Biology subjects

Krishnan, G.

Publications and source records attributed to Krishnan, G..

16 recordsLinked to original sources

bioRxiv2025

Intrinsic ion dynamics underlies the temporal nature of resting-state functional connectivity

The neural mechanisms underlying the emergence of functional connectivity in resting-state fMRI remain poorly understood. Recent studies suggest that resting-state activity consists of brief periods of strong co-fluctuations among brain regions, which reflect overall functional connectivity. Others report a continuum in co-fluctuations over time, with varying degree of correlation to functional connectivity. These findings raise the critical question: what neural processes underlie the temporal structure of resting-state activity? To address this, we used a biophysically realistic whole-brain computational model in which resting-state activity emerged from temporal variations in the ion concentrations of potassium (K+) and sodium (Na+), intracellular chloride (Cl-), and the activity of the Na+/K+ ATPase. The model reproduced transient periods of high co-fluctuations, and the functional connectivity at different co-fluctuation levels correlated to varying degrees with the connectivity measured over the entire simulation, in line with experimental observations. The periods of high co-fluctuations were aligned with large changes in extracellular ion concentrations. Furthermore, critical parameters governing ion dynamics strongly affected both the timing of these transient events and the spatial structure of the resulting functional connectivity. The balance of excitatory and inhibitory activity further modulated their frequency and amplitude. Together, these results suggest that intrinsic fluctuations in ion dynamics could serve as a plausible neural mechanism for the temporal organization of co-fluctuations and resting-state functional connectivity.

neuroscience↗

bioRxiv2025

Nuclear and mitochondrial genome assemblies of Indrella ampulla, a terrestrial gastropod endemic to the Western Ghats

Indrella ampulla is a polymorphic, brightly coloured, forest-dwelling land snail endemic to the Western Ghats of India. Studying and understanding evolutionary processes occurring within this species has remained a challenge largely due to a paucity of genomic resources. We present high-quality annotated nuclear and mitochondrial genome assemblies of I. ampulla. The nuclear genome is assembled through a hybrid approach using Illumina short reads and Oxford Nanopore long reads, with an N50 value of 632 kb and 90.3% BUSCO genome completeness. The mitogenome is 13,887 bp long. The demographic history reconstruction based on the genomic data exhibits signatures of population decline during the last 100,000 years. This genome will aid in deciphering the colour polymorphism in I. ampulla and augmenting the general understanding of the evolution of gastropods. SignificanceIndrella ampulla is a terrestrial gastropod endemic to the Western Ghats biodiversity hotspot, and exhibits color polymorphism. The genome of I. ampulla provides a valuable resource for understanding molluscan biology, coloration genetics, adaptation, and other evolutionary processes. Our historical demographic analysis offers insights into past population dynamics of this species endemic to the Western Ghats of India, contributing to broader research on biodiversity patterns in tropical ecosystems. The bioinformatics pipeline used in this study provides a reliable framework for assembling high-quality genomes with long-read coverage as low as 10X, making it especially useful for gastropods and other species where obtaining high coverage data is a challenge. Overall, this genome will complement future studies in phylogenomics, comparative genomics, and conservation of molluscs.

genomics↗

bioRxiv2025

De novo genome assemblies of threatened Asian hornbills (Bucerotidae) reveal declining population trajectories during the late Pleistocene

2.Asian hornbills are flagship species of the wet tropics that face significant threats from hunting, habitat loss, and fragmentation. Despite being conservation flagships, whole genome information is available for only two of the 32 Asian hornbill species. In this study, we provide the first de novo genome assemblies for four hornbill species (Bucerotidae) in Asia. We present hybrid genome assemblies for Buceros bicornis and Rhyticeros undulatus, and short-read genomes for Anthracoceros coronatus, and Aceros nipalensis. The genome sizes of these hornbills range from 1.1 Gb to 1.3 Gb with over 93% completeness and gene prediction BUSCO. We also provide annotated mitogenomes for each of these species. Furthermore, we estimated Pleistocene population trajectories for these four species, which vary in their habitat preferences. Our results indicate that Pleistocene climatic fluctuations have led to dramatic population declines in all four species. We believe that this study provides robust genomic resources to support future conservation genomics efforts for hornbills.

genomics↗

bioRxiv2025

Genomic signatures of terrestrial adaptation in air-breathing catfishes (Clariidae)

