbiased maps to link disease variants to genes to programs (V2G2P) in a given cell type. We applied this approach to study the role of endothelial cells in the genetics of coronary artery disease (CAD). To link variants to genes, we constructed enhancer-gene maps using the Activity-by-Contact model7,8. To link genes to programs, we applied CRISPRi-Perturb-seq9-12 to knock down all expressed genes within {+/-}500 Kb of 306 CAD GWAS signals13,14 and identify their effects on gene expression programs using single-cell RNA-sequencing. By combining these variant-to-gene and gene-to-program maps, we find that 43 of 306 CAD GWAS signals converge onto 5 gene programs linked to the cerebral cavernous malformations (CCM) pathway--which is known to coordinate transcriptional responses in endothelial cells15, but has not been previously linked to CAD risk. The strongest regulator of these programs is TLNRD1, which we show is a new CAD gene and novel regulator of the CCM pathway. TLNRD1 loss-of-function alters actin organization and barrier function in endothelial cells in vitro, and heart development in zebrafish in vivo. Together, our study identifies convergence of CAD risk loci into prioritized gene programs in endothelial cells, nominates new genes of potential therapeutic relevance for CAD, and demonstrates a generalizable strategy to connect disease variants to functions.

genomics↗

bioRxiv2022

The Interictal Suppression Hypothesis in Focal Epilepsy: Electrographic and Structural Evaluation

Why are people with focal epilepsy not constantly seizing? Previous molecular work has implicated gamma-aminobutyric acid balance as integral to seizure generation and termination, but is the high-level distributed brain network involved in suppressing seizures? Recent intracranial electrographic evidence has suggested that seizure onset zones have an increased inward connectivity. Accordingly, we hypothesize that seizure onset zones are actively suppressed by the rest of the brain network during interictal states. We tested this hypothesis on 81 subjects with drug resistant focal epilepsy undergoing presurgical evaluation. We utilized intracranial electrographic resting-state and neurostimulation recordings to evaluate the network connectivity of seizure onset, propagative, and non-involved regions. We then utilized diffusion imaging to acquire estimates of white matter connectivity to evaluate structure-function coupling effects on connectivity findings. Finally, using our observations, we generated a resting-state classification model to assist clinicians in detecting seizure onset and propagative zones without the need for multiple ictal recordings. Our findings indicate that seizure onset and propagative zones demonstrate markedly increased inward connectivity and decreased outward connectivity on both resting-state and neurostimulation analyses. When controlling for distance between regions, the difference between inward vs. outward connectivity remained stable up to 80 mm between brain connections. Structure-function coupling analyses revealed that seizure onset zones exhibit abnormally enhanced coupling (hypercoupling) of surrounding regions compared to presumably healthy tissue. Using these observations, our classification models achieved a maximum held-out testing set accuracy of 92.0{+/-}2.2%. These results indicate that seizure onset zones are actively segregated and suppressed by a widespread brain network. Furthermore, this electrographically observed functional suppression is disproportionate to any observed structural connectivity alterations of the seizure onset zones. These findings have implications for the identification of seizure onset zones using only brief resting-sate recordings to reduce patient morbidity and augment the presurgical evaluation of drug resistant epilepsy. Furthermore, testing of the interictal suppression hypothesis can provide insight into potential new resective, ablative, and neuromodulation approaches to improve surgical success rates in those suffering from drug resistant focal epilepsy.

neuroscience↗

bioRxiv2022

Time-varying hierarchical core voxels disclosed by k-core percolation on dynamic inter-voxel connectivity resting-state fMRI

k-core percolation on the scale-free static brain connectivity revealed hierarchical structure of inter-voxel correlations, which was successfully visualized by hyperbolic disc embedding on resting-state fMRI. In static study, flagplots and brain rendered kmax-core display showed the changes of hierarchical structures of voxels belonging to functional independent components (IC). In this dynamic sliding-window study, temporal progress of hierarchical structure of voxels were investigated in individuals and in sessions of an individual. kmax-core and coreness k values characterizing time-varying core voxels were visualized on animated stacked-histogram/flagplots and animated brain-rendered images. Resting-state fMRI of Human Connectome Project and of Kirby weekly revealed the slow progress and multiple abrupt state transitions of the voxels of coreness k and at the uppermost hierarchy, representing their correlative time-varying mental states in individuals and in sessions. We suggest this characteristic core voxels-IC compositions on dynamic study fingerprint the time-varying resting states of human minds. One Sentence SummaryDynamic state transitions of hierarchical functional inter-voxel connectivity implied time-varying mental states at rest on fMRI

neuroscience↗

bioRxiv2022

Along-tract quantification of resting-state BOLD hemodynamic response functions in white matter

