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Sankar, R.

Publications and source records attributed to Sankar, R..

10 recordsLinked to original sources

Dual pathway architecture in songbirds enables robust sensorimotor learning

The acquisition of sensorimotor skills critically depends on basal ganglia (BG)-thalamo-cortical circuits. Prevailing theories propose that the BG optimize motor output through reinforcement learning (RL), using internal performance evaluations to approximate stochastic gradient ascent. However, this framework struggles in non-convex performance landscapes, where local optima hinder efficient learning. Songbirds provide a compelling biological example of robust sensorimotor learning, mastering complex vocalizations through trial-and-error within a specialized BG-thalamo-cortical architecture. Here, we present a computational model constrained by the anatomy, physiology, and developmental trajectory of the zebra finch song system. The model combines a BG-driven RL pathway with a parallel cortical motor pathway that progressively consolidates successful motor patterns via Hebbian plasticity. In addition, we incorporate synaptic volatility within the BG pathway, introducing structured variability across learning. Through simulations of vocal learning using both a biophysical syrinx model and synthetic performance landscapes, we demonstrate that this dual-pathway architecture reliably converges to global optima and outperforms standard and noise-annealed RL approaches. The model reproduces key experimental features of song learning, including non-monotonic learning trajectories, a gradual reduction in motor variability, and the developmental transfer of motor control from subcortical to cortical circuits. Mechanistically, delayed maturation of the cortical pathway provides an implicit regulation of the exploration-exploitation trade-off, while synaptic volatility enables escape from local optima. These results highlight the importance of neural circuit architecture and dynamics in efficient learning, and suggest biologically inspired design principles for improving the robustness and sample efficiency of artificial RL systems in complex sensorimotor domains.

neuroscience↗

Acute exposure of mouse and human hippocampal slices to tau oligomers reversibly impairs sharp-wave ripples

Sharp-wave ripple (SWR) oscillations are crucial for memory consolidation and deteriorate in Alzheimers disease (AD). Tau oligomers are suggested to lead to synaptic and neuronal degeneration in AD, but their effects on SWRs are unknown. To study this, we prepared mouse and human hippocampal slices and bath-applied tau oligomer preparations after spontaneous SWR generation. In human slices, acute exposure to tau resulted in decreased ripple duration, whereas in mouse slices it was SWR rate, amplitude, and power that decreased, sparing duration. In a different set of experiments, mouse slices were pre-incubated directly in either tau-ACSF or control-ACSF right after slicing for 2.5-5.5 hours, resulting only in diminished SWR rate. These effects were specific to the presence of {beta}-sheets, as a different tau preparation that lacked {beta}-sheets failed to alter SWRs. This method is therefore suitable to study SWR alterations after short-term exposure to different tau and/or A{beta} species, allows a higher throughput screening of possible therapeutics compared to in vivo animal experiments, and permits direct comparison of SWR alterations in mice and humans.

neuroscience↗

Inhomogeneous Tau polymerization, core-shell organization, and seed formation during Tau condensate aging

Several proteins aggregating in neurodegenerative diseases spontaneously segregate into liquid condensates, which can catalyze protein aggregation. How liquid-solid transitions are catalyzed in the confined condensate volume is not clear. For the microtubule associated protein Tau, aggregating intra-neuronally in Alzheimer's disease, we show that, during maturation, Tau condensates convert into elastic protein networks, accompanied by inhomogeneous polymerization of the condensate interior and the formation of high-density nodes and a 'shell'. During condensation, Tau molecules extend, favoring intermolecular interactions and priming for progressive parallel Tau arrangement that can enable amyloid-like Tau oligomerization. In cells, aged condensates seed small Tau clusters in cytosol and at the nuclear envelope, precursors of larger aggregates. By bridging molecular to condensate level, we present mechanistic insight into how Tau condensates evolve into pathological, beta-structure containing seeds. The interior of aged Tau condensates remains accessible for smaller molecules, providing the opportunity to molecularly target Tau seed formation inside condensates.

biochemistry↗

FACT depletion results in a temporal cascade of chromatin disruption preceding transcriptional collapse in stem cells

The histone chaperone FACT is essential for chromatin organization and stem cell identity, yet the sequence of events through which FACT maintains chromatin integrity remains unclear. We generate a high-resolution temporal map of events leading to chromatin destabilization and cell identity loss in murine embryonic stem cells following dTAG-mediated depletion of FACT. Loss of FACT initiates a rapid cascade, with nucleosome phasing disruption and reduced H3K4me3 beginning within 10 minutes in a transcription-dependent manner. This architectural destabilization enables pluripotency transcription factors to ectopically occupy gene bodies. FACT loss results in RNA Polymerase II accumulation within 30 minutes and altered H3K36me3 deposition preceding a global transcriptional collapse at 2 hours of FACT depletion. FACT restoration fails to rescue these defects, demonstrating they are largely irreversible. Our findings define a temporal hierarchy in which FACT loss drives progressive deterioration of chromatin architecture, leading to transcriptional collapse in stem cells.

