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bioRxiv2017

Methods in field chronobiology

Chronobiological research has seen a continuous development of novel approaches and techniques to measure rhythmicity at different levels of biological organization from locomotor activity (e.g. migratory restlessness) to physiology (e.g. temperature and hormone rhythms, and relatively recently also in genes, proteins and metabolites). However, the methodological advancements in this field have been mostly and sometimes exclusively used only in indoor laboratory settings. In parallel, there has been an unprecedented and rapid improvement in our ability to track animals and their behaviour in the wild. However, while the spatial analysis of tracking data is widespread, its temporal aspect is largely unexplored. Here, we review the tools that are available or have potential to record rhythms in the wild animals with emphasis on currently overlooked approaches and monitoring systems. We then demonstrate, in three question-driven case studies, how the integration of traditional and newer approaches can help answer novel chronobiological questions in free-living animals. Finally, we highlight unresolved issues in field chronobiology that may benefit from technological development in the future. As most of the studies in the field are descriptive, the future challenge lies in applying the diverse technologies to experimental set-ups in the wild.

animal behavior and cognition↗

bioRxiv2017

Independent erosion of conserved transcription factor binding sites points to shared hindlimb, vision, and scrotum loss in different mammals

Genetic variation in cis-regulatory elements is thought to be a major driving force in morphological and physiological change. However, identifying transcription factor binding events which code for complex traits remains a challenge, motivating novel means of detecting putatively important binding events. Using a curated set of 1,154 high-quality transcription factor motifs, we demonstrate that independently eroded binding sites are enriched for independently lost traits in three distinct pairs of placental mammals. We show that these independently eroded events pinpoint the loss of hindlimbs in dolphin and manatee, degradation of vision in naked mole-rat and star-nosed mole, and the loss of scrotum in white rhinoceros and Weddell seal. Our study exhibits a novel methodology to detect cis-regulatory mutations which help explain a portion of the molecular mechanism underlying complex trait formation and loss.\n\nAuthor SummaryEvolution has produced an astounding variety of species with incredibly diverse phenotypes. A central question in evolutionary developmental biology is how (and which) DNA evolves to encode all of these different traits. A prevailing hypothesis is that changes in regulatory DNA, short stretches of DNA which control the expression of protein-coding genes, drive important differences in trait formation between species. The basic building block of regulatory DNA is thought to be transcription factor binding sites, shortl genomic sequences which attract proteins whose central role is to control the rate of transcription. In this study, we asked whether the independent erosion of otherwise highly conserved transcription factor binding sites points to a trait shared between species which have undergone similar adaptations. We show that our method is able to point to the loss of hindlimbs in dolphin and manatee, poor vision in naked mole-rat and star-nosed mole, and loss of scrotum in Weddell seal and white rhinoceros. Overall, our study exhibits a means of detecting evolutionarily important genomic regions which help explain a portion of complex trait loss and retention.

evolutionary biology↗

bioRxiv2017

Cell surface vimentin is involved in matrix stiffness-dependent infection of endothelial cells by Listeria monocytogenes

Extracellular matrix (ECM) stiffness is one of many mechanical forces acting on mammalian adherent cells that influence cellular function. We have addressed the open question of how ECM stiffness might alter the susceptibility of host cells to infection by bacterial pathogens. We manufactured hydrogels of varying physiologically-relevant stiffness and seeded human microvascular endothelial cells (HMEC-1) on them. We then infected HMEC-1 with the bacterial pathogen Listeria monocytogenes (Lm) and found that adhesion of Lm onto host cells increases monotonically with increasing matrix stiffness, an effect that requires the activity of focal adhesion kinase (FAK). We identified cell surface vimentin as a candidate surface receptor mediating stiffness-dependent adhesion of Lm to HMEC-1, and demonstrated that bacterial infection of these host cells is decreased when surface vimentin is perturbed. Our results provide the first evidence that ECM stiffness can mediate the susceptibility of host cells to bacterial infection.

microbiology↗

bioRxiv2017

Occipital tACS bursts during a visual task impact ongoing neural oscillation power, coherence and LZW complexity

