bioRxiv Subject Collection: Neuroscience's Journal
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Tuesday, July 16th, 2024
| Time |
Event |
| 3:32a |
Physical Exercise Improves Working Memory through Ripple-Spindle Coupling
Spindle-ripple coupling enhances memory consolidation during sleep. Ripples, representing the compressed reactivation of environmental information, provide a mechanism for retaining memory information in chronological order and are also crucial for working memory (WM) during wakefulness. Brief sessions of physical exercise (PE) are proposed to boost WM. In concurrent EEG/MEG sessions, we investigated the role of PE in WM performance and high-frequency-ripple to spindle coupling. Ripples, identified in MEG sensors covering the medial temporal lobe (MTL) region, predicted individual WM performance. Ripples were locked to robust oscillatory patterns in the EEG defined spindle band. Spindle activity and ripples decrease during initial stimulus presentation and rebound after 1 sec. Behaviorally, PE enhanced WM performance. Neurophysiologically, PE scaled the ripple rate with the number of items to be kept in WM and strengthened the coupling between ripple events and spindle oscillations. These findings reveal that PE enhances WM by coordinating ripple-spindle interaction. | | 3:32a |
Coordinated Response Modulations Enable Flexible Use of Visual Information
We use sensory information in remarkably flexible ways. We can generalize by ignoring task-irrelevant features, report different features of a stimulus, and use different actions to report a perceptual judgment. These forms of flexible behavior are associated with small modulations of the responses of sensory neurons. While the existence of these response modulations is indisputable, efforts to understand their function have been largely relegated to theory, where they have been posited to change information coding or enable downstream neurons to read out different visual and cognitive information using flexible weights. Here, we tested these ideas using a rich, flexible behavioral paradigm, multi-neuron, multi-area recordings in primary visual cortex (V1) and mid-level visual area V4. We discovered that those response modulations in V4 (but not V1) contain the ingredients necessary to enable flexible behavior, but not via those previously hypothesized mechanisms. Instead, we demonstrated that these response modulations are precisely coordinated across the population such that downstream neurons have ready access to the correct information to flexibly guide behavior without making changes to information coding or synapses. Our results suggest a novel computational role for task-dependent response modulations: they enable flexible behavior by changing the information that gets out of a sensory area, not by changing information coding within it. | | 5:32p |
Biophysical Modeling and Experimental Analysis of the Dynamics of C. elegans Body-Wall Muscle Cells
This study combines experimental techniques and mathematical modeling to investigate the dynamics of C. elegans body-wall muscle cells. Specifically, by conducting voltage clamp and mutant experiments, we identify key ion channels, particularly the L-type voltage-gated calcium channel (EGL-19) and potassium channels (SHK-1, SLO-2), which are crucial for generating action potentials. We develop Hodgkin-Huxley-based models for these channels and integrate them to capture the cells' electrical activity. To ensure the model accurately reflects cellular responses under depolarizing currents, we develop a parallel simulation-based inference method for determining the model's free parameters. This method performs rapid parallel sampling across high-dimensional parameter spaces, fitting the model to the responses of muscle cells to specific stimuli and yielding accurate parameter estimates. We validate our model by comparing its predictions against cellular responses to various current stimuli in experiments and show that our approach effectively determines suitable parameters for accurately modeling the dynamics in mutant cases. Additionally, we discover an optimal response frequency in body-wall muscle cells, which corresponds to a burst firing mode rather than regular firing mode. Our work provides the first experimentally constrained and biophysically detailed muscle cell model of C. elegans, and our analytical framework combined with robust and efficient parametric estimation method can be extended to model construction in other species. | | 6:48p |
Characterization of focused ultrasound blood-brain barrier disruption effect on inflammation as a function of treatment parameters
