Biology subjects

Trussell, L. O.

Publications and source records attributed to Trussell, L. O..

10 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↗

bioRxiv2025

Noise-induced hearing loss enhances Ca2+-dependent spontaneous bursting activity in lateralcochlear efferents

Exposure to loud and/or prolonged noise damages cochlear hair cells and triggers downstream changes in synaptic and electrical activity in multiple brain regions, resulting in hearing loss and altered speech comprehension. It remains unclear however whether or not noise exposure also compromises the cochlear efferent system, a feedback pathway in the brain that fine-tunes hearing sensitivity in the cochlea. We examined the effects of noise-induced hearing loss on the spontaneous action potential (AP) firing pattern in mouse lateral olivocochlear (LOC) neurons. This spontaneous firing exhibits a characteristic burst pattern dependent on Ca2+ channels, and we therefore also examined the effects of noise-induced hearing loss on the function of these and other ion channels. The burst pattern was sustained by an interaction between inactivating Ca2+ currents contributed largely by L-type channels, and steady outward currents mediated by Ba2+-sensitive inwardly-rectifying and two-pore domain K+ channels. One week following exposure to loud broadband noise, hearing thresholds were significantly elevated, and the duration of AP bursts was increased, likely as a result of an enhanced Ca2+ current. Additional effects of noise-induced hearing loss included alteration of Ca2+-dependent inactivation of Ca2+ currents and a small elevation of outward K+ currents. We propose that noise-induced hearing loss enhances efferent activity and may thus amplify the release of neurotransmitters and neuromodulators (i.e., neuropeptides), potentially altering sensory coding within the damaged cochlea. Significance StatementAlthough the effects of noise-induced hearing loss on the auditory afferent system have been extensively studied, little is known about its impact on the auditory efferent system, which modulates hearing sensitivity via feedback from the brain. Additionally, while Ca2+ channels are related to numerous neurological diseases, their involvement in auditory disorders is underexplored. This study bridges these gaps by examining Ca2+ channel-driven spontaneous burst firing in lateral olivocochlear (LOC) neurons, the most numerous auditory efferent neurons. Noise-induced hearing loss differentially affects Ca2+ channel subtypes by increasing high-voltage activated currents that further prolong burst firing and suggesting altered intracellular Ca2+ signaling. These significant changes in LOC firing behavior may profoundly impact their downstream targets in the cochlea.

neuroscience↗

bioRxiv2023

Calcium-sensitive subthreshold oscillations and electrical coupling in principal cells of mouse dorsal cochlear nucleus

In higher sensory brain regions, slow oscillations (0.5-5 Hz) associated with quiet wakefulness and attention modulate multisensory integration, predictive coding, and perception. Although often assumed to originate via thalamocortical mechanisms, the extent to which sub-cortical sensory pathways are independently capable of slow oscillatory activity is unclear. We find that in the first station for auditory processing, the cochlear nucleus, fusiform cells from juvenile mice (of either sex) generate robust 1-2 Hz oscillations in membrane potential and exhibit electrical resonance. Such oscillations were absent prior to the onset of hearing, intrinsically generated by hyperpolarization-activated cyclic nucleotide-gated (HCN) and persistent Na+ conductances (NaP) interacting with passive membrane properties, and reflected the intrinsic resonance properties of fusiform cells. Cx36-containing gap junctions facilitated oscillation strength and promoted pairwise synchrony of oscillations between neighboring neurons. The strength of oscillations were strikingly sensitive to external Ca2+, disappearing at concentrations > 1.7 mM, due in part to the shunting effect of small-conductance calcium-activated potassium (SK) channels. This effect explains their apparent absence in previous in vitro studies of cochlear nucleus which routinely employed high-Ca2+ extracellular solution. In contrast, oscillations were amplified in reduced Ca2+ solutions, due to relief of suppression by Ca2+ of Na+ channel gating. Our results thus reveal mechanisms for synchronous oscillatory activity in auditory brainstem, suggesting that slow oscillations, and by extension their perceptual effects, may originate at the earliest stages of sensory processing. SIGNIFICANCE STATEMENT (120 words max.)Many studies show that electrical activity in higher brain regions is regulated by brain oscillations. Here we show that such oscillatory activity can arise even in the first levels of auditory processing in the cochlear nucleus of the brainstem (fusiform cells), and is generated not by neural networks but by the biophysical properties of individual neurons. Oscillations are highly sensitive to external Ca2+ due to interplay of multiple ionic conductances. Gap junctions between cells allows for amplification and synchrony of such activity. Oscillations are absent in pre-hearing neurons, suggesting that sound activity might be important for their emergence. We propose that such early-level oscillations may serve to enhance signaling associated with particular environmental stimuli.