Little is known about the precise neural mechanisms by which tACS affects the human cortex. Current hypothesis suggest that transcranial current stimulation (tCS) can directly enhance ongoing brain oscillations and induce long - lasting effects through the activation of synaptic plasticity mechanisms [1]. Entrainment has been demonstrated in in - vitro studies, but its presence in non-invasive human studies is still under debate [2,3]. Here, we aim to investigate the immediate and short-term effects of tACS bursts on the occipital cortex of participants engaged in a change - of - speed detection task, a task that has previously reported to have a clear physiology - behavior relationship, where trials with faster responses also have increased power in {gamma} - oscillations (50 - 80 Hz) [4]. The dominant brain oscillations related to the visual task are modulated using multichannel tACS at 10 and 70 Hz within occipital cortex. We found that tACS stimulation at 10 Hz (tACS 10) enhanced both (8 - 13 Hz) and {gamma} oscillations, in hand with an increase in reaction time (RT) in the change - of - speed detection visual task. On the other hand, tACS at 70Hz desynchronized visual cortices, impairing both phase - locked and endogenous {gamma} - power while increasing RT. While both tACS protocols seem to revert the relationship reported in [4], we argue that tACS produces a shift in attentional resources within visual cortex while leaving unaltered the resources required to conduct the task. This theory is supported by the fact that the correlation between fast RT and high {gamma}- power trials is maintained for tACS sessions too. Finally, we measured cortical excitability by analyzing Event - Related - Potentials (ERP) Lempel - Ziv - Welch Complexity (LZW). In control sessions we observe that lower {gamma} - LZW complexity correlates to faster reaction times. Both metrics are altered by tACS stimulation, as tACS 10 decreased amplitude of the P300 peak, while increasing {gamma}- LZW complexity. To this end, our study highlights the nonlinear cross - frequency interaction between exogenous stimulation and endogenous brain dynamics, and proposes the use of complexity metrics, as LZW, to characterize excitability patterns of cortical areas in a behaviorally relevant timescale. These insights will hopefully contribute to the design of adaptive and personalized tACS protocols where cortical excitability can be characterized through complexity metrics.\n\nAdditional Title Page FootnotesO_LIWe introduce a bursting tACS protocol to study semi-concurrent tACS effects in the visual system and their impact on behavior as measured by reaction time.\nC_LIO_LIBurst 10 Hz tACS (tACS10) applied to the visual cortex entrained {gamma}-oscillations and increased RTs in a change-of-speed detection visual task more than 70 Hz tACS (tACS70) or Control conditions.\nC_LIO_LIBurst tACS10 also decreased amplitude of the P300 peak, while increasing -power and {gamma}-LZW complexity.\nC_LIO_LIPhysiological and behavioral impact of occipital tACS10 and tACS70 was frequency-specific. tACS70 reduced {gamma}-oscillations after 20min of tACS stimulation.\nC_LIO_LICognitive task may determine cortical excitation levels as measured by complexity metrics, as lower {gamma}-LZW complexity correlates to faster reaction times.\nC_LI

neuroscience↗

bioRxiv2017

Experience-dependent modulation of behavioral features in sensory navigation of nematodes and bats revealed by machine learning

Animal behavior is the final and integrated output of the brain activity. Thus, recording and analyzing behavior is critical to understand the underlying brain function. While recording animal behavior has become easier than ever with the development of compact and inexpensive devices, detailed behavioral data analysis requires sufficient previous knowledge and/or high content data such as video images of animal postures, which makes it difficult for most of the animal behavioral data to be efficiently analyzed to understand brain function. Here, we report a versatile method using a hybrid supervised/unsupervised machine learning approach to efficiently estimate behavioral states and to extract important behavioral features only from low-content animal trajectory data. As proof of principle experiments, we analyzed trajectory data of worms, fruit flies, rats, and bats in the laboratories, and penguins and flying seabirds in the wild, which were recorded with various methods and span a wide range of spatiotemporal scales--from mm to 1000 km in space and from sub-seconds to days in time. We estimated several states during behavior and comprehensively extracted characteristic features from a behavioral state and/or a specific experimental condition. Physiological and genetic experiments in worms revealed that the extracted behavioral features reflected specific neural or gene activities. Thus, our method provides a versatile and unbiased way to extract behavioral features from simple trajectory data to understand brain function.

