Biology subjects

Ngodup, T.

Publications and source records attributed to Ngodup, T..

5 recordsLinked to original sources

bioRxiv2026

Essential role for plasma membrane glutamate transporters in stimulus intensity coding in auditory neurons

Plasma membrane glutamate transporters, also known as excitatory amino acid transporters (EAATs), serve to remove glutamate from extracellular spaces following transmitter release. Generally, this process is slow enough that EAAT activity controls the levels of background glutamate rather than the magnitude and time course of synaptic responses. We show here a striking exception to this pattern in the auditory system where neurons receive ongoing high-frequency synaptic signals. The effect of blocking EAATs on synaptic function was tested in neurons of the ventral cochlear nucleus in brain slices from mouse, focusing on auditory nerve inputs to T-stellate cells, neurons used to encode the spectrum of complex sounds. Complete block of EAATs caused a gradual accumulation of glutamate leading to a large depolarization in T-stellate cells and cessation of excitability. Partial EAAT blockade maintained resting potential but severely compromised the ability of the neurons to linearly encode the frequency of presynaptic spike activity with changes in postsynaptic firing, an essential feature of T-stellate cell function in sound intensity coding. After EAAT blockade, even a few high-frequency presynaptic spikes were sufficient to accumulate glutamate and cause repetitive postsynaptic firing lasting for tens to hundreds of milliseconds. Both glial and neuronal transporters were found to contribute to this rapid uptake necessary to maintain normal synaptic transmission. Altering the number of active auditory nerve fibers revealed that glutamate did not spill over between bouton synapses made by different nerve fibers, suggesting that synaptic boutons onto T-stellate cells restrict the diffusion of glutamate, necessitating an enhanced, local uptake activity. Notably, spike coding by the giant endbulb synapses on bushy cells was little affected by EAAT blockade, indicating a cell-type specificity to rapid glutamate uptake. Thus, rapid glutamate uptake enables the intensity coding function of neurons within the auditory system.

neuroscience↗

bioRxiv2023

The Na+ leak channel NALCN controls spontaneous activity and mediates synaptic modulation by α2-adrenergic receptors in auditory neurons

Cartwheel interneurons of the dorsal cochlear nucleus (DCN) potently suppress multisensory signals that converge with primary auditory afferent input, and thus regulate auditory processing. Noradrenergic fibers from locus coeruleus project to the DCN, and 2-adrenergic receptors inhibit spontaneous spike activity but simultaneously enhance synaptic strength in cartwheel cells, a dual effect leading to enhanced signal- to-noise for inhibition. However, the ionic mechanism of this striking modulation is unknown. We generated a glycinergic neuron-specific knockout of the Na+ leak channel NALCN, and found that its presence was required for spontaneous firing in cartwheel cells. Activation of 2-adrenergic receptors inhibited both NALCN and spike generation, and this modulation was absent in the NALCN knockout. Moreover, 2-dependent enhancement of synaptic strength was also absent in the knockout. GABAB receptors mediated inhibition through NALCN as well, acting on the same population of channels as 2 receptors, suggesting close apposition of both receptor subtypes with NALCN. Thus, multiple neuromodulatory systems determine the impact of synaptic inhibition by suppressing the excitatory leak channel, NALCN.

neuroscience↗

bioRxiv2023

Comprehensively defining cellular specializations for initiating parallel auditory pathways in the mouse cochlear nucleus

The cochlear nuclear complex (CN), the starting point for all central auditory processing, comprises a suite of neuronal cell types that are highly specialized for neural coding of acoustic signals, yet molecular logic governing cellular specializations remains unknown. By combining single-nucleus RNA sequencing and Patch-seq analysis, we reveal a set of transcriptionally distinct cell populations encompassing all previously observed types and discover multiple new subtypes with anatomical and physiological identity. The resulting comprehensive cell-type taxonomy reconciles anatomical position, morphological, physiological, and molecular criteria, enabling the determination of the molecular basis of the remarkable cellular phenotypes in the CN. In particular, CN cell-type identity is encoded in a transcriptional architecture that orchestrates functionally congruent expression across a small set of gene families to customize projection patterns, input-output synaptic communication, and biophysical features required for encoding distinct aspects of acoustic signals. This high-resolution account of cellular heterogeneity from the molecular to the circuit level illustrates molecular logic for cellular specializations and enables genetic dissection of auditory processing and hearing disorders with unprecedented specificity.

neuroscience↗

bioRxiv2022

Hypoxia promotes an inflammatory phenotype of fibroblasts in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive fibroinflammatory stroma and often experiences conditions of insufficient oxygen availability, or hypoxia. Cancer-associated fibroblasts (CAF) are a predominant and heterogeneous population of stromal cells within the pancreatic tumor microenvironment. Here, we uncover a previously unrecognized role for hypoxia in driving an inflammatory phenotype in PDAC CAFs. We identify hypoxia as a strong inducer of tumor IL1 expression, which is required for inflammatory CAF (iCAF) formation. Notably, iCAFs preferentially reside in hypoxic regions of PDAC. Our data implicate hypoxia as a critical regulator of CAF heterogeneity in PDAC.

cancer biology↗

bioRxiv2020

Discovery of a novel inhibitory neuron class, the L-Stellate cells of the cochlear nucleus

Auditory processing depends upon inhibitory signaling by interneurons, even at its earliest stages in the ventral cochlear nucleus (VCN). Remarkably, to date only a single subtype of inhibitory neuron has been documented in the VCN, a projection neuron termed the D-stellate cell. With the use of a transgenic mouse line, optical clearing and imaging techniques, combined with electrophysiological tools, we revealed a population of glycinergic cells in the VCN distinct from the D-stellate cell. These novel multipolar glycinergic cells were smaller in soma size and dendritic area, but over 10-fold more numerous than D-stellate cells. They were activated by auditory nerve fibers and T-stellate cells, and made local inhibitory synaptic contacts on principal cells of the VCN. Given their abundance, combined with their narrow dendritic fields and axonal projections, it is likely that these neurons, here termed L-stellate cells, play a significant role in frequency-specific processing of acoustic signals.

neuroscience↗