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Communications Biology May 2024Neurons grow neurites of several tens of micrometers in length, necessitating active transport from the cell body by motor proteins. By tracking fluorophores as...
Neurons grow neurites of several tens of micrometers in length, necessitating active transport from the cell body by motor proteins. By tracking fluorophores as minimally invasive labels, MINFLUX is able to quantify the motion of those proteins with nanometer/millisecond resolution. Here we study the substeps of a truncated kinesin-1 mutant in primary rat hippocampal neurons, which have so far been mainly observed on polymerized microtubules deposited onto glass coverslips. A gentle fixation protocol largely maintains the structure and surface modifications of the microtubules in the cell. By analyzing the time between the substeps, we identify the ATP-binding state of kinesin-1 and observe the associated rotation of the kinesin-1 head in neurites. We also observed kinesin-1 switching microtubules mid-walk, highlighting the potential of MINFLUX to study the details of active cellular transport.
Topics: Kinesins; Animals; Rats; Neurites; Microtubules; Hippocampus; Cells, Cultured
PubMed: 38811803
DOI: 10.1038/s42003-024-06358-4 -
BioRxiv : the Preprint Server For... May 2024Desensitization is a prominent feature of nearly all ligand gated ion channels. Acid-sensing ion channels (ASIC) undergo desensitization within hundreds of milliseconds...
Desensitization is a prominent feature of nearly all ligand gated ion channels. Acid-sensing ion channels (ASIC) undergo desensitization within hundreds of milliseconds to seconds upon continual extracellular acidification. The ASIC mechanism of desensitization is primarily due to the isomerization or "flipping" of a short linker joining the 11 and 12 beta sheets in the extracellular domain. In the resting and active states this β11-12 linker adopts an "upward" conformation while in the desensitized conformation the linker assumes a "downward" state. To accommodate this "downward" state, specific peptide bonds within the linker adopt either trans-like or cis-like conformations. Since proline-containing peptide bonds undergo cis-trans isomerization very slowly, we hypothesized that introducing proline residues in the linker may slow or even abolish ASIC desensitization, potentially providing a valuable research tools. Proline substitutions in the chicken ASIC1 β11-12 linker (L414P and Y416P) slowed desensitization decays approximately 100 to 1000-fold as measured in excised patches. Both L414P and Y416P shifted the steady state desensitization curves to more acidic pHs while activation curves and ion selectivity of these slow-desensitizing currents were largely unaffected. To investigate the functional stoichiometry of desensitization in the trimeric ASIC, we created families of L414P and Y416P concatemers with zero, one, two or three proline substitutions in all possible configurations. Introducing one or two L414P or Y416P mutations only slightly attenuated desensitization, suggesting that conformational changes in the remaining faster wild type subunits were sufficient to desensitize the channel. These data highlight the unusual cis-trans isomerization mechanism of ASIC desensitization and support a model where a single subunit is sufficient to desensitize the entire channel.
PubMed: 38798386
DOI: 10.1101/2024.05.09.593312 -
Nature Communications May 2024Olfaction feedback systems could be utilized to stimulate human emotion, increase alertness, provide clinical therapy, and establish immersive virtual environments....
Olfaction feedback systems could be utilized to stimulate human emotion, increase alertness, provide clinical therapy, and establish immersive virtual environments. Currently, the reported olfaction feedback technologies still face a host of formidable challenges, including human perceivable delay in odor manipulation, unwieldy dimensions, and limited number of odor supplies. Herein, we report a general strategy to solve these problems, which associates with a wearable, high-performance olfactory interface based on miniaturized odor generators (OGs) with advanced artificial intelligence (AI) algorithms. The OGs serve as the core technology of the intelligent olfactory interface, which exhibit milestone advances in millisecond-level response time, milliwatt-scale power consumption, and the miniaturized size. Empowered by robust AI algorithms, the olfactory interface shows its great potentials in latency-free mixed reality (MR) and fast olfaction enhancement, thereby establishing a bridge between electronics and users for broad applications ranging from entertainment, to education, to medical treatment, and to human machine interfaces.
Topics: Humans; Wearable Electronic Devices; Smell; Odorants; Artificial Intelligence; Algorithms; User-Computer Interface; Adult; Male
PubMed: 38796514
DOI: 10.1038/s41467-024-48884-z -
Brain Sciences May 2024The sensorimotor gating is a nervous system function that modulates the acoustic startle response (ASR). Prepulse inhibition (PPI) phenomenon is an operational measure...
The sensorimotor gating is a nervous system function that modulates the acoustic startle response (ASR). Prepulse inhibition (PPI) phenomenon is an operational measure of sensorimotor gating, defined as the reduction of ASR when a high intensity sound (pulse) is preceded in milliseconds by a weaker stimulus (prepulse). Brainstem nuclei are associated with the mediation of ASR and PPI, whereas cortical and subcortical regions are associated with their modulation. However, it is still unclear how the modulatory units can influence PPI. In the present work, we developed a computational model of a neural circuit involved in the mediation (brainstem units) and modulation (cortical and subcortical units) of ASR and PPI. The activities of all units were modeled by the leaky-integrator formalism for neural population. The model reproduces basic features of PPI observed in experiments, such as the effects of changes in interstimulus interval, prepulse intensity, and habituation of ASR. The simulation of GABAergic and dopaminergic drugs impaired PPI by their effects over subcortical units activity. The results show that subcortical units constitute a central hub for PPI modulation. The presented computational model offers a valuable tool to investigate the neurobiology associated with disorder-related impairments in PPI.