neuroscience↗

bioRxiv2017

Sleep and the gut microbiome: antibiotic-induced depletion of the gut microbiota reduces nocturnal sleep in mice

Several bacterial cell wall components such as peptidoglycan and muramyl peptide are potent inducers of mammalian slow-wave sleep when exogenously administered to freely behaving animals. It has been proposed that the native gut microflora may serve as a quasi-endogenous pool of somnogenic bacterial cell wall products given their quantity and close proximity to the intestinal portal. This proposal suggests that deliberate manipulation of the host's intestinal flora may elicit changes in host sleep behavior. To test this possibility, we evaluated 24 h of sleep-wake behavior after depleting the gut microbiota with a 14 d broad-spectrum antibiotic regimen containing high doses of ampicillin, metronidazole, neomycin, and vancomycin. High-throughput sequencing of the bacterial 16S rDNA gene was used to confirm depletion of fecal bacteria and sleep-wake vigilance states were determined using videosomnography techniques based on previously established behavioral criteria shown to highly correlate with standard polysomnography-based methods. Additionally, considering that germ-free and antibiotic-treated mice have been earlier shown to display increased locomotor activity, and since locomotor activity has been used as a reliable proxy of sleep, we suspected that the elevated locomotor activity previously reported in these animals may reflect an unreported reduction in sleep behavior. To examine this potential relationship, we also quantified locomotor activity on a representative subsample of the same 24 h of video recordings using the automated video-tracking software ANY-maze. We found that antibiotic-induced depletion of the gut microbiota reduced nocturnal sleep, but not diurnal sleep. Likewise, antibiotic-treated mice showed increased nocturnal locomotor activity, but not diurnal locomotor activity. Taken together, these results support a link between the gut microbiome and nocturnal sleep and locomotor physiology in adult mice. Additionally, our findings indicate that antibiotics may be insomnogenic via their ability to diminish gut-derived bacterial somnogens. Given that antibiotics are among the most commonly prescribed drugs in human medicine, these findings have important implications for clinical practice with respect to prolonged antibiotic therapy, insomnia, and other idiopathic sleep-wake and circadian-rhythm disorders affecting an estimated 50-70 million people in the United States alone.\n\nHighlights- 14 d broad-spectrum antibiotic treatment effectively depletes the gut microbiota.\n- Gut microbiota depletion reduces nocturnal sleep, but not diurnal sleep.\n- Gut microbiota depletion increases nocturnal locomotion, but not diurnal locomotion.\n- Antibiotics may be insomnogenic: implications for idiopathic sleep disorders.

animal behavior and cognition↗

bioRxiv2017

A novel zebrafish intestinal tumor model reveals a role for cyp7a1-dependent tumor-liver crosstalk in tumor's adverse effects on host

The nature of host organs and genes that underlie tumor-induced physiological disruption on host remains ill-defined. Here, we establish a novel zebrafish intestinal tumor model that is optimized for addressing this issue, and find that hepatic cyp7a1, the rate-limiting factor for synthesizing bile acids (BAs), is such a host gene. Inducing krasG12D by Gal4 specifically expressed in the posterior intestine resulted in formation of an intestinal tumor classified as dysplasia. The local intestinal tumor caused systemic detrimental effects on host including liver inflammation, hepatomegaly, growth defects, and organismal death. Whole-organismal level gene expression analysis and metabolite measurements revealed that the intestinal tumor reduced total BAs levels via down-regulation of hepatic cyp7a1. Genetically rescuing cyp7a1 expression in the liver restored the BAs synthesis and ameliorated tumor-induced liver inflammation, but not other tumor-dependent phenotypes. Thus, we found a previously unknown role of cyp7a1 as the host gene that links the intestinal tumor, hepatic cholesterol-BAs metabolism, and liver inflammation in tumor-bearing fish. Our model provides an important basis to discover host genes responsible for tumor-induced phenotypes and to uncover mechanisms underlying how tumors adversely affect host organisms.