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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

Electrical Signaling in Cochlear Efferents is Driven by an Intrinsic Neuronal Oscillator

Efferent neurons are believed to play essential roles in maintaining auditory function. The lateral olivocochlear (LOC) neurons, which project from the brainstem to the inner ear where they release multiple transmitters including peptides, catecholamines and acetylcholine, are the most numerous yet least understood elements of efferent control of the cochlea. Using in vitro calcium imaging and patch-clamp recordings, we found that LOC neurons in juvenile and young adult mice exhibited extremely slow waves of activity (~0.1 Hz). These seconds-long bursts of Na+ spikes were driven by an intrinsic oscillator dependent on L-type Ca2+ channels, and were not observed in prehearing mice, suggesting an age-dependent mechanism underlying the intrinsic oscillator. Using optogenetic approaches, we identified both ascending (cochlear nucleus) and descending (auditory cortex) sources of synaptic excitation, as well as the synaptic receptors used for such excitation. Additionally, we identified potent inhibition originating in the glycinergic medial nucleus of trapezoid body (MNTB). Conductance-clamp experiments revealed an unusual mechanism of electrical signaling in LOC neurons, in which synaptic excitation and inhibition served to switch on and off the intrinsically generated spike burst mechanism, allowing for prolonged periods of activity or silence controlled by brief synaptic events. Protracted bursts of action potentials may be essential for effective exocytosis of the diverse transmitters released by LOC fibers in the cochlea. Significance StatementThe lateral olivocochlear (LOC) neurons, being the most abundant auditory efferent control of the ear, remained largely unexplored. Here we reported that LOC neurons displayed patterned electrical activity at an unusually slow pace (~0.1 Hz), mediated by a calcium-dependent intrinsic oscillator. This is surprising given the speed and precision were believed to be the currency of signaling in the lower auditory system. Optogenetic experiments determined the glutamatergic and glycinergic sources of synaptic inputs to these neurons, while conductance-clamp experiments revealed that synaptic activity acts like switches for turning on or off prolonged spike activity driven by the intrinsic oscillator. This extended spike activity may be essential for effective exocytosis of the diverse transmitters released by LOC fibers in the cochlea.

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bioRxiv2022

Kv7 channel antagonists block glycine receptors

XE991 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone) is currently the most widely used and specific antagonist of the Kv7 (KCNQ) family of K+ channels. We report an unexpected antagonistic effect of this drug on ionotropic glycine receptors. In recordings of synaptic transmission in two brainstem nuclei (the medial nucleus of the trapezoid body and the dorsal cochlear nucleus), 10 M XE991, a concentration typical for Kv7 studies in brain tissue, inhibited evoked glycinergic inhibitory postsynaptic currents (IPSCs) without altering paired-pulse ratio, and also reduced the amplitude of glycinergic miniature IPSCs. These results are indicative of a direct effect of the drug on postsynaptic glycine receptors. XE991 also produced dose-dependent block of the response to exogenously applied glycine, to a degree comparable to the block of synaptic transmission. Moreover, the drug inhibited homomeric glycine receptors expressed on presynaptic membrane of the calyx of Held. The degree of block was independent of glycine concentration, suggesting an allosteric interaction. The effects of XE991 on glycine responses are not likely to reflect block of the glycine-activated Cl- channels themselves, because block was voltage independent, and because GABA-activated Cl- currents were resistant to XE991 at concentrations up to 100 {micro}M. Linopirdine, but not retigabine, also antagonized glycine receptor currents. Given the prevalence of glycine receptor signaling in the brain, these observations should be taken into account in studies of the roles of Kv7 channels in neural circuit function and disease.