PubMed: 38790479
DOI: 10.3390/brainsci14050502 -
Journal of Cardiovascular Development... May 2024Cardiac rehabilitation (CR) plays a crucial role in managing patients who have undergone coronary intervention (CI) following acute myocardial infarction. While...
Cardiac rehabilitation (CR) plays a crucial role in managing patients who have undergone coronary intervention (CI) following acute myocardial infarction. While water-based exercise is gaining recognition as an exercise modality in this patient population, its impact on the subgroup of older adults remains unexplored. In this post hoc analysis, we investigated the effects of water-based exercise on adults older than 60 years undergoing CR after CI, comparing it to land-based exercise and a control group. In total, 45 patients aged over 60 participated in 14-day exercise programs, featuring two daily 30-min sessions. We assessed exercise capacity (VO), vascular function (flow-mediated vasodilation (FMD)), heart rate variability (HRV), and blood markers (Interleukins 6, 8, and 10, P-Selectin, ICAM, and High-sensitivity CRP) before and after CR. VO in the water-based group improved significantly after CR in comparison with the land-based group: 1.35 kg/mL/min (95% CI [0.20-2.50], = 0.022). The significant difference between water-based and land-based groups was observed in several HRV parameters: Total power -1129.20 ms (95% CI [-1951.92--306.49], = 0.008); peak LF 0.04 Hz (95% CI [0.00-0.08], = 0.036); SD1 -9.02 millisecond (95% CI [-16.86--1.18], = 0.025); and SD2 -19.71 ms (95% CI [-35.08--4.34], = 0.013). FMD and blood markers did not vary significantly based on the exercise group. These findings suggest that short-term water-based CR may have potential as an alternative to traditional land-based CR, improving VO and cardiorespiratory fitness among adults over 60 years undergoing CR after CI.
PubMed: 38786973
DOI: 10.3390/jcdd11050151 -
Biomolecules May 2024During neurotransmission, neurotransmitters are released less than a millisecond after the arrival of the action potential. To achieve this ultra-fast event, the...
During neurotransmission, neurotransmitters are released less than a millisecond after the arrival of the action potential. To achieve this ultra-fast event, the synaptic vesicle must be pre-docked to the plasma membrane. In this primed state, SNAREpins, the protein-coiled coils whose assembly provides the energy to trigger fusion, are partly zippered and clamped like a hairpin and held open and ready to snap close when the clamp is released. Recently, it was suggested that three types of regulatory factors, synaptophysin, synaptotagmins, and complexins act cooperatively to organize two concentric rings, a central and a peripheral ring, containing up to six SNAREpins each. We used a mechanical model of the SNAREpins with two separate states, half-zippered and fully zippered, and determined the energy landscape according to the number of SNAREpins in each ring. We also performed simulations to estimate the fusion time in each case. The presence of the peripheral SNAREpins generally smoothens the energy landscape and accelerates the fusion time. With the predicted physiological numbers of six central and six peripheral SNAREpins, the fusion time is accelerated at least 100 times by the presence of the peripheral SNAREpins, and fusion occurs in less than 10 μs, which is well within the physiological requirements.
Topics: Synaptic Vesicles; SNARE Proteins; Membrane Fusion; Synaptic Transmission; Animals; Humans
PubMed: 38786007
DOI: 10.3390/biom14050600 -
Frontiers in Human Neuroscience 2024The combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) allows researchers to explore cortico-cortical connections. To study...
A simulation study: comparing independent component analysis and signal-space projection - source-informed reconstruction for rejecting muscle artifacts evoked by transcranial magnetic stimulation.
INTRODUCTION
The combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) allows researchers to explore cortico-cortical connections. To study effective connections, the first few tens of milliseconds of the TMS-evoked potentials are the most critical. Yet, TMS-evoked artifacts complicate the interpretation of early-latency data. Data-processing strategies like independent component analysis (ICA) and the combined signal-space projection-source-informed reconstruction approach (SSP-SIR) are designed to mitigate artifacts, but their objective assessment is challenging because the true neuronal EEG responses under large-amplitude artifacts are generally unknown. Through simulations, we quantified how the spatiotemporal properties of the artifacts affect the cleaning performances of ICA and SSP-SIR.
METHODS
We simulated TMS-induced muscle artifacts and superposed them on pre-processed TMS-EEG data, serving as the ground truth. The simulated muscle artifacts were varied both in terms of their topography and temporal profiles. The signals were then cleaned using ICA and SSP-SIR, and subsequent comparisons were made with the ground truth data.