cancer biology↗

bioRxiv2017

Distress feeding of depredatory birds in Sunflower and Sorghum protected by bioacoustics

One of the most ignored aspects of bioacoustic technology employed worldwide is lack of understanding between acclimatisation and distress feeding by depredatory birds. Acclimatisation results in gradual increase in resistance to bioacoustics in comparison to distress feeding, which makes sudden surge in instances of feeding by depredatory birds. Acclimatisation and distress feeding are independent functions of feeding behaviour. Distress feeding in itself is a function of physiological conditions of bird, extent of cropped area, distance traveled to obtain food, population dynamics, other natural habitats and cropping pattern in an area and is greatly influenced by them. There are no studies conducted to understand the distress feeding of birds in agricultural landscape. Experiments proved that bioacoustics could offer protection against distress feeding by birds although at reduced efficiency.

ecology↗

bioRxiv2017

Neocortical microdissection at columnar and laminar resolution for molecular interrogation

The heterogeneous organization of the mammalian neocortex poses a challenge to elucidate the molecular mechanisms underlying its physiological processes. Although high-throughput molecular methods are increasingly deployed in neuroscience, their anatomical specificity is often lacking. Here we introduce a targeted microdissection technique that enables extraction of high-quality RNA and proteins at high anatomical resolution from acutely prepared brain slices. We exemplify its utility by isolating single cortical columns and laminae from the mouse primary somatosensory (barrel) cortex. Tissues can be isolated from living slices in minutes, and the extracted RNA and protein are of sufficient quantity and quality to be used for RNA-sequencing and mass spectrometry. This technique will help to increase the anatomical specificity of molecular studies of the neocortex, and the brain in general as it is applicable to any brain structure that can be identified using optical landmarks in living slices.

neuroscience↗

bioRxiv2017

Variants in RNA-Seq data show a continued mutation rate during strain preservation of Schizophyllum commune

BackgroundTypical microorganism studies link genetic markers to physiological observations, like growth and survival. Experiments are carefully designed, comparing wildtype strains with knockout strains, and replications are conducted to capture biological variation. To maintain monoclonal strains, strain preservation systems are used to keep the number of generations between the primary stock and the experimental measurement low, to decrease the influence of spontaneous mutations on the experimental outcome. The impact of spontaneous mutations during the minimal number of growth cycles for the experimental design is, however, poorly studied.\n\nResultsWe set out to characterize the mutation landscape using a transcriptomic dataset of Schizophyllum commune, a laboratory model for mushroom formation. We designed a methodology to detect SNPs from the RNA-seq data, and found a mutation rate of 1.923 10-8 per haploid genome per base per generation, highly similar to the previously described mutation rate of S. commune in the wild. Our results imply that approximately 300 mutations are generated during growth of a colony on an agar plate, of which 5 would introduce stop codons. Knock-outs did not incur an increase of mutations and chromosomal recombination occurring at mating type loci was frequent. We found that missense and nonsense SNPs were selected against throughout the experiment. Also, most mutations show a low variant allele frequency and appear only in a small part of the population. Yet, we found 40 genes that gained a nonsense mutation affecting one of its annotated protein domains, and more than 400 genes having a missense mutation inside an annotated protein domain. Further, we found transcription factors, metabolic genes and cazymes having gained a mutation. Hence, the mutation landscape is wide-spread and has many functional annotations.\n\nConclusionsWe have shown that spontaneous mutations accumulate in typical microorganism experiments, where one usually assumes that these do not happen. As these mutations possibly confound experiments they should be minimized as much as possible, or, at least, be trackable. Therefore, we recommend labs to ensure that biological replicates originate from different parental plates, as much as possible.

genomics↗

bioRxiv2017

Measurement of leaf day respiration using a new isotopic disequilibrium method compared with the Laisk method

