bioRxiv Subject Collection: Neuroscience's Journal
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Friday, December 27th, 2024
| Time |
Event |
| 12:31a |
Ultrastructural membrane dynamics of mouse and human cortical synapses
Live human brain tissues provide unique opportunities for understanding the physiology and pathophysiology of synaptic transmission. Investigations have been limited to anatomy, electrophysiology, and protein localization--while crucial parameters such as synaptic vesicle dynamics were not visualized. Here we utilize zap-and-freeze time-resolved electron microscopy to overcome this hurdle. First we validate the approach with acute mouse brain slices to demonstrate that axons parallel to the electrical field can be stimulated to produce calcium signaling. Next we show that ultrafast endocytosis is induced and can be captured in both mouse and human brain slices. Crucially, in both species a protein essential for ultrafast endocytosis Dynamin 1xA (Dyn1xA) localizes to the region peripheral to the active zone, the putative endocytic zone, indicating a likely mechanism conservation between mouse and human. This approach has the potential to reveal dynamic, high-resolution information about synaptic membrane trafficking in intact human brain slices. | | 12:31a |
Aggression experience and observation promote shared behavioral and neural changes
The ability to observe the social behavior of others and use observed information to bias future action is a fundamental building block of social cognition1,2. A foundational question is whether social observation and experience engage common circuit mechanisms that enable behavioral change. While classic studies on social learning have shown that aggressive behaviors can be learned through observation3, it remains unclear whether aggression observation promotes persistent neural changes that generalize to new contexts. Here, to directly compare the effects of aggression experience and observation at brain-wide scale, we develop a strategy to perform large-scale cell-type specific recordings across subcortical networks for social behavior control and learning. We record longitudinally while animals "train" through direct experience or observation, then probe shared differences in behavior and neural activity in a novel "hard" aggression context. Using supervised and unsupervised methods for behavioral quantification, we detect unique signatures of a shared behavioral strategy not present in animals with no training. During observation, we find widespread activation that mimics experience in networks for behavior generation, with critical differences in signals associated with reward and threat learning. After observation, we observe that changes persist into the novel aggression context, with increased similarity in the neural dynamics between experience and observation groups. Network-level modeling reveals persistent shared changes to a core aggression network, with widespread decoupling of inhibition from a key hypothalamic output region. This demonstrates that "experience-like" activity during observation can recruit a shared plasticity mechanism that biases behavior toward adaptive defensive strategies in new contexts. | | 12:31a |
Pro-cognitive reshaping of neuronal dynamics by a human CSF-based factor
Neuronal connection dysfunction is a convergent cause of cognitive deficits in mental disorders. Cognitive processes are finely regulated at the synaptic level by membrane proteins, some of which are shed and detectable in patients cerebrospinal fluid (CSF). However, whether these soluble synaptic proteins can harnessed as innovative pro-cognitive factors to treat brain disorders remains unclear. Here, we use quantitative proteomics to identify shed synaptic proteins dysregulated in the CSF of subjects with schizophrenia (SCZ), a mental disorder characterized by cognitive and synaptic dysfunction. The level of a yet uncharacterized soluble form of the voltage-gated calcium channel auxiliary subunit, 2{delta}-1, is robustly reduced in SCZ CSF. Remarkably, soluble 2{delta}-1 is convergently downregulated across several brain disorder CSF proteomes. We show that the brain releases soluble 2{delta}-1 in an activity-dependent manner, which can reorganize neuronal network dynamics by binding to synaptic targets and promoting inhibitory neuron plasticity. A single brain injection of a synthetic soluble 2{delta}-1 improved interneuron and cognitive deficits in a mutant mouse model of SCZ and cortical dysfunction. These findings underscore the potential of shed synaptic proteins as novel therapeutic agents capable of enhancing brain function in diverse brain disorders characterized by cognitive impairment. | | 12:31a |
Sub-second characterization of locomotor activities of mouse models of Parkinsonism
The degeneration of midbrain dopamine (DA) neurons disrupts the neural control of natural behavior, such as walking, posture, and gait in Parkinsons disease. While some aspects of motor symptoms can be managed by dopamine replacement therapies, others respond poorly. Recent advancements in machine learning-based technologies offer opportunities for unbiased segmentation and quantification of natural behavior in both healthy and diseased states. In the present study, we applied the motion sequencing (MoSeq) platform to study the spontaneous locomotor activities of neurotoxin and genetic mouse models of Parkinsonism as the midbrain DA neurons progressively degenerate. We also evaluated the treatment efficacy of levodopa (L-DOPA) on behavioral modules at fine time scales. We revealed robust changes in the kinematics and usage of the behavioral modules that encode spontaneous locomotor activity. Further analysis demonstrates that fast behavioral modules with higher velocities were more vulnerable to loss of DA and preferentially affected at early stages of Parkinsonism. Last, L-DOPA effectively improved the velocity, but not the usage and transition probability, of behavioral modules of Parkinsonian animals. In conclusion, the hypokinetic phenotypes in Parkinsonism are mediated by the decreased velocities of behavioral modules and the disrupted temporal organization of sub-second modules into actions. Moreover, we showed that the therapeutic effect of L-DOPA is mainly mediated by its effect on the velocities of behavior modules at fine time scales. This work documents robust changes in the velocity, usage, and temporal organization of behavioral modules and their responsiveness to dopaminergic treatment under the Parkinsonian state. | | 1:46a |