The technology of focused ultrasound-mediated disruption of the blood-brain barrier (FUS-BBB opening) has now been used in over 20 Phase 1 clinical trials to validate the safety and feasibility of BBB opening for drug delivery in patients with brain tumors and neurodegenerative diseases. The primary treatment parameters, FUS intensity and microbubble dose, are chosen to balance sufficient BBB disruption to achieve drug delivery against potential acute vessel damage leading to microhemorrhage. This can largely be achieved based on both empirical results from animal studies and by monitoring the microbubble cavitation signal in real time during the treatment. However, other safety considerations due to second order effects caused by BBB disruption, such as inflammation and alteration of neurovascular function, are not as easily measurable, may take longer to manifest and are only beginning to be understood. This study builds on previous work that has investigated the inflammatory response following FUS-BBB opening. In this study, we characterize the effect of FUS intensity and microbubble dose on the extent of BBB disruption, observed level of microhemorrhage, and degree of inflammatory response at three acute post-treatment time points in the wild-type mouse brain. Additionally, we evaluate differences related to biological sex, presence and degree of the anti-inflammatory response that develops to restore homeostasis in the brain environment, and the impact of multiple FUS-BBB opening treatments on this inflammatory response. | | 6:48p |
Investigating the effects of transcutaneous Vagus Nerve Stimulation on motor cortex excitability and inhibition through paired-pulse Transcranial Magnetic Stimulation
Transcutaneous Vagus Nerve stimulation (tVNS) has been proposed as a prospective treatment for clinical conditions with altered GABAergic transmission. While possible effects of tVNS on behavioral performance in inhibitory control tasks have been previously reported, neurophysiological evidence showing its effects on GABA-mediated inhibition in the motor cortex is limited. Concurrently, the possible influence of the gender and state conditions of participants remains unexplored. Here, we applied, single- and paired-pulse TMS to the right or the left primary motor in two different groups of participants. We measured corticospinal excitability (CSE), short and long intracortical inhibition (SICI and LICI), cortical silent period (cSP) and intracortical facilitation (ICF) indexes. The measures were taken, in separated sessions of a within-subject design, at baseline prior to tVNS and after delivering active and sham tVNS in the Cymba conchae of the left ear. To exploit state dependent effects and assess the role of tVNS in motor learning, tVNS was applied, during the execution of a computerized visuomotor task. In the left TMS group, we observed better visuomotor performance during active than sham tVNS, regardless the gender of the participants. Interestingly, in both groups, we found a specific increase of SICI, which is mediated by GABAa activity, after active compared to sham-tVNS and baseline evaluations, which was specifically limited to female participants. No effects on CSE, ICF or GABAb-mediated intracortical inhibition indexes were observed. The results show specific effects of tVNS on motor learning and GABAa-mediated motor inhibition, providing supportive evidence for the application of tVNS as an alternative and coadjuvant treatment for disorders featured by altered inhibition mechanisms. | | 6:48p |
Influence of truthful and misleading instructions on statistical learning across the autism spectrum
Bayesian studies of perception have documented how the brain learns the statistics of a new environment and uses them to interpret sensory information. Impairments in this process have been hypothesised to be central to autism spectrum disorders. However, very few such studies have differentiated between implicit and explicit learning. We manipulated the instructions given before a cue-stimulus association task to investigate their effects on statistical learning, in 335 participants with varying autistic traits. In the implicit condition, where no information was provided, participants acquired weak prior beliefs about the task regularities. Conversely, explicit information about the presence of regularities resulted in strong priors, correctly reflecting the task's statistics, regardless of the information's veracity. Autistic traits correlated with greater uncertainty and faster updating in the implicit condition, but no significant differences were found in the influence of priors. Our findings illuminate how instructions affect statistical learning and how these effects differ across the autism spectrum. | | 7:17p |
Preclinical validation and kinetic modelling of the SV2A PET ligand UCB-J in mice
Synaptic vesicle protein 2A (SV2A) is ubiquitously expressed in presynaptic terminals where it functions as a neurotransmission regulator protein. Synaptopathy has been reported during healthy ageing and in a variety of neurodegenerative diseases. Positron emission tomography (PET) imaging of SV2A can be used to evaluate synaptic density. The PET ligand [11C]UCB-J has high binding affinity and selectivity for SV2A but has a short physical half-life due to the 11C isotope. Here we report the characterization and validation of its 18F-labeled equivalent, [18F]UCB-J, in terms of specificity, reproducibility and stability in C57BL/6J mice. Plasma analysis revealed at least one polar radiometabolite. Kinetic modelling was performed using a population-based metabolite corrected image-derived input function (IDIF). [18F]UCB-J showed relatively fast kinetics and a reliable measure of the IDIF-based volume of distribution (VT(IDIF)). [18F]UCB-J specificity for SV2A was confirmed through a levetiracetam blocking assay (50 to 200 mg/kg). Reproducibility of the VT(IDIF) was determined through test-retest analysis, revealing significant correlation (r2=0.7730, p<0.0001). Time-stability analyses indicate a scan duration of 60min to be sufficient to obtain a reliable VT(IDIF). In conclusion, [18F]UCB-J is a selective SV2A ligand with optimal kinetics in mice. Further investigation is warranted for (pre)clinical applicability of [18F]UCB-J in synaptopathies. | | 7:17p |