Detailed knowledge of the BOLD hemodynamic response function (HRF) is crucial for accurate analysis and interpretation of functional MRI data. Considerable efforts have been made to characterize the HRF in gray matter (GM) but much less is known about BOLD effects in white matter (WM). However, recent reports have demonstrated reliable detection and analyses of WM BOLD signals after stimulation and in a resting state. WM and GM differ in energy requirements and blood flow, so neurovascular couplings may well be different. We aimed to derive a comprehensive characterization of the HRF in WM across a population, including accurate measurements of its shape and its variation along and between WM pathways, using resting-state fMRI acquisitions. Our results show that the HRF is significantly different between WM and GM. Features of the HRF, such as a prominent initial dip, show strong relationships with features of the tissue microstructure derived from diffusion imaging, and these relationships differ between WM and GM, consistent with BOLD signal fluctuations reflecting different energy demands and differences in neurovascular coupling between tissues of different composition. We also show that the HRF varies significantly along WM pathways, and is different between different WM pathways. Thus, much like in GM, changes in flow and/or oxygenation are different for different parts of the WM. These features of the HRF in WM are especially relevant for interpretation of the biophysical basis of BOLD effects in WM.

neuroscience↗

bioRxiv2022

Short superficial white matter and aging: a longitudinal multi-site study of 1,293 subjects and 2,711 sessions

It is estimated that short association fibers, or "U-shaped" fibers running immediately beneath the cortex, may make up as much as 60% of the total white matter volume. However, these have been understudied relative to the long-range association, projection, and commissural fibers of the brain. This is largely because of limitations of diffusion MRI fiber tractography, which is the primary methodology used to non-invasively study the white matter connections. Inspired by recent anatomical considerations and methodological improvements in U-fiber tractography, we aim to characterize changes in these fiber systems in cognitively normal aging, which provide insight into the biological foundation of age-related cognitive changes, and a better understanding of how age-related pathology differs from healthy aging. To do this, we used three large, longitudinal and cross-sectional datasets (N = 1293 subjects, 2711 sessions) to quantify microstructural features and length/volume features of several U-fiber systems. We find that axial, radial, and mean diffusivities show positive associations with age, while fractional anisotropy has negative associations with age in superficial white matter throughout the entire brain. These associations were most pronounced in the frontal, temporal, and temporoparietal regions. Moreover, measures of U-fiber volume and length decrease with age in a heterogenous manner across the brain, with prominent effects observed for pre- and post-central gyri. These features, and their variations with age, provide the background for characterizing normal aging, and, in combination with larger association pathways and gray matter microstructural features, may provide insight into fundamental mechanisms associated with aging and cognition.

neuroscience↗

bioRxiv2022

Variant Polycomb complexes in Drosophila consistent with ancient functional diversity

Polycomb group (PcG) mutants were first identified in Drosophila based on their failure to maintain proper Hox gene repression during development. The proteins encoded by the corresponding fly genes mainly assemble into one of two discrete Polycomb Repressive Complexes: PRC1 or PRC2. However, biochemical analyses in mammals have revealed alternative forms of PRC2, and multiple distinct types of non-canonical or variant PRC1. Through a series of proteomic analyses, we identify analogous PRC2 and variant PRC1 complexes in Drosophila, as well as a broader repertoire of interactions implicated in early development. Our data provide strong support for the ancient diversity of PcG complexes, and a framework for future analysis in a longstanding and versatile genetic system.

developmental biology↗

bioRxiv2022

Stable nebulization and muco-trapping properties of Regdanvimab/IN-006 support its development as a potent, dose-saving inhaled therapy for COVID-19

The respiratory tract represents the key target for antiviral delivery in early interventions to prevent severe COVID-19. While neutralizing monoclonal antibodies (mAb) possess considerable efficacy, their current reliance on parenteral dosing necessitates very large doses and places a substantial burden on the healthcare system. In contrast, direct inhaled delivery of mAb therapeutics offers the convenience of self-dosing at home, as well as much more efficient mAb delivery to the respiratory tract. Here, building on our previous discovery of Fc-mucin interactions crosslinking viruses to mucins, we showed that regdanvimab, a potent neutralizing mAb already approved for COVID-19 in several countries around the world, can effectively trap SARS-CoV-2 virus-like-particles in fresh human airway mucus. IN-006, a reformulation of Regdanvimab, was stably nebulized across a wide range of concentrations, with no loss of activity and no formation of aggregates. Finally, nebulized delivery of IN-006 resulted in 100-fold greater mAb levels in the lungs of rats compared to serum, in marked contrast to intravenously dosed mAbs. These results not only support our current efforts to evaluate the safety and efficacy of IN-006 in clinical trials, but more broadly substantiate nebulized delivery of human antiviral mAbs as a new paradigm in treating SARS-CoV-2 and other respiratory pathologies.

