Endogenous Cholinergic Signaling Modulates Sound-Evoked Responses of the Medial Nucleus of the Trapezoid Body

Abstract

The medial nucleus of trapezoid body (MNTB) is a major source of inhibition in auditory brainstem circuitry. The MNTB projects well-timed inhibitory output to principal sound-localization nuclei in the superior olive (SOC) as well as other computationally important centers. Acoustic information is conveyed to MNTB neurons through a single calyx of Held excitatory synapse arising from the cochlear nucleus. The encoding efficacy of this large synapse depends on its activity rate, which is primarily determined by sound intensity and stimulus frequency. However, MNTB activity rate is additionally influenced by inhibition and possibly neuromodulatory inputs, albeit their functional role is unclear. Happe and Morley ( 2004) discovered prominent expression of a7 nAChRs in rat SOC, suggesting possible engagement of ACh-mediated modulation of neural activity in the MNTB. However, the existence and nature of this putative modulation have never been physiologically demonstrated. We probed nicotinic cholinergic influences on acoustic responses of MNTB neurons from adult gerbils (Meriones unguiculatus) of either sex. We recorded tone-evoked MNTB single-neuron activity in vivo using extracellular single-unit recording. Piggyback multibarrel electrodes enabled pharmacological manipulation of nAChRs by reversibly applying antagonists to two receptor types, a7 and a4b2. We observed that tone-evoked responses are dependent on ACh modulation by both nAChR subtypes. Spontaneous activity was not affected by antagonist application. Functionally, we demonstrate that ACh contributes to sustaining high discharge rates and enhances signal encoding efficacy. Additionally, we report anatomic evidence revealing novel cholinergic projections to MNTB arising from pontine and superior olivary nuclei.

Multiple Sources of Cholinergic Input to the Superior Olivary Complex

“…Cholinergic neurons in the PMT project broadly to CN, IC, and auditory thalamus (Schofield et al, 2011). We previously showed that the MNTB receives input from cholinergic cells of the SOC and the PMT (Zhang et al, 2021). In that report, we showed a tracer deposit restricted to the MNTB resulted in labeled cholinergic cells in the PMT and SOC.…”

“…Developmental knock-out of alpha-7 nicotinic receptors suggests that ACh may contribute to temporal processing in the superior paraolivary nucleus (Felix et al, 2019). We have shown previously that, in the MNTB, ACh affects suprathreshold response magnitude, enhances near-threshold level discrimination, and enhances coding for signal in noise (Zhang et al, 2021).…”

“…Adult Mongolian gerbils (Meriones unguiculatus) aged at least 3 months of either sex were used in all experiments. Tract tracer injections were made using methods described previously (Zhang et al, 2021). Initial anesthesia was administered with an intraperitoneal injection (5 ml/kg body weight) of a mixture consisting of 20% ketamine (100 mg/ml) and 2% xylazine (100 mg/ml) in 0.9% NaCl solution, yielding a final dose of 100 mg/kg body weight for ketamine and 10 mg/kg body weight for xylazine.…”

“…The PMT comprises the pedunculopontine tegmental nucleus (PPT) and the laterodorsal tegmental nucleus (LDT), both of which contain cholinergic and non-cholinergic neurons. The SOC contains multiple groups of cholinergic cells, including the well-known olivocochlear cells as well as lesserknown cholinergic cells that project to the cochlear nucleus or the MNTB (Sherriff and Henderson, 1994;Zhang et al, 2021). Cholinergic neurons in the PMT project broadly to CN, IC, and auditory thalamus (Schofield et al, 2011).…”

α3β4* Nicotinic acetylcholine receptors strongly modulate the excitability of VIP neurons in the mouse inferior colliculus

“…Growing evidence indicates that cholinergic signaling through nicotinic acetylcholine receptors (nAChRs) critically shapes sound processing in the central auditory system (Goyer et al, 2016;Askew et al, 2017;Felix et al, 2019;Zhang et al, 2021). The inferior colliculus (IC), the midbrain hub of the central auditory system, receives extensive input from cholinergic neurons in the pontomesencephalic tegmentum (PMT; , and expresses several nAChR subunits, including α3, α4, α7, β2, β3, and β4 (Clarke et al, 1985;Wada et al, 1989;Morley & Happe, 2000;Whiteaker et al, 2002;Salas et al, 2003;Gahring et al, 2004;Happe & Morley, 2004;Bieszczad et al, 2012;Sottile et al, 2017).…”