Biology subjects

Li, A. Y.

Publications and source records attributed to Li, A. Y..

7 recordsLinked to original sources

bioRxiv2025

Effects of different slow paced breathing regimes on cerebrospinal fluid (CSF) oscillations

Cerebrospinal fluid (CSF) transport is crucial for clearing waste from the brain and is largely driven by blood vessel oscillatory dynamics. During non-REM sleep, large oscillations occur in the infraslow range around 0.02-0.03 Hz, where noradrenergically driven vasomotion, blood volume and CSF flow are tightly coupled. Whether an infraslow oscillation induced by respiration can engage comparable dynamics during wakefulness is unknown. Utilizing a fast neuroimaging technique, we investigated the effects of four different slow paced respiratory conditions on CSF oscillations in 35 healthy adults (aged 18-30): paced breathing at 0.09-0.11 Hz and 0.05-0.07 Hz, and paced sighing at 0.05-0.07 Hz and 0.02-0.03 Hz. All four conditions increased respiratory volume, low-frequency respiratory power, CSF oscillatory power and BOLD global signal amplitude relative to rest, and CSF power did not differ among them. However, the infraslow slow sighing produced significantly higher CSF-BOLD coupling than all the other conditions, together with the largest global signal amplitude, an index associated with reduced arousal. This effect of infraslow sighing was not linked with respiratory power, as paced breathing at 0.05-0.07 Hz had the greatest respiratory power yet the weakest CSF-BOLD coupling, falling below rest. Cardiac spectral power was also lower during infraslow sighing than during any other breathing manipulation. Stimulating oscillatory dynamics via respiration during wakefulness therefore may recruit neurovascular-CSF coupling due to the same infraslow-specific dynamics that are believed to drive sleep-dependent waste clearance. Our study provides evidence that slow paced breathing increases CSF oscillations during wakefulness. Furthermore, we found that sighing at the frequency of the infraslow band linked to glymphatic clearance increases the coupling between blood and CSF dynamics.

neuroscience↗

bioRxiv2023

Somatic mutation as an explanation for epigenetic aging

DNA methylation marks have recently been used to build models known as "epigenetic clocks" which predict calendar age. As methylation of cytosine promotes C-to-T mutations, we hypothesized that the methylation changes observed with age should reflect the accrual of somatic mutations, and the two should yield analogous aging estimates. In analysis of multimodal data from 9,331 human individuals, we find that CpG mutations indeed coincide with changes in methylation, not only at the mutated site but also with pervasive remodeling of the methylome out to {+/-}10 kilobases. This one-to-many mapping enables mutation-based predictions of age that agree with epigenetic clocks, including which individuals are aging faster or slower than expected. Moreover, genomic loci where mutations accumulate with age also tend to have methylation patterns that are especially predictive of age. These results suggest a close coupling between the accumulation of sporadic somatic mutations and the widespread changes in methylation observed over the course of life.

genomics↗

bioRxiv2023

Electrophysiological signatures of visual recognition memory across all layers of mouse V1

In mouse primary visual cortex (V1), familiar stimuli evoke significantly altered responses when compared to novel stimuli. This stimulus-selective response plasticity (SRP) was described originally as an increase in the magnitude of visual evoked potentials (VEPs) elicited in layer (L) 4 by familiar phase-reversing grating stimuli. SRP is dependent on NMDA receptors (NMDAR) and has been hypothesized to reflect potentiation of thalamocortical synapses in L4. However, recent evidence indicates that the synaptic modifications that manifest as SRP do not occur on L4 principal cells. To shed light on where and how SRP is induced and expressed, the present study had three related aims: (1) to confirm that NMDAR are required specifically in glutamatergic principal neurons of V1, (2) to investigate the consequences of deleting NMDAR specifically in L6, and (3) to use translaminar electrophysiological recordings to characterize SRP expression in different layers of V1. We find that knockout of NMDAR in L6 principal neurons disrupts SRP. Current-source density analysis of the VEP depth profile shows augmentation of short latency current sinks in layers 3, 4 and 6 in response to phase reversals of familiar stimuli. Multiunit recordings demonstrate that increased peak firing occurs to in response to phase reversals of familiar stimuli across all layers, but that activity between phase reversals is suppressed. Together, these data reveal important aspects of the underlying phenomenology of SRP and generate new hypotheses for the expression of experience-dependent plasticity in V1. Significance StatementRepeated exposure to stimuli that portend neither reward nor punishment leads to behavioral habituation, enabling organisms to dedicate attention to novel or otherwise significant features of the environment. The neural basis of this process, which is so often dysregulated in neurological and psychiatric disorders, remains poorly understood. Learning and memory of stimulus familiarity can be studied in mouse visual cortex by measuring electrophysiological responses to simple phase-reversing grating stimuli. The current study advances knowledge of this process by documenting changes in visual evoked potentials, neuronal spiking activity, and oscillations in the local field potentials across all layers of mouse visual cortex. In addition, we identify a key contribution of a specific population of neurons in layer 6 of visual cortex.