Air-breathing catfishes of the family Clariidae exhibit extraordinary adaptations that enable them to survive outside water for extended periods, yet the genetic and genomic basis of these adaptations remain poorly understood. To study these adaptations, we sequenced and assembled two high-quality genomes of two clariid species, Clarias gariepinus and Clarias dussumieri and compare them with previously available genomes of 23 catfish species across nine families. By reconstructing the whole-genome phylogeny and examining patterns of positive selection and gene family evolution, we found unique signatures associated with terrestrial adaptation in clariids. Our analysis revealed that a high proportion of genes were positively selected in clariids, that play critical roles in hypoxia tolerance, thermoregulation, metabolism, and DNA repair, which are key traits for terrestrial adaptation. Additionally, we observed significant expansions in gene families, including Myoglobin (involved in oxygen transport), immunity-related genes, and xenobiotic degradation pathways, highlighting their importance in environmental resilience and detoxification. Together, these findings provide a comprehensive understanding of the genomic changes facilitating the terrestrial adaptation of clariids. This study also highlights the contribution of genome evolution to their resilience, adaptability to novel environments, and invasiveness, offering valuable insights into the genetic basis of ecological niche diversification.

evolutionary biology↗

bioRxiv2024

Traumatic injury causes selective degeneration and TDP-43 mislocalization in human iPSC-derived C9orf72-associated ALS/FTD motor neurons

A hexanucleotide repeat expansion (HRE) in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, patients with the HRE exhibit a wide disparity in clinical presentation and age of symptom onset suggesting an interplay between genetic background and environmental stressors. Neurotrauma, resulting from traumatic brain or spinal cord injury has been shown to increase the risk of ALS in epidemiological studies. Here, we combine patient-specific induced pluripotent stem cells (iPSCs) with a custom-built device to deliver biofidelic stretch trauma to C9orf72 patient and isogenic control motor neurons (MNs) in vitro. We find that mutant but not control MNs exhibit selective degeneration after a single incident of severe trauma, which can be partially rescued by pretreatment with a C9orf72 antisense oligonucleotide. A single incident of mild trauma does not cause degeneration but leads to cytoplasmic accumulation of TDP-43 in C9orf72 MNs. This mislocalization, which only occurs briefly in isogenic controls, is eventually restored in C9orf72 MNs after 6 days. Lastly, repeated mild trauma ablates the ability of patient MNs to recover. These findings highlight alterations in TDP-43 dynamics in C9orf72 ALS patient MNs following traumatic injury and demonstrate that neurotrauma compounds neuropathology in C9orf72 ALS. More broadly, our work establishes an in vitro platform that can be used to interrogate the mechanistic interactions between ALS and neurotrauma.

neuroscience↗

bioRxiv2024

Thalamic feedback shapes brain responses evoked by cortical stimulation in mice and humans

Cortical stimulation with single pulses is a common technique in clinical practice and research. However, we still do not understand the extent to which it engages subcortical circuits which contribute to the associated evoked potentials (EPs). Here we find that cortical stimulation generates remarkably similar EPs in humans and mice, with a late component similarly modulated by the subjects behavioral state. We optogenetically dissect the underlying circuit in mice, demonstrating that the late component of these EPs is caused by a thalamic hyperpolarization and rebound. The magnitude of this late component correlates with the bursting frequency and synchronicity of thalamic neurons, modulated by the subjects behavioral state. A simulation of the thalamo-cortical circuit highlights that both intrinsic thalamic currents as well as cortical and thalamic GABAergic neurons contribute to this response profile. We conclude that the cortical stimulation engages cortico-thalamo-cortical circuits highly preserved across different species and stimulation modalities. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/578243v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@cae203org.highwire.dtl.DTLVardef@1bc5223org.highwire.dtl.DTLVardef@b48e43org.highwire.dtl.DTLVardef@1e7fe34_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Cholinergic modulation supports DMN suppression during resting state

Brain activity during the resting state is widely used to examine brain organization, cognition and alterations in disease states. While it is known that neuromodulation and the state of alertness impact resting-state activity, neural mechanisms behind such modulation of resting-state activity are unknown. In this work, we used a computational model to demonstrate that change in excitability and recurrent connections, due to cholinergic modulation, impacts resting-state activity. The results of such modulation in the model match closely with experimental work on direct cholinergic modulation of Default Mode Network (DMN) in rodents. We further extended our study to the human connectome derived from diffusion-weighted MRI. In human resting-state simulations, an increase in cholinergic input resulted in a brain-wide reduction of functional connectivity. Furthermore, selective cholinergic modulation of DMN closely captured experimentally observed transitions between the baseline resting state and states with suppressed DMN fluctuations associated with attention to external tasks. Our study thus provides insight into potential neural mechanisms for the effects of cholinergic neuromodulation on resting-state activity and its dynamics.