O_LIQuantification of leaf respiration is of great importance for the understanding of plant physiology and ecosystem biogeochemical processes. Leaf respiration continues in light (RL) but supposedly at a lower rate compared to the dark (RD). Yet, there is no method for direct measurement of RL and most available methods require unphysiological measurement conditions.\nC_LIO_LIA method based on isotopic disequilibrium quantified RL (RL 13C) and mesophyll conductance of young and old fully-expanded leaves of six species compared RL 13C to RL values determined by the Laisk method (RL Laisk).\nC_LIO_LIRL 13C and RL Laisk were consistently lower than RD. Leaf ageing negatively affected photosynthetic performance, but had no significant effect on RL or RL/RD as determined by both methods. RL Laisk and RL 13C were measured successively on the same leaves and correlated positively (r2=0.38), but average RL Laisk was 28% lower than RL13C. Using A/Cc curves instead of A/Ci curves, a higher photocompensation point {Gamma}* (by 5 mol mol-1) was found but the correction had no influence on RL Laisk estimates.\nC_LIO_LIThe results suggest that the Laisk method underestimated RL. The isotopic disequilibrium method is useful for assessing responses of RL to irradiance and CO2, improving our mechanistic understanding of RL.\nC_LI

plant biology↗

bioRxiv2017

Electrophysiological Signature Reveals Laminar Structure of the Porcine Hippocampus

The hippocampus is integral to working and episodic memory, and is a central region of interest in diseases affecting these processes. Pig models are widely used in translational research, and may provide an excellent bridge between rodents and non-human primates for CNS disease models due to their gyrencephalic neuroanatomy and significant white matter composition. However, the laminar structure of the pig hippocampus has not been well characterized. Therefore, we histologically characterized the dorsal hippocampus of Yucatan miniature pigs and quantified the cytoarchitecture of the hippocampal layers. We then utilized stereotaxis combined with single unit electrophysiological mapping to precisely place multichannel laminar silicon probes into the dorsal hippocampus without the need for image guidance. We used in vivo electrophysiological recordings of simultaneous laminar field potentials and single unit activity in multiple layers of the dorsal hippocampus to physiologically identify and quantify these layers under anesthesia. Consistent with previous reports, we found the porcine hippocampus to have the expected archicortical laminar structure with some anatomical and histological features comparable to the rodent and others to the primate hippocampus. Importantly, we found these distinct features to be reflected in the laminar electrophysiology. This characterization, as well as our electrophysiology-based methodology targeting the porcine hippocampal lamina combined with high channel count silicon probes will allow for analysis of spike-field interactions during normal and disease states in both anesthetized and future awake behaving neurophysiology in this large animal.\n\nSignificance StatementThe hippocampus is central to working and episodic memory and is critically affected by diverse disease processes. In order to investigate hippocampal electrophysiology in translational large animal models, we developed an imaging-free stereotaxis and intraoperative electrophysiology methodology with custom silicon probes to precisely localize probe placement within the hippocampal laminar structure. We report for the first time the profile of single units and local field potentials in the pig dorsal hippocampus and relate them to a histological description. This characterization forms the basis for accessible translational pig models to study diseases of the central nervous system affecting hippocampal circuitry in the large animal gyrencephalic brain, as well as the groundwork for potential awake behaving neurophysiology of the porcine hippocampus.\n\nFunding SourcesThe Department of Veterans Affairs, IK2-RX001479, I01-RX001097. The National Institutes of Health, NINDS R01-NS-101108-01, T32-NS043126. CURE Foundation, Taking Flight Award. DoD ERP CDMRP, W81XWH-16-1-0675.

neuroscience↗

bioRxiv2017

Angiogenesis inhibiting capacity of Basella rubra and Syszygium cumini fruit extracts using chorioallantoic membrane assay

