Biology subjects

Balasubramanian, K.

Publications and source records attributed to Balasubramanian, K..

7 recordsLinked to original sources

bioRxiv2025

A dNmnat-sensitized in vivo platform for unbiased discovery of regulators of neurodegeneration

Axon degeneration drives nervous system dysfunction in diverse neurological diseases and injuries. While key regulators of injury-induced Wallerian degeneration have been identified, approaches have largely relied on axotomy, a particularly extreme injury for a neuron. Here, we developed a forward genetic screening platform in the adult Drosophila wing that sensitizes neurons to degeneration through depletion of nicotinamide mononucleotide adenylyltransferase (dNmnat), the essential NAD+ biosynthetic enzyme. We screened 9,393 mutagenized chromosomes and recovered 59 mutations that suppress neurodegeneration induced by dNmant depletion, including the known pro-degenerative molecule dSarm, thereby validating our approach. We show loss of CG4098, the Drosophila homolog of the mammalian enzyme NUDT9, robustly preserved axons and induced widespread remodeling of NAD+-related metabolites, which provides a new link between cADP-ribose hydrolase activity and neuronal survival. We further show mutations in the transcription factor Abrupt resulted in elevated dNmnat protein levels and blocked axon degeneration, suggesting Abrupt normally tunes dNmnat levels and neuronal NAD+ homeostasis. dNmnat depletion is thus a versatile approach for unbiased discovery of axon death pathway components, each of which may provide new entry points for therapeutic strategies to preserve axons in neurodegenerative diseases.

neuroscience↗

bioRxiv2023

Hyperactivation of MEK1 in cortical glutamatergic neurons results in projection axon deficits and aberrant motor learning

Abnormal Extracellular Regulated Kinase 1/2 (ERK1/2) signaling is linked to multiple neurodevelopmental diseases, especially the RASopathies, which typically exhibit ERK1/2 hyperactivation in neurons and non-neuronal cells. To better understand how excitatory neuron-autonomous ERK1/2 activity regulates the development of the mouse motor cortex, we conditionally expressed a hyperactive MEK1S217/221E variant using Nex/NeuroD6:Cre. Our results show that MEK1S217/221E expression led to persistent hyperactivation of ERK1/2 in neocortical axons, but not excitatory neuron somas or nuclei. We noted reduced axonal arborization of multiple subcortical target domains in mutants and reduced cortical expression of the activity dependent gene, ARC. These changes did not coincide with significant differences in voluntary locomotor activity or motor performance in the accelerating rotarod task. However, motor learning in a single-pellet retrieval task was significantly diminished in Nex/NeuroD6:Cre; MEK1S217/221E mutants. Restriction of MEK1S217/221E expression to layer V cortical neurons recapitulated axonal outgrowth deficits, however, had no effect on motor learning. Collectively, these results indicate that within the cortex, glutamatergic neuron-autonomous hyperactivation of MEK1 is sufficient to drive deficits in axon outgrowth, activity dependent gene expression, and skilled motor learning. Summary statementMEK-ERK1/2 hyperactivation in developing cortical excitatory neurons is sufficient to decrease long-range axonal outgrowth, which coincides with reduced Arc expression and deficits in aspects of skilled motor learning by adulthood.

neuroscience↗

bioRxiv2022

Characteristics and Impact of the rNST GABA Network on Neural and Behavioral Taste Responses

