Biology subjects

Dhiman, N.

Publications and source records attributed to Dhiman, N..

5 recordsLinked to original sources

bioRxiv2026

Dynamical Interrogation of Serpentine Medulla Circuits in the Drosophila Optic Lobe

Dense connectomes invite a tempting leap: if we can "wire up" a circuit, perhaps its dynamics (and even its function) will emerge. In practice, connectomic constraints leave large biophysical degrees of freedom (synapse signs/strengths, neuromodulation, gap junctions), so qualitative dynamical claims can be fragile. We present a simple forensic workflow for testing connectome-to-dynamics hypotheses that is deliberately hostile to wishful thinking: each stage is gated by sanity checks, run across multiple random seeds, and reported with effect sizes and negative controls. As a case study, we instantiate the Serpentine Medulla (Sm) interneuron family from FlyWire as a current-based adaptive exponential integrate-and-fire (AdEx) network and test a sharp narrative: whether strong recurrence supports a working-memory-style bistable attractor. Under strict attractor criteria (noise removed after the kick), we find no robust evidence for bistability (paired Wilcoxon p = 0.099, within-subject dz = - 0.25). For oscillations, a corrected reproduction across 20 random seeds shows that recurrent coupling strongly amplifies integrated 30-80 Hz power when comparing the fully coupled condition (Full W) to an uncoupled control (W = 0) (paired Wilcoxon p = 1.9 x 10-6; dz = 5.96). We also observe a fast negative-coupling signature in input decomposition (mean peak correlation r {approx} - 0.40 at [~] 4 ms lag), while stressing that these signatures are conditional on the chosen model class and operating point. Overall, the main contribution is methodological: an auditable template for falsifying attractive connectome-based stories rather than polishing them.

neuroscience↗

bioRxiv2024

Lipid Disbalance Affects Neuronal Dendrite Growth and Maintenance in a Human Ceramide Synthase Disease Model

The brain is susceptible to disturbances in lipid metabolism. Among the rare, genetically-linked epilepsies Progressive Myoclonic Epilepsy Type 8 (PME8), associated with the loss of Ceramide Synthase (CerS) activity, causes epileptic symptoms accompanied by neurodegenerative traits. We show that expression of a disease-causing cerS allele in Drosophila sensory neurons yielded developmental and degenerative dendrite loss. In cerS mutants, C18-C24 ceramides and membrane-forming complex sphingolipids, into which ceramides are converted, were reduced. At the same time bioactive signaling lipids including (dh)Sphingosine-1-P, deriving from the CerS substrate, were increased. To clarifying the etiology of PME8, we thus performed in vivo experiments to cell-autonomously rescue the individual metabolic alterations. We report that restoring specific long-chain ceramides while in parallel decreasing (dh)Sphingosine-1-P fully rescues the cerS mutant phenotype. Thus, despite the complex metabolic alterations, our data provide essential information about the metabolic origin of PME8 and delineate a potential therapy.

neuroscience↗

bioRxiv2024

Axon length-dependent synapse loss is mediated by neuronal cytokine-induced glial phagocytosis

Many neurodegenerative disorders (NDDs) preferentially affect neurons with long or complex axonal arbors, but our understanding of this specific vulnerability is limited. Using Drosophila larval class IV dendrite arborization (C4da) neurons, we found that neuronal activation of the integrated stress response (ISR) induces axon length-dependent degeneration (LDD). We identified the Interleukin-6 homologue unpaired 3 (upd3) as both necessary and sufficient for LDD in C4da neurons. Upd3 recruits glial cells to phagocytose presynapses preferentially on neurons with long axons, revealing an intrinsic axon length-dependent vulnerability to glia-mediated presynapse removal. Finally, we found that axon length-dependent presynapse loss in fly models of human NDDs utilized this pathway. Altogether, our studies identify inflammatory cytokine signaling from neurons to glia as a key determinant in axon length-dependent vulnerability. One-Sentence SummarySensory neurons exhibit intrinsic length-dependent vulnerability to presynapse removal driven by cytokine activation of glia.

neuroscience↗

bioRxiv2023

Neural circuits underlying context-dependent competition between defensive actions in Drosophila larva

To ensure their survival, animals must be able to respond adaptively to threats within their environment. However, the precise neural circuit mechanisms that underlie such flexible defensive behaviors remain poorly understood. Using neuronal manipulations, machine-learning-based behavioral detection, Electron Microscopy (EM) connectomics and calcium imaging in Drosophila larva, we have mapped the second-order interneurons differentially involved in the competition between different defensive actions and the main pathways to the motor side putatively involved in inhibiting startle-type behaviors and promoting escape behaviors in a context dependent manner. We found that mechanosensory stimulation modulates the nociceptive escape sequences and inhibits C-shape bends and Rolls in favor of startle-like behaviors. This suggests a competition between mechanosensory-induced startle responses and escape behaviors. Structural and functional connectivity revealed that the second order interneurons receive their main input from projection neurons that integrate mechanosensory and nociceptive stimuli. The analysis of their postsynaptic connectivity in EM revealed that they make indirect connections to the pre-motor and motor neurons. Finally, we identify a pair of descending neurons that could promote modulate the escape sequence and promote startle behaviors. Altogether, these results characterize the pathways involved in the Startle and Escape competition, modulated by the sensory context.

neuroscience↗

bioRxiv2018

Rab converter DMon1 constitutes a novel node in the brain-gonad axis essential for female germline maturation

Monensin-sensitive 1 (Mon1) is an endocytic regulator that participates in the conversion of Rab5 positive early endosomes to Rab7 positive late endosomes. In Drosophila, loss of mon1 (Dmon1) leads to sterility. The Dmon1 mutant females have extremely small ovaries with complete absence of late stage egg chambers-a phenotype reminiscent of mutations in the insulin pathway genes. Consistently, we find that expression of many Drosophila insulin-like peptides (Dilps) is down regulated in Dmon1 mutants. Conversely, feeding an insulin-rich diet can rescue the ovarian defects induced by the loss of Dmon1.\n\nSurprisingly however, Dmon1 is required in the tyramine/octopaminergic neurons (OPNs) and not in the ovaries or the insulin producing cells (IPCs). Thus, knockdown of Dmon1 in just the OPNs is sufficient to mimic the ovarian phenotype while expression of Dmon1 in the OPNs alone, is sufficient to rescue the mutant defect.\n\nLastly, we have identified dilp5 as a critical target of Dmon1. Both, protein and mRNA levels of Dilp5 levels are reduced in Dmon1 mutants and IPC-specific dilp5 over expression can ameliorate the Dmon1 dependent sterility defect. The study thus identifies Dmon1 as a novel molecular player in the brain-gonad axis and underscores the significance of inter-organ systemic communication during development.\n\nSignificance Statement Functional significance of the long-distance systemic communication during organogenesis has emerged as a major area of enquiry. We have focused our attention on an endocytic regulator DMon1, that appears to participate in a remote control type of mechanism. We report a novel tripartite circuitry that involves Dmon1 activity in Octopaminergic neurons, its influence on insulin production in the insulin producing cells (IPCs) which, in turn, is required for the progression of oogenesis. Our results document a spatially remote non-autonomous control mechanism involving neuronal cross-talk that orchestrates developmental regulation of oogenesis. Importantly our data provide a unique example of how distinct neuronal hubs can engineer metabolic pathways underlying growth/differentiation and highlight the importance of systemic regulation of organogenesis.

developmental biology↗