neuroscience↗

bioRxiv2022

Translation of dipeptide repeat proteins in C9ORF72-ALS/FTD through unique and redundant AUG initiation codons

A hexanucleotide repeat expansion in the first intron of C9ORF72 is the most common monogenic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A hallmark of ALS/FTD pathology is the presence of dipeptide repeat (DPR) proteins, produced from both sense GGGGCC (poly-GA, poly-GP, poly-GR) and antisense CCCCGG (poly-PR, poly-PG, poly-PA) transcripts. Although initiation codons and regulatory factors have been identified for sense DPR translation, they remain mostly unknown for antisense DPRs. Here, we show that an AUG initiation codon is necessary for poly-PR synthesis, suggesting canonical AUG dependent translation. Remarkably, although an AUG located 194 base pairs (bp) upstream of the repeat is the main start codon for poly-PG synthesis, two other AUG codons (-212 bp, -113 bp) can also initiate translation, demonstrating a striking redundancy in start codon usage. eIF2D is required for CUG start codon-dependent poly-GA translation from the sense transcript in human motor neurons derived from induced pluripotent stem cells of C9ORF72 ALS/FTD patients, but AUG-dependent poly-PG or poly-PR synthesis does not require eIF2D, indicating that distinct translation initiation factors control DPR synthesis from sense and antisense transcripts. Our findings provide key molecular insights into DPR synthesis from the C9ORF72 locus, which may be broadly applicable to many other nucleotide-repeat expansion disorders.

molecular biology↗

bioRxiv2022

CRISPR/Cas9-Mediated Excision of ALS/FTD-Causing Hexanucleotide Repeat Expansion in C9ORF72 rescues major disease mechanisms in vivo and in vitro

A hexanucleotide repeat expansion (HRE) consisting of GGGGCC24+ in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both are fatal neurodegenerative diseases with no current approved treatments that significantly slow disease progression or extend life expectancy. Several hypotheses have emerged to explain how this HRE causes neuronal death, including C9ORF72 haploinsufficiency, sequestration of RNA-binding proteins in the nucleus, and production of dipeptide repeat proteins. In the present study we used a CRISPR/Cas9 gene-editing approach to remove the HRE from the C9ORF72 genomic locus, designing guide RNAs (gRNAs) flanking the HRE, and delivered Cas9 and gRNAs using adeno-associated virus serotype 9 (AAV9) vectors. Here, we demonstrate successful excision of the HRE in C9ORF72 in primary cortical neurons and brains of three mouse models containing the C9ORF72 expanded HRE (ranging from 500-600 repeats) as well as in patient-derived iPSC motor neurons and brain organoids (450 repeats). This resulted in a reduction of RNA foci, poly-dipeptides and haploinsufficiency, the major hallmarks of C9-ALS/FTD, making this an extremely attractive therapeutic approach to these diseases.

molecular biology↗

bioRxiv2020

Differential covariance: A new method to estimate functional connectivity in fMRI

Measuring functional connectivity from fMRI recordings is important in understanding processing in cortical networks. However, because the brains connection pattern is complex, currently used methods are prone to producing false functional connections. We introduce differential covariance analysis, a new method that uses derivatives of the signal for estimating functional connectivity. We generated neural activities from Dynamical Causal Modeling and a neural network of Hodgkin-Huxley neurons and then converted them to hemodynamic signals using the forward Balloon model. The simulated fMRI signals together with the ground truth connectivity pattern were used to benchmark our method with other commonly used methods. Differential covariance achieved better results in complex network simulations. This new method opens an alternative way to estimate functional connectivity.

neuroscience↗

bioRxiv2019

Stimulation augments spike sequence replay and memory consolidation during slow-wave sleep