The rostral nucleus of the solitary tract (rNST), the initial CNS site for processing gustatory information, is comprised of two major cell types, glutamatergic excitatory and GABAergic inhibitory neurons. Many investigators have described taste responses of rNST neurons, but the phenotypes of these cells were unknown. The current investigation used mice expressing ChR2 under the control of GAD65, a synthetic enzyme for GABA. In vivo single-unit recording of rNST cells during optogenetic stimulation allowed us to address two important questions: (1) what are the gustatory response characteristics of "optotagged", putative GABAergic (G+TASTE) neurons? and (2) how does optogenetic activation of the rNST GABA network impact taste responses in non-GABAergic (G-TASTE) neurons? We observed that chemosensitive profiles of G+TASTE neurons were similar to non-GABA taste neurons but had much lower response rates. We further observed that there was a population of GABA cells unresponsive to taste stimulation (G+UNR) and located more ventrally in the nucleus. Activating rNST inhibitory circuitry suppressed gustatory responses of G-TASTE neurons across all qualities and types of chemosensitive neurons. Tuning curves were modestly sharpened but the overall shape of response profiles and the ensemble pattern remained highly stable. These neurophysiological effects were consistent with the behavioral consequences of activating GAD65-expressing inhibitory neurons using DREADDs. In a brief-access licking task, concentration-response curves to both palatable (sucrose, maltrin) and unpalatable (quinine) stimuli were shifted to the right when GABA neurons were activated. Thus, the rNST GABAergic network is poised to modulate taste intensity across the qualitative and hedonic spectrum. SIGNIFICANCE STATEMENTThe rNST, the CNS gateway for taste, is rich in GABAergic neurons and synapses. Our in vivo recordings from GAD65/ChR2 mice reveal that gustatory response profiles of optotagged GABAergic neurons resemble non-GABAergic neurons, but with much reduced amplitudes. A novel population of GABA neurons were unresponsive to oral stimulation suggesting they are targets for centrifugal influences. Activating rNST inhibitory circuitry modestly sharpened gustatory tuning but preserved the ensemble pattern for taste quality despite markedly suppressed responses. In behaving mice, activating rNST GAD65-expressing neurons with DREADDs shifted response-concentration curves for palatable and unpalatable stimuli, but preserved appropriate behaviors. These observations unveil previously unknown features of rNST GABA cells and demonstrate substantial inhibitory modulation at the first central taste relay.

neuroscience↗

bioRxiv2020

Automatic Identification of SARS Coronavirus using Compression-Complexity Measures

AO_SCPLOWBSTRACTC_SCPLOWFinding vaccine or specific antiviral treatment for global pandemic of virus diseases (such as the ongoing COVID-19) requires rapid analysis, annotation and evaluation of metagenomic libraries to enable a quick and efficient screening of nucleotide sequences. Traditional sequence alignment methods are not suitable and there is a need for fast alignment-free techniques for sequence analysis. Information theory and data compression algorithms provide a rich set of mathematical and computational tools to capture essential patterns in biological sequences. In 2013, our research group (Nagaraj et al., Eur. Phys. J. Special Topics 222(3-4), 2013) has proposed a novel measure known as Effort-To-Compress (ETC) based on the notion of compression-complexity to capture the information content of sequences. In this study, we propose a compression-complexity based distance measure for automatic identification of SARS coronavirus strains from a set of viruses using only short fragments of nucleotide sequences. We also demonstrate that our proposed method can correctly distinguish SARS-CoV-2 from SARS-CoV-1 viruses by analyzing very short segments of nucleotide sequences. This work could be extended further to enable medical practitioners in automatically identifying and characterizing SARS coronavirus strain in a fast and efficient fashion using short and/or incomplete segments of nucleotide sequences. Potentially, the need for sequence assembly can be circumvented. NoteThe main ideas and results of this research were first presented at the International Conference on Nonlinear Systems and Dynamics (CNSD-2013) held at Indian Institute of Technology, Indore, December 12, 2013. In this manuscript, we have extended our preliminary analysis to include SARS-CoV-2 virus as well.