Angiogenesis is a physiological process of new blood vessel development from pre-existing capillaries. This process is also the main qualification for tumor growth and plays a vital role in tumor invasion and metastasis. Nevertheless, angiogenesis inhibitors can be used to impede abnormal blood vessel growth. The study was conducted to assess angiogenesis inhibiting potential of B. rubra (Alugbati) and S. cumini (Lumboy) fruit extracts as cell mass growth retardants using Chorioallantoic Membrane (CAM) Assay in Anas platyrhyncho (common Duck) embryo. The treatments were individually compared to Retinol palmitate as positive control and 0.9% sterilized normal saline solution as negative control. Data were gathered and analyzed using Analysis of Variance (ANOVA) and Least Significant Difference (LSD) to test for the significant anti-angiogenic activity and pair-wise comparison among the treatments respectively using a p-value of less than 0.01. Analysis showed that there is no significant difference between the fruit extracts and positive control while a significant difference between the fruit extracts and negative control was observed. Both treatments showed very good anti-angiogenic effect with average scores of 1.33 and 1.67 respectively compared to the positive control with a scoring averaging of 1.78. Furthermore, toxicity test is recommended for both treatments.

developmental biology↗

bioRxiv2017

Molecular evolutionary trends and feeding ecology diversification in the Hemiptera, anchored by the milkweed bug genome

BackgroundThe Hemiptera (aphids, cicadas, and true bugs) are a key insect order, with high diversity for feeding ecology and excellent experimental tractability for molecular genetics. Building upon recent sequencing of hemipteran pests such as phloem-feeding aphids and blood-feeding bed bugs, we present the genome sequence and comparative analyses centered on the milkweed bug Oncopeltus fasciatus, a seed feeder of the family Lygaeidae.\n\nResultsThe 926-Mb Oncopeltus genome is well represented by the current assembly and official gene set. We use our genomic and RNA-seq data not only to characterize the protein-coding gene repertoire and perform isoform-specific RNAi, but also to elucidate patterns of molecular evolution and physiology. We find ongoing, lineage-specific expansion and diversification of repressive C2H2 zinc finger proteins. The discovery of intron gain and turnover specific to the Hemiptera also prompted evaluation of lineage and genome size as predictors of gene structure evolution. Furthermore, we identify enzymatic gains and losses that correlate with feeding biology, particularly for reductions associated with derived, fluid-nutrition feeding.\n\nConclusionsWith the milkweed bug, we now have a critical mass of sequenced species for a hemimetabolous insect order and close outgroup to the Holometabola, substantially improving the diversity of insect genomics. We thereby define commonalities among the Hemiptera and delve into how hemipteran genomes reflect distinct feeding ecologies. Given Oncopeltus's strength as an experimental model, these new sequence resources bolster the foundation for molecular research and highlight technical considerations for the analysis of medium-sized invertebrate genomes.

genomics↗

bioRxiv2017

Tonic and transient oscillatory brain activity during acute exercise

The physiological changes that occur in the main body systems and organs during physical exercise are well described in the literature. Despite the key role of brain in processing afferent and efferent information from organ systems to coordinate and optimize their functioning, little is known about how the brain works during exercise. The present study investigated tonic and transient oscillatory brain activity during a single bout of aerobic exercise. Twenty young males (19-32 years old) were recruited for two experimental sessions on separate days. Electroencephalographic (EEG) activity was recorded during a session of cycling at 80% (moderate-to-high intensity) of VO2max (maximum aerobic capacity) while performing an oddball task where participants had to detect infrequent targets presented among frequent non-targets. This was compared to a (baseline) light intensity session (30% VO2max). The light intensity session was included to control for any potential effect of dual-tasking (i.e., pedaling and performing the oddball task). A warm-up and cool down periods were completed before and after exercise, respectively. A cluster-based nonparametric permutations test showed an increase in power across the entire frequency spectrum during the moderate-to-high intensity exercise, with respect to light intensity. Further, we found that the more salient target lead to lower increase in (stimulus-evoked) theta power in the 80% VO2max with respect to the light intensity condition. On the contrary, higher decrease alpha and lower beta power was found for standard trials in the moderate-to-high exercise condition than in the light exercise condition. The present study unveils, for the first time, a complex brain activity pattern during acute exercise (at 80% of maximum aerobic capacity). These findings might help to elucidate the nature of changes that occur in the brain during physical exertion.