genomics↗

Tau interactions with inner nuclear envelope proteins modulates chromatin

Abstract/SummaryThe intracellular re-distribution of the neuronal microtubule-associated protein Tau, from the axon into the somatodendritic compartment, is a physiological stress-related event and occurs early in Alzheimers disease (AD). Nuclear envelope distortions have been linked to the presence and aggregation of pathological Tau near the nucleus in these diseases. How physiologically increased soma Tau levels, enabling Tau interactions with the nucleus, impact nuclear integrity and neuronal physiology is unclear. Combining proximity biotinylation interactomics with chromatin imaging and molecular assays, we show that soluble Tau interacts with proteins coordinating chromatin at the inner nuclear membrane, including lamin B receptor and SUN1. This interaction promotes nuclear envelope invaginations and damage and changes the coordination of DNA at the nuclear lamina. Increasing somatodendritic Tau is sufficient to upregulate the expression of multiple transcription factors implicated in AD pathogenesis and to reduce expression of genes involved in cholesterol biosynthesis, which seem coordinated at lamin associated domains. These nuclear envelope-related mechanisms suggest that physiological, neuronal stress-related somatodendritic Tau missorting can initiate chromatin-related cascades important for early changes in AD and tauopathies.

neuroscience↗

Direct binding of TDP-43 and Tau drives their co-condensation, but suppresses Tau fibril formation and seeding

Neuronal Tau aggregates are a hallmark of Alzheimers disease (AD), but more than half of the patients exhibit additional TDP-43 inclusions and some have co-aggregates of both proteins. The presence of Tau/TDP-43 co-pathology is associated with increased disease severity, although the causal relationship remains unclear. Here we demonstrate that Tau and TDP-43 mutually promote each others condensation through direct interaction in vitro, forming irregularly shaped or multiphasic co-condensates with lower TDP-43 mobility, but higher Tau dynamics. While Tau promotes TDP-43 aggregation in vitro, TDP-43 suppresses formation of Tau fibrils and instead causes formation of oligomeric Tau and Tau/TDP-43 species. These co-assemblies hinder Tau seeding in a biosensor assay specific for proteopathic Tau seeds. Consistent with this data, SarkoSpin extracts from AD brains with Tau/TDP-43 co-pathology exhibit reduced Tau seeding compared to Tau-only AD brains. In contrast, patient-derived extracts from AD brains with Tau/TDP-43 co-pathology are highly potent in seeding TDP-43 neoaggregates in a TDP-43 reporter cell line. Our results suggest that direct interaction of TDP-43 and Tau may suppress Tau pathology, while promoting TDP-43 pathology. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/662960v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1ed5dfaorg.highwire.dtl.DTLVardef@b4ef07org.highwire.dtl.DTLVardef@b8dbe8org.highwire.dtl.DTLVardef@6d9b49_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

PyHFO: Lightweight Deep Learning-poweredEnd-to-End High-Frequency Oscillations AnalysisApplication

In the context of epilepsy studies, intracranially-recorded interictal high-frequency oscillations (HFOs) in EEG signals are emerging as promising spatial neurophysiological biomarkers for epileptogenic zones. While significant efforts have been made in identifying and understanding these biomarkers, deep learning is carving novel avenues for biomarker detection and analysis. Yet, transitioning such methodologies to clinical environments is difficult due to the rigorous computational needs of processing EEG data via deep learning. This paper presents our development of an advanced end to end software platform, PyHFO, aimed at bridging this gap. PyHFO provides an integrated and user-friendly platform that includes time-efficient HFO detection algorithms such as short-term energy (STE) and Montreal Neurological Institute and Hospital (MNI) detectors and deep learning models for artifact and HFO with spike classification. This application functions seamlessly on conventional computer hardware. Our platform has been validated to adeptly handle datasets from 10-minute EEG recordings captured via grid/strip electrodes in 19 patients. Through implementation optimization, PyHFO achieves speeds up to 50 times faster than the standard HFO detection method. Users can either employ our pre-trained deep learning model for their analyses or use their EEG data to train their model. As such, PyHFO holds great promise for facilitating the use of advanced EEG data analysis tools in clinical practice and large-scale research collaborations.

neuroscience↗

Dual pathway architecture underlying vocal learning in songbirds

Song acquisition and production in songbirds is governed by a dedicated neural circuitry that involves two parallel pathways: a motor pathway for the production and a basal ganglia (BG) pathway for the acquisition. Juveniles learn by imitating adult vocalizations and proceed by trial and error, errors being conveyed by a dopaminergic signal. The complex nature of the relationship between neural control and syrinx musculature makes song learning a complicated problem to solve. Reinforcement learning (RL) has been widely hypothesized to underlie such sensorimotor learning even though this can lead to sub-optimal solutions under uneven contours in continuous action spaces. In this article, we propose to re-interpret the role of a dual pathway architecture, underlying avian vocal learning, that helps overcome these limitations. We posit that the BG pathway conducts exploration by inducing large daily shifts in the vocal production while the motor pathway gradually consolidates this exploration. This process can be understood as a modified form of a simulated annealing process. Simulations on Gaussian performance landscapes and a syrinx-based performance landscape are demonstrated and compared with standard approaches. Taking behavioral constraints into account (60 days of learning, 1000 trials per day), the model allows to reach the global optimum in complex landscapes and thus provides a sound insight into the role of the dual pathway architecture underlying vocal learning.