Newly acquired memory traces are spontaneously reactivated during slow-wave sleep (SWS), leading to the consolidation of recent memories. Empirical studies found that sensory stimulation during SWS selectively enhances memory consolidation and the effect depends on the phase of stimulation. In this new study, we aimed to understand the mechanisms behind the role of sensory stimulation on memory consolidation using computational models implementing effects of neuromodulators to simulate transitions between awake and SWS sleep, and synaptic plasticity to allow the change of synaptic connections due to the training in awake or replay during sleep. We found that when closed-loop stimulation was applied during the Down states (900-2700) of sleep slow oscillation, particularly right before transition from Down to Up state, it significantly affected the spatio-temporal pattern of the slow-waves and maximized memory replay. In contrast, when the stimulation was presented during the Up states (2700-3600 and 00-900), it did not have a significant impact on the slow-waves or memory performance after sleep. For multiple memories trained in awake, presenting stimulation cues associated with specific memory trace could selectively augment replay and enhance consolidation of that memory and interfere with consolidation of the others (particularly weak) memories. Our study proposes a synaptic level mechanism of how memory consolidation is affected by sensory stimulation during sleep.\n\nSignificance statementStimulation, such as training-associated cues or auditory stimulation, during sleep can augment consolidation of the newly encoded memories. In this study, we used a computational model of the thalamocortical system to describe the mechanisms behind the role of stimulation in memory consolidation during slow-wave sleep. Our study suggested that stimulation preferentially strengthens the memory traces when delivered at specific phase of slow oscillations just before Down to Up state transition when it makes the largest impact on the spatio-temporal pattern of sleep slow waves. In the presence of multiple memories, presenting sensory cues during sleep could selectively strengthen selected memories. Our study proposes a synaptic level mechanism of how memory consolidation is affected by sensory stimulation during sleep.

neuroscience↗

bioRxiv2019

Can sleep protect memories from catastrophic forgetting?

Continual learning remains to be an unsolved problem in artificial neural networks. Biological systems have evolved mechanisms by which they can prevent catastrophic forgetting of old knowledge during new training and allow lifelong learning. Building upon data suggesting the importance of sleep in learning and memory, here we test a hypothesis that sleep protects memories from catastrophic forgetting. We found that training in a thalamocortical network model of a \"new\" memory that interferes with previously stored \"old\" memory may result in degradation and forgetting of the old memory trace. Simulating NREM sleep immediately after new learning leads to replay, which reverses the damage and ultimately enhances both old and new memory traces. Surprisingly, we found that sleep replay goes beyond recovering old memory traces that were damaged by new learning. When a new memory competes for the neuronal/synaptic resources previously allocated to the old memory, sleep replay changes the synaptic footprint of the old memory trace to allow for the overlapping populations of neurons to store multiple memories. Different neurons become preferentially supporting different memory traces to allow successful recall. We compared synaptic weight dynamics during sleep replay with that during interleaved training - a common approach to overcome catastrophic forgetting in artificial networks - and found that interleaved training promotes synaptic competition and weakening of reciprocal synapses, effectively reducing an ensemble of neurons contributing to memory recall. This leads to suboptimal recall performance compared to that after sleep. Together, our results suggest that sleep provides a powerful mechanism to achieve continual learning by combining consolidation of new memory traces with reconsolidation of old memory traces to minimize memory interference.

neuroscience↗

bioRxiv2019

Interaction of Hippocampal Ripples and Cortical Slow Waves Leads to Coordinated Large-Scale Sleep Rhythm

The dialogue between cortex and hippocampus is known to be crucial for sleep dependent consolidation of long lasting memories. During slow wave sleep memory replay depends on slow oscillation (SO) and spindles in the (neo)cortex and sharp wave-ripple complexes (SWR) in the hippocampus, however, the mechanisms underlying interaction of these rhythms are poorly understood. Here, we examined the interaction between cortical SOs and hippocampal SWRs in a computational model of the hippocampo-cortico-thalamic network and compared the results with human intracranial recordings during sleep. We observed that ripple occurrence peaked following the onset of SO (Down-to-Up-state transition) and that cortical input to hippocampus was crucial to maintain this relationship. Ripples influenced the spatiotemporal structure of cortical SO and duration of the Up/Down-states. In particular, ripples were capable of synchronizing Up-to-Down state transition events across the cortical network. Slow waves had a tendency to initiate at cortical locations receiving hippocampal ripples, and these \"initiators\" were able to influence sequential reactivation within cortical Up states. We concluded that during slow wave sleep, hippocampus and neocortex maintain a complex interaction, where SOs bias the onset of ripples, while ripples influence the spatiotemporal pattern of SOs.