neuroscience↗

bioRxiv2018

Panama: a tool for ion channel biophysics simulation

I have created an online tool and an R library that simulates biophysics of voltage-gated ion channels. It is made publicly available as an R library called Panama at github.com/anuj2054/panama and as a web app at neuronsimulator.com. A need for such a tool was observed after surveying available software packages. I found that the available packages are either not robust enough to simulate multiple ion channels, too complicated, usable only as desktop software, not optimized for mobile devices, not interactive, lacking intuitive graphical controls, or not appropriate for undergraduate education. My app simulates the physiology of 11 different channels - voltage-gated sodium, potassium, and chloride channels; channels causing A-current, M-current, and After-HyperPolarization (AHP) current; calcium-activated potassium channels; low threshold T type calcium channels and high threshold L type calcium channels; leak sodium and leak potassium channels. It can simulate these channels under both current clamp and voltage clamp conditions. As we change the input values on the app, the output can be instantaneously visualized on the web browser and downloaded as a data table to be further analyzed in a spreadsheet program. The app is a first of its kind, mobile-friendly and touch-screen-friendly online tool that can be used to teach undergraduate neuroscience classes. It can also be used by researchers on their local computers as part of an R library. It has intuitive touch-optimized controls, instantaneous graphical output, and yet is pedagogically robust for education and casual research purposes.\n\nNeuroscience education, ion channel biophysics, Hodgkin-Huxley simulation, web app for neuroscience

bioinformatics↗

bioRxiv2017

Theta phase coordinated memory reactivation reoccurs in a slow-oscillatory rhythm during NREM sleep

It has been proposed that sleeps contribution to memory consolidation is to reactivate prior encoded information. To elucidate the neural mechanisms carrying reactivation-related mnemonic information, we investigated whether content-specific memory signatures associated with memory reactivation during wakefulness reoccur during subsequent sleep. We show that theta oscillations orchestrate the reactivation of memories, irrespective of the physiological state. Reactivation patterns during sleep autonomously re-emerged at a rate of 1 Hz, indicating a coordination by slow oscillatory activity.

neuroscience↗

bioRxiv2017

RECONSTITUTION OF HELICAL SOLUBLE α-SYNUCLEIN THROUGH TRANSIENT INTERACTION WITH LIPID INTERFACES

-synuclein (Syn) is one of the key players in the pathogenesis of Parkinsons disease (PD) and other synucleinopathies. Its misfolding and subsequent aggregation into intracellular inclusions are the pathological hallmark of these diseases and may also play a central role in the molecular cascade leading to neurodegeneration. In this work, we report the existence of a novel soluble -helical conformer of Syn, an archetypal \"intrinsically disordered protein\" (IDP), obtained through transient interaction with lipid interfaces. We describe how the stability of this conformer is highly dependent on the continuous, dynamic oligomerization of the folded species. The conformational space of Syn appears to be highly context-dependent, and lipid bilayers might play crucial roles as molecular chaperones for cytosolic species in a cellular environment, as they do in the case of this previously unreported structure.\n\nSignificance StatementBoth genetic and histopathologic evidence tie -synuclein (Syn) to the pathogenesis of Parkinsons disease (PD), a widespread neurodegenerative disorder. Lipids play a central role in the dynamics of Syn in physiology and disease. Syn undergoes a coil-to-helix transition when binding to lipid vesicles and it is involved in the regulation of synaptic vesicle trafficking. Furthermore, recently discovered -helical, aggregation-resistant \"multimers\" of Syn could constitute a protective conformational pathway. We report the existence of a folded, lipid-unbound Syn conformer that forms upon transient interaction with lipids and is stabilized by dynamic homooligomerization, suggesting that synaptic activity could modulate resistance towards aggregation. Our results are therefore important both for the molecular pathology of PD and the structural biology of intrinsically disordered proteins.

biophysics↗