bioinformatics↗

bioRxiv2019

Ictal recruitment of anterior nucleus of thalamus in human focal epilepsy

The thalamic nuclei play diverse roles in the initiation, propagation, and termination of temporal lobe seizures. The role of the anterior nucleus of the thalamus (ANT) - a node that is integral to the limbic network is unclear. The objective of this study was to characterize temporal and - spectral patterns of ANT ictal recruitment in drug-resistant temporal lobe epilepsy (TLE). We hypothesized that seizures localized to the temporolimbic network are likely to recruit ANT, and the odds of recruitment were higher in seizures that had altered consciousness. Ten patients undergoing stereo-electroencephalography (SEEG) were recruited prospectively to record field potentials from the ANT. Using epileptogenicity index and line length, we computed the number of seizures that recruited the ANT (recruitment ratio), the recruitment latencies between the ANT and the epileptogenic zone (EZ), and latency of ANT recruitment to clinical manifestation for seventy-nine seizures. We observed that seizures localized to mesial temporal subregions (hippocampus, amygdala, anterior cingulate) have a higher predilection for ANT recruitment, and the recruitment was faster (ranged 5-12 secs) and preceded clinical onset for seizures that impaired consciousness. Seizures that recruited ANT lasted significantly longer (t=1.795, p=0.005). Recruitment latency was inversely correlated to seizure duration (r=-0.78, p=0.004). Electrical stimulation of the EZ induced seizures, in which early recruitment of ANT was confirmed. Stimulation of ANT did not induce a seizure. Finally, we tested the hypothesis that spectral and entropy-based features extracted from thalamic field potentials can distinguish its state of ictal recruitment from other interictal states (including awake, sleep). For this, we employed classification machine learning that discriminated thalamic ictal state from other interictal states with high accuracy (92.8%) and precision (93.1%). Among the features, the emergence of the theta rhythm (4-8 Hz) maximally discriminated the endogenous ictal state from other interictal states of vigilance. These results prompt a mechanistic role for the ANT in the early organization and sustaining of seizures, and the possibility to serve as a target for therapeutic closed-loop stimulation in TLE.

neuroscience↗

bioRxiv2019

Propagating patterns of activity across motor cortex facilitate movement initiation

Voluntary movement initiation involves the modulation of neurons in the primary motor cortex (M1) around movement onset. Yet, similar modulations of M1 activity occur during movement planning when no movement occurs. Here, we show that a sequential spatio-temporal pattern of excitability based on beta oscillation amplitude attenuation propagates across M1 prior to the initiation of reaching movements in one of two oppositely oriented directions along the rostro-caudal axis. Using spatiotemporal patterns of intracortical microstimulation, we find that reaction time increases significantly when stimulation is delivered against but not with the natural propagation orientation suggesting that movement initiation requires a precise recruitment pattern in M1. Functional connections among M1 units emerge at movement onset that are oriented along the same rostro-caudal axis but not during movement planning. Finally, we show that beta amplitude profiles can more accurately decode muscle activity when these patterns conform to the natural propagating patterns. These findings provide the first causal evidence that large-scale, spatially organized propagating patterns of cortical excitability and activity are behaviorally relevant and may be a necessary component of movement initiation.

neuroscience↗

bioRxiv2018

A Highly Efficient and Faithful MDS Patient-Derived Xenotransplantation Model for Pre-Clinical Studies

Comprehensive preclinical studies of Myelodysplastic Syndromes (MDS) have been elusive due to limited ability of MDS stem cells to engraft current immunodeficient murine hosts. We developed a novel MDS patient-derived xenotransplantation model in cytokine-humanized immunodeficient \"MISTRG\" mice that for the first time provides efficient and faithful disease representation across all MDS subtypes. MISTRG MDS patient-derived xenografts (PDX) reproduce patients' dysplastic morphology with multi-lineage representation, including erythro- and megakaryopoiesis. MISTRG MDS-PDX replicate the original sample's genetic complexity and can be propagated via serial transplantation. MISTRG MDS-PDX demonstrate the cytotoxic and differentiation potential of targeted therapeutics providing superior readouts of drug mechanism of action and therapeutic efficacy. Physiologic humanization of the hematopoietic stem cell niche proves critical to MDS stem cell propagation and function in vivo. The MISTRG MDS-PDX model opens novel avenues of research and long-awaited opportunities in MDS research.

cancer biology↗