Biology subjects

Paul, B. K.

Publications and source records attributed to Paul, B. K..

4 recordsLinked to original sources

bioRxiv2026

Rejuvenation rankings from CRISPRi screens change with the aging cohort and track cell growth programs

Ranking gene knockdowns by how well they reverse an aging expression signature is a common way to find rejuvenation targets, but the stability of these rankings has not been tested. We built TRACE, an open-source set of tests, to score 18,746 knockdown profiles from five CRISPR interference (CRISPRi) screens in four human cell lines. Rankings built from fibroblasts of 111 donors and from Genotype-Tissue Expression (GTEx) fibroblasts were unrelated ({rho} = -0.05). In an exploratory test, the 200 strongest age genes of the first cohort changed in the opposite direction in GTEx ({rho} = -0.55), but this was not significant after correction and shrank when GTEx batch was modeled. Raw scores followed the broad programs inside each signature: strongly for proliferation with the fibroblast signature, weakly for stress with a GTEx-derived signature. Proliferation alone matched the fibroblast scores' agreement with senescence labels. TRACE runs on other aging cohorts and screens.

bioinformatics↗

bioRxiv2026

Predicting Pain Using a Data-Driven Agent-Based Model of the Bilateral Central Amygdala

Sensory processing in the amygdala is a complex, dynamic process. Decades of surgical, electrical, pharmacological, optogenetic, and chemogenetic in vivo manipulations have revealed the nociceptive functions of anatomically- and genetically-restricted neuronal populations. In parallel, molecular and electrophysiological approaches have allowed for high-resolution, temporal examination of nociceptive-induced alterations in amygdala plasticity. Computational integration of this data is critical for future therapeutic development; in practice, these models would allow for in silico prediction of amygdala activity following injury, and in a reciprocal fashion, changes in pain-like behaviors following manipulation of discrete amygdala neuronal populations. To this end, we developed a three-dimensional computer model of the bilateral central nucleus of the amygdala (CeA). We employed agent-based modelling to integrate wet-lab data from two CeA cell populations: Calcitonin Gene-Related Peptide Receptor (CGRPR; Calcrl) expressing cells and Protein Kinase C delta (PKC{delta}; Prkcd) expressing cells. We integrated the spatial location, connectivity, neuronal activity, and electrophysiological properties of these neurons in our realistic bilateral model architecture. Our model captures properties of the amygdala that drive pain modulation, including hemisphere-specific physiological differences, and generates predictions of nociception related to bladder injury. Predictions from the model were compared retrospectively to pain outcomes during manipulation of CGRPR-expressing neurons in whole mice. These comparisons show strong alignment between our model and in vivo outcomes. Significance StatementNociceptive processing in the amygdala emerges from interactions among cell types. No framework has been developed that recapitulates this complexity. Here, we generated a 3-D agent-based computational model of the bilateral central amygdala (CeA) using data that accounts for pain-associated changes in neuronal physiology, cellular identity, anatomical positioning, and temporal specificity. The model revealed that hemispheric differences in intrinsic CeA neuronal excitability are dominant drivers of nociceptive output. Furthermore, when manipulated to mimic injury-associated plasticity, the model accurately predicted behavioral outcomes. This model is a publicly available computational tool that predicts hemisphere-targeted pain therapy efficacy. Moreover, the flexibility of this framework will allow future adaptations to other brain areas and disease contexts.

neuroscience↗

bioRxiv2025

The role of amygdala calcitonin gene-related peptide receptors on the development of persistent bladder pain in mice.

Bladder pain significantly impacts millions worldwide, severely affecting their quality of life and posing a major clinical challenge. Understanding the mechanisms underlying persistent bladder pain is critical for developing better therapeutic strategies. In this study, we investigate the effects of cyclophosphamide (CYP)-induced persistent bladder sensitization to explore the lateralized contribution of amygdala calcitonin gene-related peptide receptors (CGRP-Rs) on pain-like changes in mice. We demonstrate that CYP induces hypersensitivity lasting up to 14 days post-injury (DPI) in the urinary bladder distention assay and up to 21 DPI when assessing abdominal mechanical sensitivity. Despite persistent pain-like changes, no significant bladder histological changes were observed. Based on previous findings that CGRP signaling from the parabrachial nucleus contributes to central amygdala (CeA) lateralization, we hypothesized that CGRP-Rs play a key role in driving visceral bladder pain-related hemispherical differences. We show that inhibiting CGRP-R activity with the antagonist CGRP8-37, in the right CeA attenuates bladder pain-like behavior, whereas left CeA inhibition sustains CYP-induced hypersensitivity. Electrophysiological recordings revealed increased firing frequency in CGRP-R positive cells in the right CeA 7 DPI. In vivo single photon calcium imaging demonstrated increased Ca transients in CGRP-R-positive cells in the right CeA, upon the presentation of a stimulus at 0 DPI, and overall at 2DPI, further confirming the pronociceptive role of CGRP-Rs in the right CeA. Taken together, these findings provide a crucial foundation for understanding pain-induced CeA lateralization and for further studies identifying how targeting CGRP signaling could provide bladder pain relief.

neuroscience↗

bioRxiv2022

Neural activity and theta rhythmicity in the anterior hypothalamic nucleus are involved in regulating social investigation

Social interactions are highly complex, involving both approach and avoidance actions towards specific individuals, dependent on the social context. Currently, the brain regions subserving these behaviors are not fully known. The anterior hypothalamic nucleus (AHN) is a relatively unstudied and poorly defined brain area, known as part of the medial hypothalamic defensive system. Recent studies that examined the role of the AHN in various contexts have yielded contradicting results regarding its contribution to approach, avoidance, and escape behaviors. Yet, none of these studies has directly examined its role in social interactions. Here we explored the role of AHN neurons in regulating approach and avoidance actions towards distinct stimuli during various types of social interactions, using electrophysiological recording of neural activity in the AHN of behaving mice, c-Fos staining, and direct optogenetic stimulation. We found that theta rhythmicity in the AHN was enhanced during affiliative interactions, but decreased during aversive ones. Moreover, spiking activity of AHN neurons was found to be elevated more persistently during investigation of social stimuli, as compared to objects. Notably, AHN neuronal firing was found to be modulated by theta rhythmicity during social interactions. Finally, we found that during social interaction, direct optogenetic stimulation of AHN neurons augmented approach behavior towards stimuli associated with the optogenetic activation. Overall, our results suggest a context-dependent role for AHN neuronal activity in regulating approach behavior during social interactions, and for theta rhythmicity in mediating the valence of the social context.

neuroscience↗