neuroscience↗

bioRxiv2022

Multimodal Object Representations Rely on Integrative Coding

Combining information from multiple senses is essential to object recognition. Yet how the mind combines sensory input into coherent multimodal representations - the multimodal binding problem - remains poorly understood. Here, we applied multi-echo fMRI across a four-day paradigm, in which participants learned 3-dimensional multimodal object representations created from well-characterized visual shape and sound features. Our novel paradigm decoupled the learned multimodal object representations from their baseline unimodal shape and sound features, thus tracking the emergence of multimodal concepts as they were learned by healthy adults. Critically, the representation for the whole object was different from the combined representation of its individual parts, with evidence of an integrative object code in anterior temporal lobe structures. Intriguingly, the perirhinal cortex - an anterior temporal lobe structure - was by default biased towards visual shape, but this initial shape bias was attenuated with learning. Pattern similarity analyses suggest that after learning the perirhinal cortex orthogonalized combinations of visual shape and sound features, transforming overlapping feature input into distinct multimodal object representations. These results provide evidence of integrative coding in the anterior temporal lobes that is distinct from the distributed sensory features, advancing the age-old question of how the mind constructs multimodal objects from their component features.

neuroscience↗

bioRxiv2021

The effect of magnesium on calcium binding to cardiac troponin C related hypertrophic cardiomyopathy mutants

Cardiac troponin C (cTnC) is the calcium (Ca2+) sensing component of the troponin complex. Binding of Ca2+ to cTnC triggers a cascade of myofilament conformational changes that culminate in force production. Mutations in cTnC linked to hypertrophic myocardial myopathy (HCM) induce a a greater degree and duration of Ca2+ binding, which may underly the hypertrophic phenotype. Recent evidence from our laboratories demonstrated novel modifications of cTnC Ca2+ binding by cellular magnesium (Mg2+) that we hypothesize may be of significance in promoting HCM. Regulation of contraction has long been thought to occur exclusively through Ca2+ binding to site II of cTnC. However, abundant cellular Mg2+ is a potential competitor for binding to the same sites; work by several groups also suggests this is possible. We have used isothermal titration calorimetry (ITC) to explore the thermodynamic properties associated with the interaction between Ca2+/Mg2+ and site II of cTnC; these experiments demonstrated that physiological concentrations of Mg2+ may compete with Ca2+ to bind site II of cTnC. In experiments reported here, we studied a series of mutations in cTnC thought to be causal in HCM. Three mutants (A8V, L29Q, and A31S) slightly elevated the affinity for both Ca2+ and Mg2+, whereas other mutants (L48Q, Q50R, and C84Y), that are closer to the C-terminal domain and surrounding the EF hand binding motif of site II had a more significant effect on affinity and the thermodynamics of the binding interaction. To the best of our knowledge, this work is the first to explore the role of Mg2+ in modifying the Ca2+ affinity ofcTnC mutations linked to HCM. Our results indicate a physiologically significant role for cellular Mg2+ at baseline conditions and when elevated on the control of the dynamics of contraction by modifications in the Ca2+ binding properties of cTnC.

cell biology↗

bioRxiv2021

Latent representation of the human pan-celltype epigenome through a deep recurrent neural network

The availability of thousands of assays of epigenetic activity necessitates compressed representations of these data sets that summarize the epigenetic landscape of the genome. Until recently, most such representations were celltype specific, applying to a single tissue or cell state. Recently, neural networks have made it possible to summarize data across tissues to produce a pan-celltype representation. In this work, we propose Epi-LSTM, a deep long short-term memory (LSTM) recurrent neural network autoencoder to capture the long-term dependencies in the epigenomic data. The latent representations from Epi-LSTM capture a variety of genomic phenomena, including gene-expression, promoter-enhancer interactions, replication timing, frequently interacting regions and evolutionary conservation. These representations outperform existing methods in a majority of cell-types, while yielding smoother representations along the genomic axis due to their sequential nature.

bioinformatics↗

bioRxiv2019

Visual interference can help and hinder memory: Measuring memory fidelity using a novel circular shape space

Although we can all agree that interference induces forgetting, there is surprisingly little consensus regarding what type of interference most likely disrupts memory. We previously proposed that the similarity of interference differentially impacts the representational detail of color memory. Here, we extend this work by applying the Validated Circular Shape Space (Li et al., 2020) for the first time to a continuous retrieval task, in which we quantified both the visual similarity of distracting information as well as the representational detail of shape memory. We found that the representational detail of memory was systematically and differentially altered by the similarity of distracting information. Dissimilar distractors disrupted both fine- and coarse-grained information about the target, akin to memory erasure. In contrast, similar distractors disrupted fine-grained target information but increased reliance on coarse-grained information about the target, akin to memory blurring. Notably, these effects were consistent across two mixture models that each implemented a different scaling metric (either angular distance or perceived target similarity), as well as a parameter-free analysis that did not fit the mixture model. These findings suggest that similar distractors will help memory in cases where coarse-grained information is sufficient to identify the target. In other cases where precise fine-grained information is needed to identify the target, similar distractors will impair memory. As these effects have now been observed across both stimulus domains of shape and color, and were robust across multiple scaling metrics and methods of analyses, we suggest that these results provide a general set of principles governing how the nature of interference impacts forgetting.

neuroscience↗