neuroscience↗

Refining epileptogenic high-frequency oscillations using deep learning: a reverse engineering approach

Intracranially-recorded interictal high-frequency oscillations (HFOs) have been proposed as a promising spatial biomarker of the epileptogenic zone. However, visual verification of HFOs is time-consuming and exhibits poor inter-rater reliability. Furthermore, no method is currently available to distinguish HFOs generated from the epileptogenic zone (epileptogenic HFOs: eHFOs) from those generated from other areas (non-epileptogenic HFOs: non-eHFOs). To address these issues, we constructed a deep learning (DL)-based algorithm using HFO events from chronic intracranial electroencephalogram (iEEG) data via subdural grids from 19 children with medication-resistant neocortical epilepsy to: 1) replicate human expert annotation of artifacts and HFOs with or without spikes, and 2) discover eHFOs by designing a novel weakly supervised model (HFOs from the resected brain regions are initially labeled as eHFOs, and those from the preserved brain regions as non-eHFOs). The "purification power" of DL is then used to automatically relabel the HFOs to distill eHFOs. Using 12,958 annotated HFO events from 19 patients, the model achieved 96.3% accuracy on artifact detection (F1 score = 96.8%) and 86.5% accuracy on classifying HFOs with or without spikes (F1 score = 80.8%) using patient-wise cross-validation. Based on the DL-based algorithm trained from 84,602 HFO events from nine patients who achieved seizure-freedom after resection, the majority of such DL-discovered eHFOs were found to be HFOs with spikes (78.6%, p < 0.001). While the resection ratio of detected HFOs (number of resected HFOs/number of detected HFOs) did not correlate significantly with post-operative seizure freedom (the area under the curve [AUC]=0.76, p=0.06), the resection ratio of eHFOs positively correlated with post-operative seizure freedom (AUC=0.87, p=0.01). We discovered that the eHFOs had a higher signal intensity associated with ripple (80-250 Hz) and fast ripple (250-500 Hz) bands at the HFO onset and with a lower frequency band throughout the event time window (the inverted T-shaped), compared to non-eHFOs. We then designed perturbations on the input of the trained model for non-eHFOs to determine the models decision-making logic. The model probability significantly increased towards eHFOs by the artificial introduction of signals in the inverted T-shaped frequency bands (mean probability increase: 0.285, p < 0.001), and by the artificial insertion of spike-like signals into the time domain (mean probability increase: 0.452, p < 0.001). With this DL-based framework, we reliably replicated HFO classification tasks by human experts. Using a reverse engineering technique, we distinguished eHFOs from others and identified salient features of eHFOs that aligned with current knowledge. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/458385v1_ufig1.gif" ALT="Figure 1"> View larger version (81K): org.highwire.dtl.DTLVardef@39977dorg.highwire.dtl.DTLVardef@108b182org.highwire.dtl.DTLVardef@1bdf864org.highwire.dtl.DTLVardef@fe9e57_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

Scalp EEG interictal high frequency oscillations as an objective EEG biomarker of infantile spasms

ObjectiveTo investigate the diagnostic utility of high frequency oscillations (HFOs) via scalp electroencephalogram (EEG) in infantile spasms. MethodsWe retrospectively analyzed interictal slow-wave sleep EEGs sampled at 2,000 Hz recorded from 30 consecutive patients who were suspected of having infantile spasms. We measured the rate of HFOs (80-500 Hz) and the strength of the cross-frequency coupling between HFOs and slow-wave activity (SWA) at 3-4 Hz and 0.5-1 Hz as quantified with modulation indices (MIs). ResultsTwenty-three patients (77%) exhibited active spasms during the overnight EEG recording. Although the HFOs were detected in all children, increased HFO rate and MIs correlated with the presence of active spasms (p < 0.001 by HFO rate; p < 0.01 by MIs at 3-4 Hz; p = 0.02 by MIs at 0.5-1 Hz). The presence of active spasms was predicted by the logistic regression models incorporating HFO-related metrics (AUC: 0.80-0.98) better than that incorporating hypsarrhythmia (AUC: 0.61). The predictive performance of the best model remained favorable (87.5% accuracy) after a cross-validation procedure. ConclusionsIncreased rate of HFOs and coupling between HFOs and SWA are associated with active epileptic spasms. SignificanceScalp-recorded HFOs may serve as an objective EEG biomarker for active epileptic spasms. HighlightsO_LIObjective analyses of scalp high frequency oscillations and its coupling with slow-wave activity in infantile spasms were feasible. C_LIO_LIIncreased rate of high frequency oscillations and its coupling with slow-wave activity correlated with active epileptic spasms. C_LIO_LIThe scalp high frequency oscillations were also detected in neurologically normal children (although at the low rate). C_LI

neuroscience↗