neuroscience↗

bioRxiv2017

Simulating human sleep spindle MEG and EEG from ion channel and circuit level dynamics

BackgroundAlthough they form a unitary phenomenon, the relationship between extracranial M/EEG and transmembrane ion flows is understood only as a general principle rather than as a well-articulated and quantified causal chain.\n\nMethodWe present an integrated multiscale model, consisting of a neural simulation of thalamus and cortex during stage N2 sleep and a biophysical model projecting cortical current densities to M/EEG fields. Sleep spindles were generated through the interactions of local and distant network connections and intrinsic currents within thalamocortical circuits. 32,652 cortical neurons were mapped onto the cortical surface reconstructed from subjects MRI, interconnected based on geodesic distances, and scaled-up to current dipole densities based on laminar recordings in humans. MRIs were used to generate a quasi-static electromagnetic model enabling simulated cortical activity to be projected to the M/EEG sensors.\n\nResultsThe simulated M/EEG spindles were similar in amplitude and topography to empirical examples in the same subjects. Simulated spindles with more core-dominant activity were more MEG weighted.\n\nComparison with Existing MethodsPrevious models lacked either spindle-generating thalamic neural dynamics or whole head biophysical modeling; the framework presented here is the first to simultaneously capture these disparate scales simultaneously.\n\nConclusionsThis multiscale model provides a platform for the principled quantitative integration of existing information relevant to the generation of sleep spindles, and allows the implications of future findings to be explored. It provides a proof of principle for a methodological framework allowing large-scale integrative brain oscillations to be understood in terms of their underlying channels and synapses.

neuroscience↗

bioRxiv2017

Computational model of brainstem circuit for state dependent control of hypoglossal motoneurons

In patients with obstructive sleep apnea (OSA) the pharyngeal muscles become relaxed during sleep, which leads to a partial or complete closure of upper airway. Empirical studies suggest that withdrawal of noradrenergic and serotonergic drives importantly contribute to depression of hypoglossal motoneurons during rapid eye-movement (REM) sleep and, therefore, may contribute to OSA pathophysiology; however, specific cellular and synaptic mechanisms remain unknown. It was recently suggested that, in order to explain experimental observations, the neuronal network for monoaminergic control of excitability of hypoglossal motoneurons has to include excitatory and inhibitory perihypoglossal interneurons that would mediate noradrenergic and serotonergic drives to the motoneurons. In this study, we applied a biophysical network model to validate the rationality of the proposed circuit and to investigate the dynamics of its neuronal populations during REM sleep-induced withdrawal of noradrenergic and serotonergic drives. The state-dependent activity of the model hypoglossal motoneurons during simulated REM sleep with or without a virtual application of noradrenergic and serotonergic drugs was in qualitative agreement with in vivo data. The study predicts the dynamics of the perihypoglossal interneurons during these conditions and corroborates the hypothesis that the excitatory interneurons may integrate both noradrenergic and serotonergic drives. The latter drive has to be mediated by the inhibitory interneurons. The study suggests that perihypoglossal interneurons may serve as novel potential targets for pharmacological treatment of OSA.

neuroscience↗

bioRxiv2017

Coupling of autonomic and central events during sleep boosts declarative memory consolidation

While anatomical pathways between forebrain cognitive and brainstem autonomic nervous centers are well defined, autonomic-central interactions during sleep and their contribution to waking performance are not understood. Here, we analyzed simultaneous central activity via electroencephalography (EEG) and autonomic heart beat-to-beat intervals (RR intervals) from electrocardiography (ECG) during wake and daytime sleep. We identified bursts of ECG activity that lasted 4-5 seconds and predominated in non-rapid-eye-movement sleep (NREM). Using event-based analysis of NREM sleep, we found an increase in delta (0.5-4Hz) and sigma (12-15Hz) power and an elevated density of slow oscillations (0.5-1Hz) about 5 secs prior to peak of the heart rate burst, as well as a surge in vagal activity, assessed by high-frequency (HF) component of RR intervals. Using regression framework, we show that these Autonomic/Central Events (ACE) positively predicted post-nap improvement in a declarative memory task after controlling for the effects of spindles and slow oscillations from sleep periods without ACE. No such relation was found between memory performance and a control nap. Additionally, NREM ACE negatively correlated with REM sleep and learning in a non-declarative memory task. These results provide the first evidence that coordinated autonomic and central events play a significant role in declarative memory consolidation.

neuroscience↗