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Medial olivocochlear (MOC) efferent neurons in the brainstem comprise the final stage of descending control of the mammalian peripheral auditory system through axon projections to the cochlea. MOC activity adjusts cochlear gain and frequency tuning, and protects the ear from acoustic trauma. The neuronal pathways that activate and modulate the MOC somata in the brainstem to drive these cochlear effects are poorly understood. Evidence suggests that MOC neurons are primarily excited by sound stimuli in a three-neuron activation loop from the auditory nerve via an intermediate neuron in the cochlear nucleus. Anatomical studies suggest that MOC neurons receive diverse synaptic inputs, but the functional effect of additional synaptic influences on MOC neuron responses is unknown. Here we use patch-clamp electrophysiological recordings from identified MOC neurons in brainstem slices from mice of either sex to demonstrate that in addition to excitatory glutamatergic synapses, MOC neurons receive inhibitory GABAergic and glycinergic synaptic inputs. These synapses are activated by electrical stimulation of axons near the medial nucleus of the trapezoid body (MNTB). Focal glutamate uncaging confirms MNTB neurons as a source of inhibitory synapses onto MOC neurons. MNTB neurons inhibit MOC action potentials, but this effect depresses with repeat activation. This work identifies a new pathway of connectivity between brainstem auditory neurons and indicates that MOC neurons are both excited and inhibited by sound stimuli received at the same ear. The pathway depression suggests that the effect of MNTB inhibition of MOC neurons diminishes over the course of a sustained sound. [ABSTRACT FROM AUTHOR]

Key points Organisms localise low frequencies using interaural time disparities (ITDs) in which specialized neurones in the medial superior olive (MSO) compute submillisecond differences in arrival time of sounds to each ear, a value that varies systematically with sound location., These neurones compute sound location over a 1012 fold range in sound intensities, despite large intensity-dependent changes in input strength. Modulation of synaptic gain has been suggested as a mechanism to maintain accurate ITD processing., Here we show that activation of GABAB receptors suppresses both the excitatory and inhibitory inputs to the MSO and alters the kinetics of inhibitory synaptic currents., Using in vitro physiological methods and computational modelling, we show that the modulation by GABAB receptor activation contributes to spatial tuning of MSO neurones., These results contribute to the understanding of how neurones maintain computational stability under widely varying input conditions., Abstract Interaural time disparities (ITDs) are the primary cues for localisation of low-frequency sound stimuli. ITDs are computed by coincidence-detecting neurones in the medial superior olive (MSO) in mammals. Several previous studies suggest that control of synaptic gain is essential for maintaining ITD selectivity as stimulus intensity increases. Using acute brain slices from postnatal day 7 to 24 (P7-P24) Mongolian gerbils, we confirm that activation of GABAB receptors reduces the amplitude of excitatory and inhibitory synaptic currents to the MSO and, moreover, show that the decay kinetics of IPSCs are slowed in mature animals. During repetitive stimuli, activation of GABAB receptors reduced the amount of depression observed, while PSC suppression and the slowed kinetics were maintained. Additionally, we used physiological and modelling approaches to test the potential impact of GABAB activation on ITD encoding in MSO neurones. Current clamp recordings from MSO neurones were made while pharmacologically isolated excitatory inputs were bilaterally stimulated using pulse trains that simulate ITDs in vitro. MSO neurones showed strong selectivity for bilateral delays. Application of both GABAB agonists and antagonists demonstrate that GABAB modulation of synaptic input can sharpen ITD selectivity. We confirmed and extended these results in a computational model that allowed for independent manipulation of each GABAB-dependent effect. Modelling suggests that modulation of both amplitude and kinetics of synaptic inputs by GABAB receptors can improve precision of ITD computation. Our studies suggest that in vivo modulation of synaptic input by GABAB receptors may act to preserve ITD selectivity across various stimulus conditions. [ABSTRACT FROM AUTHOR]

Medial olivocochlear (MOC) efferent neurons in the brainstem comprise the final stage of descending control of the mammalian peripheral auditory system through axon projections to the cochlea. MOC activity adjusts cochlear gain and frequency tuning, and protects the ear from acoustic trauma. The neuronal pathways that activate and modulate the MOC somata in the brainstem to drive these cochlear effects are poorly understood. Evidence suggests that MOC neurons are primarily excited by sound stimuli in a three-neuron activation loop from the auditory nerve via an intermediate neuron in the cochlear nucleus. Anatomical studies suggest that MOC neurons receive diverse synaptic inputs, but the functional effect of additional synaptic influences on MOC neuron responses is unknown. Here we use patch-clamp electrophysiological recordings from identified MOC neurons in brainstem slices from mice of either sex to demonstrate that in addition to excitatory glutamatergic synapses, MOC neurons receive inhibitory GABAergic and glycinergic synaptic inputs. These synapses are activated by electrical stimulation of axons near the medial nucleus of the trapezoid body (MNTB). Focal glutamate uncaging confirms MNTB neurons as a source of inhibitory synapses onto MOC neurons. MNTB neurons inhibit MOC action potentials, but this effect depresses with repeat activation. This work identifies a new pathway of connectivity between brainstem auditory neurons and indicates that MOC neurons are both excited and inhibited by sound stimuli received at the same ear. The pathway depression suggests that the effect of MNTB inhibition of MOC neurons diminishes over the course of a sustained sound. SIGNIFICANCE STATEMENT Medial olivocochlear (MOC) neurons are the final stage of descending control of the mammalian auditory system and exert influence on cochlear mechanics to modulate perception of acoustic stimuli. The brainstem pathways that drive MOC function are poorly understood. Here we show for the first time that MOC neurons are inhibited by neurons of the MNTB, which may suppress the effects of MOC activity on the cochlea., (Copyright © 2020 Torres Cadenas, Fischl et al.)