Symposium
S5 - Afferent and Efferent Circuits in the Cochlea: From Ribbon Synapses to Central Control
Chair
Juan Goutman
INGEBI - CONICET
Co-Chair
M. Eugenia Gomez-Casati
Instituto de Farmacologia, Facultad de Medicina - UBA
This symposium brings together leading experts in auditory neuroscience to present recent advances in our understanding of the afferent and efferent circuits that shape cochlear function. Talks will cover key aspects of ribbon synapses in sensory hair cells, including their morphological and functional diversity and their role in encoding sound information. In parallel, the symposium will explore the modulation of cochlear activity by the medial (MOC) and lateral (LOC) olivocochlear efferent systems, emphasizing their roles in development, synaptic plasticity, and auditory protection. Presentations will integrate a range of approaches from electrophysiology and neuroanatomy to single-cell RNA sequencing, offering a comprehensive view of the molecular identity, functional specialization, and connectivity of these auditory circuits. The goal of this symposium is to offer an integrated perspective on how afferent and efferent pathways shape auditory signaling from the cochlea to the brain, and how these circuits adapt, or become disrupted, under pathological conditions.
Carolina Wedemeyer, Ph. D.
Investigadora CONICET. Laboratorio de Fisiología y Genética de Audición, INGEBI-CONICET
Medial Olivocochlear Neurons Co-release GABA and Acetylcholine to Modulate Cochlear Efferent Inhibition
During development, inner hair cells (IHCs) in the mammalian cochlea are unresponsive to acoustic stimuli but instead exhibit spontaneous activity. During this same period, neurons originating from the medial olivocochlear (MOC) complex transiently innervate IHCs, regulating their firing pattern which is crucial for the correct development of the auditory pathway. Although the MOC-IHC is a cholinergic synapse, previous evidence indicates the widespread presence of GABA signaling markers, including presynaptic GABAB receptors (GABABR). In this study, we explore the source of GABA by optogenetically activating either cholinergic or GABAergic fibers. The optogenetic stimulation of MOC terminals from GAD;ChR2-eYFP and ChAT;ChR2-eYFP mice evoked synaptic currents in IHCs, which were blocked by α-bungarotoxin. This suggests that GABAergic fibers release acetylcholine (ACh) and activate α9α10 nicotinic acetylcholine receptors (nAChRs). Additionally, MOC cholinergic fibers release not only ACh but also GABA, as the effect of GABA on ACh response amplitude was prevented by applying a GABABR blocker. In conclusion, we provide evidence indicating that GABA and ACh are co-released from at least a subset of MOC terminals. In this circuit, GABA functions as a negative feedback mechanism, locally regulating the extent of cholinergic inhibition at certain efferent→IHC synapses during an immature stage.
Catherine Weisz, Ph.D.
Senior Investigator, Chief - Section on Neuronal Circuitry, NIH, National Institute on Deafness and Other Communication Disorders
Complex synaptic circuitry of auditory efferent neurons
The exceptional sensitivity and frequency selectivity of hearing is enabled by specialized electromotile outer hair cells (OHC), which are implicated in cochlear amplification. In addition, the auditory system can detect sounds over many orders of magnitude of intensity, but not concurrently. Instead, mechanisms are necessary to shift the gain of the auditory system between detection of softer and louder sounds, and to allow detection of salient sounds above background noise. The medial olivocochlear (MOC) efferent neurons, which are a component of the final stage of the descending auditory system, are implicated as one of the gain control mechanisms of the auditory system. They function by inhibiting OHCs, reducing overall cochlear sensitivity. The MOC system is commonly referred to as a ‘reflex’, but recent work indicates that the function of both the synaptic inputs and outputs of these neurons are more complex than previously detailed. I'm mouse models, we have identified inhibitory synaptic inputs from the medial nucleus of the trapezoid body (MNTB) that are hypothesized to delay MOC responses and ensure that the MOC system only suppresses sustained sound responses. In addition, we have detailed modulatory inputs that may influence MOC activity over slower time scales, including both serotonergic and cholinergic systems. The convergence of this diverse circuitry indicates that the MOC system is not a simple reflex, but instead is poised to dynamically modulate our auditory system under changing hearing conditions.
Mark Rutherford
Associate Professor of Otolaryngology—Head & Neck Surgery,Washington University School of Medicine, St. Louis, MO, USA.
Calcium-permeable AMPA receptors in the cochlea: role in noise-induced synapse loss and sex-specific synaptopathy in the absence of synapse loss
Unlike typical glutamatergic synapses, the ribbon synapses in the cochlea have a highproportion of GluA2-lacking, calcium-permeable AMPA type glutamate receptors (CP-AMPARs) alongside the regular calcium-impermeable ones. These CP-AMPARs havea greater sodium conductance, in addition to calcium permeability, which is probablyimportant for rapid and efficient action potential generation in response to rapidlychanging acoustic inputs to the inner hair cell receptor potential. This powerful ribbonsynapse, estimated to contain thousands of receptors, comes with a vulnerability toexcitotoxicity. We discovered that blocking the CP-AMPARs is sufficient to preventnoise-induced synapse loss and concomitant reduction of cochlear output, while at thesame time allowing hearing function to persist with transmission via the calcium-impermeable receptors. Mice lacking the GluA3 pore-forming subunit or the auxiliarysubunit TARP-gamma-2 (Stargazin) have altered expression of the remaining subunits,which leads to progressive hearing loss specifically in female mice. Potential reasonsfor this, including a shift toward greater calcium permeability, will be discussed.
Amanda Lauer Ph. D.
Vice Director for Faculty AffairsOtolaryngology - HNSJohns Hopkins University School of Medicine
Role of the auditory brainstem-to-ear feedback system in hearing across the lifespan
The role of the medial olivocochlear system in hearing has been debated for manyyears due to conflicting and variable results in human and animal studies. Emergingevidence shows that this system is plastic and changes with acoustic experience andage. We have implemented a variety of behavioral assays, non-invasive physiologicaltests, and quantitative anatomical analyses to investigate how genetic manipulations ofthe olivocochlear system, acoustic experience, and natural aging interact to affecthearing across the lifespan in mouse models. Diminished olivocochlear functionappears to be most detrimental to hearing in very young and aged auditory systems.However, plasticity in this system reveals a remarkable capacity to adapt to differentacoustic environments. I will also highlight our recent findings in wild and wild-derivedbat species that may confer protection against a lifetime of exposure to loud sounds.