Physical activity modulates early visual response and improves target detection in humans
Brain state changes affect visual perception by altering spatial resolution. Attention enhances the spatial resolution decorrelating neuronal activity in early nonhuman primate (NHP) visual cortex. Physical activity (PA) amplifies these attentional effects in rodents but impact of PA on visual perception in humans remains uncertain. We investigated the relationship between broadband high-frequency activity (BHA: 80-150 Hz) recorded with magnetoencephalography (MEG) and visual detection performance. We found that PA enhanced visual target detection predicted by a reduction of early BHA responses (<90 msec). This effect may be due to reduced interneuronal correlation to improve spatial resolution. Moreover, PA improved spatial integration time, as indicated by a linear relationship between reaction times and BHA variation with target eccentricity. These findings provide evidence that PA influences neuronal activity critical for early visual perception, optimizing visual processing at the initial stages of the visual hierarchy. | | 7:17p |
BATF2 is a regulator of interferon-gamma signaling in astrocytes during neuroinflammation
Astrocytic interferon (IFN)-gamma signaling is associated with a reduction in neuroinflammation. We have previously shown that the benefits of astrocytic IFN-gamma arise from a variety of mechanisms; however, downstream effectors responsible for regulating this protection are unknown. We address this by identifying a specific transcription factor that may play a key role in modulating the consequences of IFN-gamma signaling. RNA-sequencing of primary human astrocytes treated with IFN-gamma revealed basic leucine zipper ATF-like transcription factor (BATF)2 as a highly expressed interferon-specific gene. Primarily studied in the periphery, BATF2 has been shown to exert both inflammatory and protective functions; however, its function in the central nervous system (CNS) is unknown. Here, we demonstrate that human spinal cord astrocytes upregulate BATF2 transcript and protein in an IFN-gamma-specific manner. Additionally, we found that BATF2 prevents overexpression of interferon regulatory factor (IRF)1 and IRF1 targets such as Caspase-1, which are known downstream pro-inflammatory mediators. We also show that Batf2-/- mice exhibit exacerbated clinical disease severity in a murine model of CNS autoimmunity, characterized by an increase in both CNS immune cell infiltration and demyelination. Batf2-/- mice also exhibit increased astrocyte-specific expression of IRF1 and Caspase-1, suggesting an amplified interferon response in vivo. Further, we demonstrate that BATF2 is expressed primarily in astrocytes in MS lesions and that this expression is co-localized with IRF1. Collectively, our results further support a protective role for IFN-gamma and implicate BATF2 as a key suppressor of overactive immune signaling in astrocytes during neuroinflammation. | | 7:17p |
Maternal dietary deficiency in choline reduced levels of MMP-2 levels in blood and brain tissue of male offspring mice
Ischemic stroke is one of the leading causes of disability and death globally, with a rising incidence in younger age groups. It is well known that maternal diet during pregnancy and lactation is vital for the early neurodevelopment of offspring. One-carbon (1C) metabolism, including folic acid and choline, plays a vital role in closure of the neural tube in utero. However, the impact of maternal dietary deficiencies in 1C on off-spring neurological function following ischemic stroke later in life remains undefined. The aim of this study was to investigate inflammation in blood and brain tissue of offspring from mothers deficient in dietary folic acid or choline. Female mice were maintained on either a control or deficient diets prior to and during pregnancy and lactation. When offspring were 3-months of age, ischemic stroke was induced. One and half months later blood and brain tissue were collected. We measured levels of matrix metalloproteases (MMP)-2 and 9 in both plasma and brain tissue, and report reduced levels of MMP-2 in both, with no changes observed in MMP-9. This observation supports our working hypothesis that maternal dietary deficiencies in folic acid or choline during early neurodevelopment impact the levels of inflammation in offspring after ischemic stroke. |
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