Biology subjects

Bandaru, S.

Publications and source records attributed to Bandaru, S..

3 recordsLinked to original sources

bioRxiv2025

Expansion of OSMR expression and signaling in the human dorsal root ganglion links OSM to neuropathic pain

RNA sequencing studies on human dorsal root ganglion (hDRG) from patients suffering from neuropathic pain show upregulation of OSM, linking this IL-6 family cytokine to pain disorders. In mice, however, OSM signaling causes itch behaviors through a direct effect on its cognate receptor expressed uniquely by pruriceptive sensory neurons. We hypothesized that an expansion in function of OSM-OSM receptor (OSMR) in sensory disorders in humans could be explained by species differences in receptor expression and signaling. Our in situ hybridization and immunohistochemical findings demonstrate broad expression of OSMR in DRG nociceptors and afferent fibers innervating the superficial and deep skin of humans. In patch-clamp electrophysiology, OSM directly activates human sensory neurons engaging MAPK signaling to promote action potential firing. Using CRISPR editing we show that OSM activation of MAPK signaling is dependent on OSMR and not LIFR in hDRG. Bulk, single-nuclei, and single-cell RNA-seq of OSM-treated hDRG cultures reveal expansive similarities in the transcriptomic signature observed in pain DRGs from neuropathic patients, indicating that OSM alone can orchestrate transcriptomic signatures associated with pain. We conclude that OSM-OSMR signaling via MAPKs is a critical signaling factor for DRG plasticity that may underlie neuropathic pain in patients.

neuroscience↗

bioRxiv2024

Identifying the Brain Circuits that Regulate Pain-Induced Sleep Disturbances

Pain therapies that alleviate both pain and sleep disturbances may be the most effective for pain relief, as both chronic pain and sleep loss render the opioidergic system, targeted by opioids, less sensitive and effective for analgesia. Therefore, we first studied the link between sleep disturbances and the activation of nociceptors in two acute pain models. Activation of nociceptors in both acute inflammatory (AIP) and opto-pain models led to sleep loss, decreased sleep spindle density, and increased sleep fragmentation that lasted 3 to 6 hours. This relationship is facilitated by the transmission of nociceptive signals through the spino-parabrachial pathways, converging at the wake-active PBelCGRP (parabrachial nucleus expressing Calcitonin Gene-Related Peptide) neurons, known to gate aversive stimuli. However, it has never been tested whether the targeted blocking of this wake pathway can alleviate pain-induced sleep disturbances without increasing sleepiness. Therefore, we next used selective ablations or optogenetic silencing and identified the key role played by the glutamatergic PBelCGRP in pain-induced sleep disturbances. Inactivating the PBelCGRP neurons by genetic deletion or optogenetic silencing prevented these sleep disturbances in both pain models. Furthermore, to understand the wake pathways underlying the pain-induced sleep disturbances, we silenced the PBelCGRP terminals at four key sites in the substantia innominata of the basal forebrain (SI-BF), the central nucleus of Amygdala (CeA), the bed nucleus of stria terminalis (BNST), or the lateral hypothalamus (LH). Silencing of the SI-BF and CeA also significantly reversed pain-induced sleep loss, specifically through the action on the CGRP and NMDA receptors. This was also confirmed by site-specific blockade of these receptors pharmacologically. Our results highlight the significant potential for selectively targeting the wake pathway to effectively treat pain and sleep disturbances, which will minimize risks associated with traditional analgesics. One sentence summaryParabrachial CGRP neurons regulate awakenings to pain.

neuroscience↗

bioRxiv2022

Quantitation, base identity and distribution of stably incorporated ribonucleotides in nuclear and mitochondrial DNA from murine tissues

Ribonucleotides are estimated to be the most common non-canonical nucleotides transiently incorporated in DNA. Their presence or failure of their removal can affect genome stability and mutations in factors involved in dNTP pool maintenance or ribonucleotide removal can cause Aicardi-Goutieres syndrome or promote certain human cancers. Here, we have mapped and quantitated ribonucleotides genome-wide, in nine tissues of wild-type mice. We observed tissue-specific variation in number and base identity of incorporated ribonucleotides and present evidence that a number of genomic features, such as tRNA genes, transcription start sites and G-quadruplexes, can increase the frequency of stably incorporated ribonucleotides in their proximity. Moreover, we present the non-random distribution of incorporated ribonucleotides in mtDNA and identified ribonucleotide hotspots. The study presents a framework to understand the physiological role of ribonucleotides in mammalian DNA.

genomics↗