Multimodal inputs to the granule cell domain of the cochlear nucleus

Ryugo, David K.; Haenggeli, Charles André; Doucet, John R.

doi:10.1007/s00221-003-1605-3

Cited by 77 publications

(65 citation statements)

References 77 publications

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“…According to this scheme, auditory experience-dependent increases in fusiform cell spiking could also provide the trigger to induce plastic changes in PF inputs. Alternatively, because granule cells receive auditory nerve input from higher auditory centers such as auditory cortex, the changes in auditory stimulation might cause changes in vesicular zinc via this pathway (46).…”

Section: Discussionmentioning

confidence: 99%

AMPA receptor inhibition by synaptically released zinc

Kalappa

Anderson

Goldberg

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

105

149

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The vast amount of fast excitatory neurotransmission in the mammalian central nervous system is mediated by AMPA-subtype glutamate receptors (AMPARs). As a result, AMPAR-mediated synaptic transmission is implicated in nearly all aspects of brain development, function, and plasticity. Despite the central role of AMPARs in neurobiology, the fine-tuning of synaptic AMPA responses by endogenous modulators remains poorly understood. Here we provide evidence that endogenous zinc, released by single presynaptic action potentials, inhibits synaptic AMPA currents in the dorsal cochlear nucleus (DCN) and hippocampus. Exposure to loud sound reduces presynaptic zinc levels in the DCN and abolishes zinc inhibition, implicating zinc in experience-dependent AMPAR synaptic plasticity. Our results establish zinc as an activity-dependent, endogenous modulator of AMPARs that tunes fast excitatory neurotransmission and plasticity in glutamatergic synapses.AMPA receptors | zinc | ZnT3 | synaptic plasticity | auditory T he development, function, and experience-dependent plasticity of the mammalian brain depend on the refined neuronal interactions that occur in synapses. In the majority of excitatory synapses, the release of the neurotransmitter glutamate from presynaptic neurons opens transmembrane ion channels in postsynaptic neurons, the ionotropic glutamate receptors, thereby generating the flow of excitatory signaling in the brain. As a result, these receptors play a fundamental role in normal function and development of the brain, and they are also involved in many brain disorders (1).The ionotropic glutamate receptor family consists of AMPA, kainate, and NMDA receptors (NMDARs). Although kainate receptor-mediated excitatory postsynaptic responses occur in a few central synapses (2), AMPA receptors (AMPARs) and NMDARs are localized in the postsynaptic density of the vast majority of glutamatergic synapses in the brain, mediating most of excitatory neurotransmission (1). NMDAR function is regulated by a wide spectrum of endogenous allosteric neuromodulators that fine-tune synaptic responses (3-5); however, much less is known about endogenous AMPAR neuromodulators [(1, 5), but see refs. 6 and 7]. Recent structural studies revealed that the amino terminal domain (ATD) and ligand-binding domain (LBD) are tightly packed in NMDARs but not AMPARs (8-10). These structural differences explain some of the functional differences in allosteric modulation between AMPARs and NMDARs, such as why the ATD of NMDARs, unlike that of AMPARs, modulates function and contains numerous binding sites for allosteric regulators. Nonetheless, given the importance of fine-tuning both synaptic AMPAR and NMDAR responses for brain function, it is puzzling that there is not much evidence for endogenous, extracellular AMPAR modulation. The discovery and establishment of endogenous AMPAR modulators is crucial both for understanding ionotropic glutamate receptor signaling and for developing therapeutic agents for the treatment of AMPAR-related disorders, such as d...

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Section: Discussionmentioning

confidence: 99%

AMPA receptor inhibition by synaptically released zinc

Kalappa

Anderson

Goldberg

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

105

149

View full text Add to dashboard Cite

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“…Granule cells of the DCN receive multimodal inputs from various sources [25,31], and send information to the pyramidal, giant, and cartwheel neurones via the parallel fibre network. The exact physiological role of this circuitry is not known at present, but widely accepted hypotheses emphasize its similarity to those present in the cerebellum.…”

Section: Muscarinic Modulation Of Dcn Granule Cellsmentioning

confidence: 99%

“…Their axons travel towards the outer layers of the DCN, and eventually form the parallel fibre network which provides a major excitatory, glutamatergic input for the apical dendritic trees of the pyramidal cells, and for the superficially situated dendrites of the giant neurones ( [20,31,40]; for a review see [25]). Granule cells, in turn, are contacted by axons carrying somatosensory information, mainly originating from the cuneate nucleus.…”

Section: Introductionmentioning

confidence: 99%

“…Granule cells, in turn, are contacted by axons carrying somatosensory information, mainly originating from the cuneate nucleus. Some of the granule cells are also contacted by acoustic fibres [19] and by axons arriving from higher acoustic centres [4,31], hence they are often regarded as neurones that integrate acoustic and somatosensory information and modify the activity of projection neurones accordingly.…”

Section: Introductionmentioning

confidence: 99%

“…Although the majority of the fibres contacting the granule cells are glutamatergic [1,31,40], some of them (e.g., the cochlear mossy fibres) are thought to release acetylcholine (ACh), as indirectly inferred by the acetylcholinesterase positivity detected in the granule cell region [20,31]. This observation raises the possibility that the activity of the granule cells may also be adjusted by cholinergic modulation.…”

Section: Introductionmentioning

confidence: 99%

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Activation of muscarinic receptors increases the activity of the granule neurones of the rat dorsal cochlear nucleus—a calcium imaging study