Longer Interstimulus Intervals Enhance Efficacy of Automated Phase-Targeted Auditory Stimulation on Procedural Memory Consolidation
Up-phase-targeted auditory stimulation (up-PTAS) during slow-wave sleep has become a valuable tool for modulating slow oscillations and slow-oscillation-spindle-coupling in favor of overnight memory retention. Developing effective, automated protocols for translation into more naturalistic or clinical settings is an ongoing challenge, especially given that current PTAS protocols and their behavioral effects vary greatly between different studies. Here, we assessed the electrophysiological and behavioral effects of systematically varying interstimulus intervals (ISIs) in automated up-PTAS in the home setting, using a mobile PTAS device and app-based behavioral tasks. Building on studies suggesting a non-linear relationship between stimulus number and PTAS effects, we show that applying fewer stimuli with longer ISIs enhanced overnight memory consolidation of a finger-tapping sequence more effectively than applying more stimuli with shorter ISIs. The behavioral response was predicted by the number of stimuli with auditory evoked K-complexes relative to the number of stimuli without K-complexes. PTAS stimuli applied at longer ISIs (> 1.25) were associated with a higher likelihood of K-complex responses and fast spindles nesting in the K-complex up-phase. Our results suggest that up-PTAS can be optimized for overnight memory consolidation by introducing ISIs of at least 1.25s. Our study highlights the feasibility of longitudinal at-home PTAS combined with app-based behavioral tasks in healthy participants while leveraging the mechanistic insights such data can offer.
Statement of SignificancePhase-targeted auditory stimulation (PTAS) holds great promise for non-invasively enhancing essential functions of slow-wave sleep. However, current protocols have produced variable results and are often confined to laboratory settings. Our study demonstrates the feasibility of a mobile application of automated PTAS and provides experimental evidence that prolonging interstimulus intervals positively affects overnight procedural memory consolidation via K-complexes and coupled sleep spindles. As K-complexes may also be involved in cardiovascular function and brain waste clearance, the proposed protocol optimization may have effects beyond memory enhancement. Together, our findings lay a foundation for a broader application of PTAS in clinical longitudinal studies to improve patient care and recovery outcomes. | | 8:37a |
The Effect of Visual Field Occlusion on Visually Induced Motion Sickness
Visually induced motion sickness (VIMS), characterized by symptoms such as dizziness, nausea, and postural instability, presents significant challenges in modern visual and interactive technologies. These symptoms undermine the immersion into and comfort of virtual and augmented reality (VR/AR) systems and reduce the usability of autonomous vehicles, highlighting the urgent need to address VIMS for broader adoption of these technologies. While previous studies have largely focused on the motion characteristics that induce VIMS, the impact of visual field configuration, such as segmentation and occlusion, has been largely unexplored. To bridge this gap, we conducted five human psychophysics experiments systematically investigating how visual field segmentation and masking influence VIMS under controlled three-dimensional optical flow conditions. Participants were exposed to different masking patterns, including variations in the number of divided sections, the masking of the central screen region, and the thickness of the masks. Paired-comparison methods were employed to assess participants susceptibility to VIMS under each condition. Our findings showed that visual field segmentation significantly influenced VIMS susceptibility. Specifically, the results revealed three key findings: (1) segmenting the visual field into multiple subsections using visual masks significantly increased VIMS susceptibility, (2) thinner masks exacerbated motion sickness more than thicker ones, and (3) masking the central region of the screen reduced susceptibility. These effects were independent of the presented motion patterns. Our findings offer new insights for optimizing the design of VR/AR systems, graphical user interfaces, and autonomous vehicles by highlighting the importance of visual field configuration in mitigating VIMS for improving user experience. | | 8:37a |
PrecisionTrack: Reliable Tracking of Large Groups of Animals Interacting in Complex Environments Over Extended Periods
Mice living in complex social groups within ethological environments exhibit a wide range of adaptive behaviors, including individual and group dynamics, often undetected in standard behavioral studies. To better understand the coping and adaptive strategies employed by each member of a social colony, it is necessary to develop tools that enable accurate, long-term monitoring of large groups of animals in a fully automated and unbiased manner. In this work, we introduce PrecisionTrack, a practical solution to the multi-animal pose tracking problem. This solution enables an accurate and reliable tracking of large groups of animal socially interacting within complex environments, even over prolonged periods. Our algorithm builds on a Transformer-CNN hybrid neural network for cross-species classification, detection, and pose estimation, leveraging pose-based matching AI-driven ArUco identification for fast and accurate re-identification. PrecisionTrack demonstrates superior performance in tracking accuracy and latency compared to current gold standards, while sustaining these capabilities over extended periods when tracking large groups of animals in complex environments. Furthermore, we trained PrecisionTrack to identify and monitor over 30 animal species. Overall, PrecisionTrack represents a reliable, accessible step toward adopting more ethological methodologies in behavioral research. | | 8:37a |