neuroscience↗

bioRxiv2021

Distinct forms of synaptic plasticity during ascending vs. descending control of medial olivocochlear efferent neurons

Activity in each brain region is shaped by the convergence of ascending and descending axonal pathways, and the balance and characteristics of these determine neural output. The medial olivocochlear (MOC) efferent system is part of a reflex arc that critically controls auditory sensitivity. Multiple central pathways contact MOC neurons, raising the question of how a reflex arc could be engaged by diverse inputs. We examined functional properties of synapses onto brainstem MOC neurons from ascending (ventral cochlear nucleus, VCN), and descending (inferior colliculus, IC) sources in mice using an optogenetic approach. We found that these pathways exhibited opposing forms of short-term plasticity, with VCN input showing depression and IC input showing marked facilitation. By using a conductance clamp approach, we found that combinations of facilitating and depressing inputs enabled firing of MOC neurons over a surprisingly wide dynamic range, suggesting an essential role for descending signaling to a brainstem nucleus.

neuroscience↗

bioRxiv2020

Incomplete removal of extracellular glutamate controls synaptic transmission and integration at a cerebellar synapse

Synapses of glutamatergic mossy fiber onto cerebellar unipolar brush cells (UBCs) generate slow excitatory (ON) or inhibitory (OFF) postsynaptic responses dependent on the complement of glutamate receptors expressed on the UBCs large dendritic brush. Using brain slice recording and computational modeling of synaptic transmission, we found that substantial glutamate is maintained in the UBC synaptic cleft, sufficient to modify spontaneous firing in OFF UBCs and tonically desensitize AMPARs of ON UBC. The source of ambient glutamate was spontaneous, spike-independent exocytosis from the mossy fiber terminal, and its level was dependent on activity of glutamate transporters EAAT1-2. Changing levels of ambient glutamate shifted the polarity of evoked synaptic responses in ON UBCs and altered the phase of responses to in vivo-like synaptic activity. Unlike classical fast synapses, receptors at the UBC synapse are virtually always exposed to a significant level of glutamate, which varies in a graded manner during transmission.

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bioRxiv2019

KCNQ channels enable reliable presynaptic spiking and synaptic transmission at high-frequency

The presynaptic action potential (AP) results in calcium influx which triggers neurotransmitter release. For this reason, the AP waveform is crucial in determining the timing and strength of synaptic transmission. The calyx of Held nerve terminals of rat show minimum changes in AP waveform during high-frequency AP firing. We found that the stability of the calyceal AP waveform requires KCNQ K+ channel activated during high-frequency spiking activity. High-frequency presynaptic spikes gradually led to accumulation of KCNQ channels in open states which kept interspike membrane potential sufficiently negative to maintain Na+ channel availability. Accordingly, blocking KCNQ channels during stimulus trains led to inactivation of presynaptic Na+, and to a lesser extent KV1 channels, thereby reducing the AP height and broadening AP duration. Thus, while KCNQ channels are generally thought to prevent hyperactivity of neurons, we find that in axon terminals these channels function to facilitate high-frequency firing needed for sensory coding. HIGHLIGHTSO_LIKCNQ channels are activated during high-frequency firing C_LIO_LIThe activity of KCNQ channels helps the recovery of Na+ and KV1 channels from inactivation and maintains action potential waveform C_LIO_LIReliable presynaptic action potential waveform preserves stable Ca2+ influx and reliable synaptic signaling C_LI

neuroscience↗