Cholinergic influences on principal neurons in the ventral part of the cochlear nucleus in mongolian gerbil

Gillet, Charlène; Kuenzel, Thomas (Thesis advisor); Kampa, Björn Michael (Thesis advisor)

Aachen (2020)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2020


For many species, localizing the source of a sound is critical for survival. Sound source localization in the azimuthal plane for low frequency signals is performed by analyzing the difference of the arrival time of a sound at the two ears. This requires neurons with the ability to precisely encode the temporal fine-structure of a sound. The low frequency spherical bushy cells, located in the anterior part of the cochlear nucleus, are phase-locking neurons, i.e. they fire action potentials at a precise phase of a sound, and therefore are perfectly suited to perform this task. These cells are directly innervated by auditory nerve fibers through giant axosomatic synapses, the endbulbs of Held, and pass on the temporal information to binaural auditory brainstem nuclei. However, besides this powerful ascending excitation from auditory nerve fibers, the cochlear nucleus also receives descending cholinergic fibers from both auditory and non-auditory sources. However, little is known about the influence of cholinergic modulation on spherical bushy cells and on hearing in general. Combined electrophysiological recordings with simultaneous pharmacological and synaptic stimulations along with immunohistochemical staining were performed to test the influence of cholinergic modulation on the spherical bushy cells. For these experiments, Mongolian gerbils (Meriones unguiculatus) were used, rodents well known to use low frequency temporal cues for sound localization. However, no data on the endbulb of Held in the gerbil was available before this study. Chapter 2 focuses on characterizing the properties of endbulb of Held synaptic transmission in the Mongolian gerbil. The results were then compared to measurements in the mouse (Mus musculus). The only difference observed between the two species was a higher number of vesicles in the readily releasable pool in the gerbil endbulb, meaning that an elarged version of the endbulb of Held seems to be sufficient to perform the specialized tasks of low frequency sound localization. Chapter 3, 4 and 5 concentrate on the cholinergic innervation and modulation of spherical bushy cells. Chapter 3 reports that carbachol, a cholinergic agonist, depolarized the resting membrane potential of these cells on two different time scales A fast and transient effect was mediated by nicotinic α7 receptors while a slow and long-lasting effect was mediated by muscarinic receptors. This resulted in an increase 2 of the neuronal excitability with conserved temporal precision. Simulations using a model of spherical bushy cells suggested, that the cholinergic effect extended the dynamic response range of the neuron. In chapter 4, we found that cholinergic fibers innervate the ventral cochlear nucleus before hearing onset but the innervation density strongly increased after P10. In addition, nicotinic receptors were mostly expressed in dendritic areas while M3 muscarinic receptors were located predominantly in somatic membranes. In chapter 5, we found that both M1 and M2 muscarinic receptors were also expressed by spherical bushy cells. Moreover, activation of muscarinic receptors affected both hyperpolarization-activated currents and classical M-currents. Interestingly, the effects of these currents on the membrane potential of the cells counteracted each other. Based on the relative strength of these effects the cholinergic influence on different spherical bushy cells could vary widely. This diversity of modulatory effects might assure reliable temporal coding over a wide range of natural sounds and listening tasks. The stimulus-dependent and independent cholinergic top-down influences on early stages of the auditory pathway could provide further adaptability in the auditory information processing.