Differentiating BOLD and non-BOLD signals in fMRI time series using cross-cortical depth delay patterns
Over the past two decades, rapid advancements in magnetic resonance technology have significantly enhanced the imaging resolution of functional Magnetic Resonance Imaging (fMRI), far surpassing its initial capabilities. Beyond mapping brain functional architecture at unprecedented scales, high-spatial-resolution acquisitions have also inspired and enabled several novel analytical strategies that can potentially improve the sensitivity and neuronal specificity of fMRI. With small voxels, one can sample from different levels of the vascular hierarchy within the cerebral cortex and resolve the temporal progression of hemodynamic changes from parenchymal to pial vessels. We propose that this characteristic pattern of temporal progression across cortical depths can aid in distinguishing neurogenic blood-oxygenation-level-dependent (BOLD) signals from typical nuisance factors arising from non-BOLD origins, such as head motion and pulsatility. In this study, we examine the feasibility of applying cross-cortical depth temporal delay patterns to automatically categorize BOLD and non-BOLD signal components in modern-resolution BOLD-fMRI data. We construct an independent component analysis (ICA)-based framework for fMRI de-noising, analogous to previously proposed multi-echo (ME) ICA, except that here we explore the across-depth instead of across-echo dependence to distinguish BOLD and non-BOLD components. The efficacy of this framework is demonstrated using visual task data at three graded spatiotemporal resolutions (voxel sizes = 1.1, 1.5, and 2.0 mm isotropic at temporal intervals = 1700, 1120, and 928 ms). The proposed framework leverages prior knowledge of the spatiotemporal properties of BOLD-fMRI and serves as an alternative to ME-ICA for cleaning moderate- and high-spatial-resolution fMRI data when multi-echo acquisitions are not available. | | 4:32p |
Prelimbic Cortex Activity Predicts Anxiety-Like Behavior in the Elevated Plus Maze
The medial prefrontal cortex (mPFC) plays a critical role in emotional regulation, and its dysregulation is linked to anxiety disorders. In particular, the prelimbic cortex (PrL) of the mPFC is thought to modulate anxiety-related behaviors, though its precise role remains debated. Here, we used endoscopic in vivo calcium imaging to assess PrL neuronal activity in male and female Sprague-Dawley rats performing in the Elevated Plus Maze (EPM), a widely used task to measure anxiety-like behavior. We found that animals that spent less time in the open arms exhibited higher PrL activity in the open arms, suggesting that heightened PrL activity may reflect greater anxiety or increased avoidance behavior. These results suggest that the PrL may play a role in regulating the emotional response to anxiety-provoking situations, potentially influencing the tolerance for exposure to threatening environments. | | 5:46p |
Effects of Age and Cognitive Functions on the Neural Tracking of Speech in Noise
Older adults often struggle to comprehend speech in noisy environments, a challenge influenced by declines in both auditory processing and cognitive functions. This study examines age-related differences in speech recognition in noise, focusing on the roles of delta (1-4 Hz) and theta (4-8 Hz) neural oscillations and their relationship with cognitive function, particularly working memory. Electroencephalography (EEG) was used to collect data from 23 young adults (20-35 years) and 23 older adults (65-80 years) with normal hearing. Cognitive assessments were administered to older adults, and both groups completed an EEG task involving speech recognition in Speech-Shaped Noise (SSN) at individualized noise levels based on their Sentence Recognition Scores (SRS). Results showed that age significantly impacted hit rates and reaction times in noisy speech recognition tasks. Theta-band neural tracking was notably stronger in older adults, while delta-band tracking showed no age-related difference. Pearsons correlations indicated significant associations between age-related cognitive decline, reduced hearing sensitivity, and Mini-Mental State Examination (MMSE) scores. Regression analyses showed that theta-band neural tracking at specific SRS levels significantly predicted word list recognition in the higher SRT group, while constructional recall was strongly predicted in the lower SRT group. The findings suggest that older adults may rely on theta-band neural tracking as a compensatory mechanism to support speech perception in noise, with indirect links between working memory and speech perception. Further research is needed to explore the causal relationship between cognitive function and hearing. | | 5:46p |
Perceiving direction of deformation-based motion
Transparent liquid flow deforms its background through light refraction, creating complex spatiotemporal patterns that challenge the visual system in discerning flow direction. This study investigates how the visual system perceptually resolves the direction of transparent liquid flow. Using two-dimensional 1/f noise as background, we sequentially deformed the noise with pre-defined displacement maps displaced across frames, systematically manipulating spatial frequency and displacement magnitude. Participants reported the perceived direction of deformation-based motion. The results emphasize the critical role of the relationship between the minimum wavelength and displacement magnitude. Performance declined when the displacement magnitude exceeded a certain proportion relative to the wavelength. Conversely, performance also dropped significantly under conditions of small displacements combined with low cut-off frequencies. Further analysis revealed the local deformation possibly hinders the detection of deformation-based motion. These findings enhance understanding of how global and local motion cues interact, providing insight into the visual system's processing of deformation-induced motion and transparency. |
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