bioengineering↗

bioRxiv2022

Aging and white matter microstructure and macrostructure: a longitudinal multi-site diffusion MRI study of 1,184 participants

Quantifying the microstructural and macrostructural geometrical features of the human brains connections is necessary for understanding normal aging and disease. Here, we examine brain white matter diffusion magnetic resonance imaging data from one cross-sectional and two longitudinal datasets totaling in 1184 subjects and 2236 sessions of people aged 50-97 years. Data was drawn from well-established cohorts, including the Baltimore Longitudinal Study of Aging dataset, Cambridge Centre for Ageing Neuroscience dataset, and the Vanderbilt Memory & Aging Project. Quantifying 4 microstructural features and, for the first time, 11 macrostructure-based features of volume, area, and length across 120 white matter pathways, we apply linear mixed effect modeling to investigate changes in pathway-specific features over time, and document large age associations within white matter. Conventional diffusion tensor microstructure indices are the most age-sensitive measures, with positive age associations for diffusivities and negative age associations with anisotropies, with similar patterns observed across all pathways. Similarly, pathway shape measures also change with age, with negative age associations for most length, surface area, and volume-based features. A particularly novel finding of this study is that while trends were homogeneous throughout the brain for microstructure features, macrostructural features demonstrated heterogeneity across pathways, whereby several projection, thalamic, and commissural tracts exhibited more decline with age compared to association and limbic tracts. The findings from this large-scale study provide a comprehensive overview of the age-related decline in white matter and demonstrate that macrostructural features may be more sensitive to heterogeneous white matter decline. Therefore, leveraging macrostructural features may be useful for studying aging and could have widespread implications for a variety of neurodegenerative disorders.

neuroscience↗

bioRxiv2021

Simultaneous Mnemonic and Predictive Representations in the Auditory Cortex

Recent studies have shown that stimulus history can be decoded via the use of broadband sensory impulses to reactivate mnemonic representations. It has also been shown that predictive mechanisms in the auditory system demonstrate similar tonotopic organization of neural activity as that elicited by the perceived stimuli. However, it remains unclear if the mnemonic and predictive information can be decoded from cortical activity simultaneously and from overlapping neural populations. Here, we recorded neural activity using electrocorticography (ECoG) in the auditory cortex of anesthetized rats while exposed to repeated stimulus sequences, where events within the sequence were occasionally replaced with a broadband noise burst or omitted entirely. We show that both stimulus history and predicted stimuli can be decoded from neural responses to broadband impulse at overlapping latencies but linked to largely independent neural populations. We also demonstrate that predictive representations are learned over the course of stimulation at two distinct time scales, reflected in two dissociable time windows of neural activity. These results establish a valuable tool for investigating the neural mechanisms of passive sequence learning, memory encoding, and prediction mechanisms within a single paradigm, and provide novel evidence for learning predictive representations even under anaesthesia.

neuroscience↗

bioRxiv2021

The omega-3-fatty acid docosahexaenoic acid modulates intracellular myo-inositol and its biosynthetic genes.

Bipolar disorder is a debilitating mood disorder characterized by recurring episodes of mania and depression. It affects 2.6% of adults and has a lifetime prevalence among adults of 3.9%. Current mood stabilizers are not always effective and/or are not well tolerated by many patients; thus, there is a need to develop or identify more effective and less harmful treatments. Omega-3-fatty acids have been shown to be effective in the treatment of bipolar disorder; however, their mechanism of action is unknown. Myo-inositol depletion has been hypothesized as the mechanism by which mood stabilizers exert their therapeutic effect. Using an enzymatic assay, we determined intracellular myo-inositol levels increased more than 2-fold when cells were grown in the presence of the omega-3 fatty acid docosahexaenoic acid (DHA). RT-qPCR was used to characterize the effects of DHA on genes in the myo-inositol biosynthetic pathway. We show DHA increases relative expression and has a concentration-dependent impact on INO1 and INM1, which encode myo-inositol-1-phosphate synthase and myo-inositol monophosphate 1-phosphatase, respectively. We therefore conclude that the omega-3-fatty acid DHA exerts its therapeutic effect on bipolar disorder by increasing intracellular myo-inositol, which may be accomplished by upregulating its biosynthetic genes.

molecular biology↗