RESULTS
ICA performed better when the artifact time courses were highly variable across the trials, whereas the effectiveness of SSP-SIR depended on the congruence between the artifact and neuronal topographies, with the performance of SSP-SIR being better when difference between topographies was larger. Overall, SSP-SIR performed better than ICA across the tested conditions. Based on these simulations, SSP-SIR appears to be more effective in suppressing TMS-evoked muscle artifacts. These artifacts are shown to be highly time-locked to the TMS pulse and manifest in topographies that differ substantially from the patterns of neuronal potentials.
DISCUSSION
Selecting between ICA and SSP-SIR should be guided by the characteristics of the artifacts. SSP-SIR might be better equipped for suppressing time-locked artifacts, provided that their topographies are sufficiently different from the neuronal potential patterns of interest, and that the SSP-SIR algorithm can successfully find those artifact topographies from the high-pass-filtered data. ICA remains a powerful tool for rejecting artifacts that are not strongly time locked to the TMS pulse.
PubMed: 38784523
DOI: 10.3389/fnhum.2024.1324958 -
Science Advances May 2024Electrochemical gradients across biological membranes are vital for cellular bioenergetics. In bacteria, the proton motive force (PMF) drives essential processes like...
Electrochemical gradients across biological membranes are vital for cellular bioenergetics. In bacteria, the proton motive force (PMF) drives essential processes like adenosine triphosphate production and motility. Traditionally viewed as temporally and spatially stable, recent research reveals a dynamic PMF behavior at both single-cell and community levels. Moreover, the observed lateral segregation of respiratory complexes could suggest a spatial heterogeneity of the PMF. Using a light-activated proton pump and detecting the activity of the bacterial flagellar motor, we perturb and probe the PMF of single cells. Spatially homogeneous PMF perturbations reveal millisecond-scale temporal dynamics and an asymmetrical capacitive response. Localized perturbations show a rapid lateral PMF homogenization, faster than proton diffusion, akin to the electrotonic potential spread observed in passive neurons, explained by cable theory. These observations imply a global coupling between PMF sources and consumers along the membrane, precluding sustained PMF spatial heterogeneity but allowing for rapid temporal changes.
Topics: Proton-Motive Force; Flagella; Single-Cell Analysis; Bacteria; Adenosine Triphosphate; Spatio-Temporal Analysis; Protons
PubMed: 38781330
DOI: 10.1126/sciadv.adl5849 -
Nature Communications May 2024In most models of neuronal plasticity and memory, dopamine is thought to promote the long-term maintenance of Long-Term Potentiation (LTP) underlying memory processes,...
In most models of neuronal plasticity and memory, dopamine is thought to promote the long-term maintenance of Long-Term Potentiation (LTP) underlying memory processes, but not the initiation of plasticity or new information storage. Here, we used optogenetic manipulation of midbrain dopamine neurons in male DAT::Cre mice, and discovered that stimulating the Schaffer collaterals - the glutamatergic axons connecting CA3 and CA1 regions - of the dorsal hippocampus concomitantly with midbrain dopamine terminals within a 200 millisecond time-window triggers LTP at glutamatergic synapses. Moreover, we showed that the stimulation of this dopaminergic pathway facilitates contextual learning in awake behaving mice, while its inhibition hinders it. Thus, activation of midbrain dopamine can operate as a teaching signal that triggers NeoHebbian LTP and promotes supervised learning.
Topics: Animals; Long-Term Potentiation; Ventral Tegmental Area; Male; Dopamine; Mice; Optogenetics; Dopaminergic Neurons; Hippocampus; Learning; Mice, Transgenic; CA1 Region, Hippocampal; Synapses; Mice, Inbred C57BL; Memory
PubMed: 38773091
DOI: 10.1038/s41467-024-47481-4 -
Cell Jun 2024Integrins link the extracellular environment to the actin cytoskeleton in cell migration and adhesiveness. Rapid coordination between events outside and inside the cell...
Integrins link the extracellular environment to the actin cytoskeleton in cell migration and adhesiveness. Rapid coordination between events outside and inside the cell is essential. Single-molecule fluorescence dynamics show that ligand binding to the bent-closed integrin conformation, which predominates on cell surfaces, is followed within milliseconds by two concerted changes, leg extension and headpiece opening, to give the high-affinity integrin conformation. The extended-closed integrin conformation is not an intermediate but can be directly accessed from the extended-open conformation and provides a pathway for ligand dissociation. In contrast to ligand, talin, which links the integrin β-subunit cytoplasmic domain to the actin cytoskeleton, modestly stabilizes but does not induce extension or opening. Integrin activation is thus initiated by outside-in signaling and followed by inside-out signaling. Our results further imply that talin binding is insufficient for inside-out integrin activation and that tensile force transmission through the ligand-integrin-talin-actin cytoskeleton complex is required.
Topics: Animals; Humans; Mice; Actin Cytoskeleton; Cell Adhesion; CHO Cells; Cricetulus; Integrins; Ligands; Protein Binding; Protein Conformation; Signal Transduction; Single Molecule Imaging; Talin
PubMed: 38772370
DOI: 10.1016/j.cell.2024.04.049