Kőszeghy

Vincze

Rusznák

et al. 2012

Pflugers Arch - Eur J Physiol

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Acetylcholine modulates the function of the cochlear nucleus via several pathways. In this study the effects of cholinergic stimulation were studied on the cytoplasmic Ca 2+ concentration of granule neurones of the rat dorsal cochlear nucleus (DCN). Ca 2+ transients were recorded in Oregon-Green-BAPTA 1-loaded brain slices using a calcium imaging technique. For the detection, identification, and characterisation of the Ca 2+ transients, a wavelet analysis-based method was developed. Granule cells were identified on the basis of their size and localisation. The action potential-coupled character of the Ca 2+ transients of the granule cells was established by recording fluorescence changes and electrical activity simultaneously. Application of the cholinergic agonist carbamyl-choline (CCh) significantly increased the frequency of the Ca 2+ transients (from 0.37 to 6.31 min -1 , corresponding to a 17.1-fold increase; n = 89).This effect was antagonised by atropine, whereas CCh could still evoke an 8.3-fold increase of the frequency of the Ca 2+ transients when hexamethonium was present.Using immunolabelling, the expression of both type 1 and type 3 muscarinic receptors (M1 and M3 receptors, respectively) was demonstrated in the granule cells. Application of 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (an M3-specific antagonist) prevented the onset of the CCh effect, whereas an M1-specific antagonist (pirenzepine) was less effective. We conclude that cholinergic stimulation increases the activity of granule cells, mainly by acting on their M3 receptors. The modulation of the firing activity of the granule cells, in turn, may modify the firing of projection neurones, and may adjust signal processing in the entire DCN.

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Reversing Synchronized Brain Circuits Using Targeted Auditory-Somatosensory Stimulation to Treat Phantom Percepts

et al. 2023

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ImportanceAnimal models have shown altered dorsal cochlear nucleus circuitry in animals that develop tinnitus; however, precise treatment using bisensory (auditory and somatosensory) stimuli can reverse altered neural patterns and lessen tinnitus.ObjectiveTo confirm and extend the findings of a pilot study, which suggested an increased efficacy of bisensory stimulation, to a clinical trial with a greater duration and greater number of participants.Design, Setting, and ParticipantsThis double-blind, crossover, single-center randomized clinical trial was conducted from March 2019, with a 3-month follow-up per participant ending in July 2022. Eligible adults were recruited from the University of Michigan Health System in Ann Arbor, Michigan. Eligibility criteria included bothersome tinnitus (Tinnitus Functional Index [TFI] score, ≥17 points), somatic tinnitus, normal to moderate hearing loss, and no other tinnitus treatments in the 6 months prior to the trial. Included participants were randomized to either treatment group 1, which received active (bisensory) treatment, or group 2, which received the control (auditory-only) treatment. Results were analyzed using intent-to-treat (ITT) and per protocol (PP) populations.InterventionPrecisely timed bisensory (combined auditory and somatosensory) treatment was delivered through a portable, custom, take-home device that was provided to each participant for daily, at-home treatments. Group 1 participants received 30 minutes per day of the bisensory treatment for 6 weeks, followed by a 6-week washout phase, and then 30 minutes per day of the auditory-only treatment followed by a second 6-week washout phase. Group 2 participants received the auditory-only treatment first, followed by a washout phase, and then the bisensory treatment followed by a second washout phase.Main Outcomes and MeasuresPrimary end points were changes in TFI score and tinnitus loudness level from baseline through week 6 and week 12.ResultsOf 337 screened individuals, 99 (mean [SD] age, 47 [12.7] years; 59 males [60%]; 85 with non-Hispanic White [86%] race and ethnicity) were enrolled into the study and randomized to treatment group 1 (n = 49) or group 2 (n = 50). The active but not the control treatment resulted in clinically significant decreases in TFI scores at week 6 of phase 1 (ITT population: –12.0 [95% CI, –16.9 to –7.9] points; P &lt; .001; PP population: –13.2 [95% CI, –16.0 to –10.5] points; P &lt; .001). Decreases in tinnitus loudness level were greater than 6 dB sensation level (SL; &gt;half as loud) at week 6 for the bisensory treatment group, with little effect for the auditory-only treatment control group at week 6 of phase 1 (ITT population: –5.8 [95% CI, –9.5 to –2.2] dB; P = .08; PP population: –7.2 [95% CI, –11.4 to –3.1] dB; P = .03), and up to 11 dB SL at week 12 of phase 2 (ITT population: –10.9 [95% CI, –15.2 to –6.5] dB; P = .001; PP population: –14.1 [95% CI, –18.4 to –9.8] dB; P &lt; .001). Decreased tinnitus loudness level and TFI scores extended into the washout phase, indicating a prolonged treatment effect.Conclusions and RelevanceThis trial found that precisely timed bisensory treatment using stimuli and timing developed in a validated animal model was effective for adults with somatic tinnitus. Prolonged reduction in tinnitus symptoms can result from using an extended treatment duration.Trial RegistrationClinicalTrials.gov Identifier: NCT03621735

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Multimodal inputs to the granule cell domain of the cochlear nucleus

Cited by 77 publications

References 77 publications

AMPA receptor inhibition by synaptically released zinc

AMPA receptor inhibition by synaptically released zinc

Activation of muscarinic receptors increases the activity of the granule neurones of the rat dorsal cochlear nucleus—a calcium imaging study

Reversing Synchronized Brain Circuits Using Targeted Auditory-Somatosensory Stimulation to Treat Phantom Percepts

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