Dendritic inputs, inhibition and modulation of mammalian phase-coding neurons
The principal neurons of the anteroventral cochlear nucleus are the spherical bushy cells (SBC). They are innervated by auditory nerve axons with giant axosomatic terminals, the Endbulbs of Held. Dependent on subtype the SBC are contacted by 1-3 auditory nerve fibers only. The SBC are time-coding neurons, whose most striking feature is the precise coupling of their action potentials to the phase of the sound stimulus. This property, also called phase-locking, is “inherited” from auditory nerve axones, which also fire phase-locked action potentials. Interestingly, the temporal accuracy is not degraded over the chemical synaptic transmission, but can even be improved. Here, the large and fast currents of the Endbulb of Held synapses likely play a crucial role . The SBC then mostly innervate binaural neurons in the superior olivary complex, specifically the medial superior olive. Here temporal precision is of great importance, because interaural time differences in the microsecond-range are processed.
Interaction of inhibition and excitation
It seems obvious at first glance that the strong synaptic connection between the Endbulb of Held and the SBC leads to a faithful transmission of excitation. Surprisingly, this is not the case. Intrinsic properties of the giant synapses and the postsynaptic membrane and, even more so, interaction with inhibitory inputs converging on the SBC cause a more complex input-output relationship. Surprisingly, in spite of all the “ultra-fast” coding and “super-precise” temporal precision in the SBC, inhibitory inputs are very slow. In recent years [2-4] we studied inhibition in the SBC in detail using in-vivo, in-vitro and in-silico methods, also in cooperation with the groups of Ivan Milenkovic and Rudolf Rübsamen in Leipzig.
Stimulus-dependent and independent cholinergic modulation
In SBC of the gerbil the interaction of excitation and inhibition was found to underlie a form of stimulus-dependent dynamics of the coding-principle of the neurons . However, there is probably also an impact of modulatory (top-down) systems on the SBC. This is intriguing insofar as the SBC, which are the first central neuron of the auditory pathway, are in a peripheral position still very close to the “sensor” and complex modulation is normally expected to occur in higher stages of the auditory pathway. In our recent projects we try to understand the role of cholinergic inputs influence sensory coding close to the auditory periphery and participate in changing the information processing at that level of the sensory pathway. We address this question, again, with a parallel approach of in-vitro slice electrophysiology, in-vivo recordings in anesthetized animals and biophysical computer models of auditory neurons.
The bushy dendrite
Although inhibitory inputs were also shown to terminate on the somata of SBC, the poorly understood eponymous bushy dendrite of SBC could play a key role in modulation. Anatomical studies of other labs revealed unexplained complexity: additional auditory nerve synapses, inhibitory synapses of various identities and sources and even non-auditory excitatory inputs are all found on the dendrites. Additionally, anatomical indications of electrical coupling of SBC dendrites were found. Physiological knowledge about all these findings is scarce or non-existent. It is therefore one of the main goals of the Künzel-lab to analyze the SBCs dendritic inputs and better understand their role in SBC signal processing. The main feature of SBC now becomes an experimental advantage: their responses are precisely phase-locked and their output eventually has to suffice for the coding interaural phase differences. Thus we possess an experimentally well-defined functional read-out that will likely reveal even subtle modulatory effects in-vitro as well as in vivo.
- Acute slices of the auditory brainstem of gerbils
- Whole-cell patch-clamp recordings
- Electrical stimulation of auditory nerve fibers, synaptic physiology of the endbulb of Held giant terminal
- In-vitro pharmacology of the cholinergic inputs to SBC
- In cooperation: in-vivo pharmacology of the cholinergic inputs to SBC (group Rübsamen)
- In later experimental phases: electrophysiological experiments in the intact animal under sound stimulation
- Computer models of a “complete” SBC including realistic representation of inhibitory inputs (group Milenkovic) and the dendritic inputs
People and Cooperations in this project
Dr. Thomas Künzel – data analysis, in-silico experiments
Charlene Gillet -- PhD student, in vitro experiments (physiology of cholinergic modulation of SBC)
Kerstin Doerenkamp -- (2018) MSc thesis, modulation of synaptic properties at the endbuld of Held
Stefanie Kurth, TA – histology and immunocytochemistry of the cholinergic system
Dr. Michael Leitner, Marburg / Dr. Christoph Körber (Heidelberg) -- imaging of PIP dynamics, virus transfection of AVCN neurons
Prof. Dr. Rudolf Rübsamen & Christian Keine (Leipzig University) – in vivo pharmacology
PD Dr. Ivan Milenkovic & Jana Nerlich (Leipzig University) – inhibitory inputs to SBC
Dr. David Goyer – in vitro experiments (Kresge Hearing Institute, Ann Arbor, Michigan)
- Felmy F, Künzel T (2014) Giant synapses in the central auditory system. e-Neuroforum Volume 5: 53-59
- Kuenzel T, Borst JG, van der Heijden M (2011) Factors controlling the input-output relationship of spherical bushy cells in the gerbil cochlear nucleus. Journal of Neuroscience 31:4260-73.
- Kuenzel T, Nerlich J, Wagner H, Rübsamen R and Milenkovic M (2015) Inhibitory properties underlying non-monotonic input-output relationship in low-frequency spherical bushy neurons of the gerbil. Frontiers in Neural Circuits. 9:14. [doi: 10.3389/fncir.2015.00014]
- Nerlich J, Kuenzel T, Keine C, Korenic A, Rübsamen R, Milenkovic I (2014) Dynamic fidelity control to the central auditory system: synergistic glycine/GABAergic inhibition in the cochlear nucleus. Journal of Neuroscience. 34:11604–20
- Goyer D, Kurth S, Gillet C, Keine C, Rübsamen R and Kuenzel T (2016) Slow cholinergic modulation of spike-probability in ultra-fast time-coding sensory neurons. ENeuro 3 (5) ENEURO.0186-16.2016 [doi: 10.1523/ENEURO.0186-16.2016]
- Künzel T, Wagner H. Cholinergic top-down influences on the auditory brainstem. e-Neuroforum.
- Gillet C, Goyer D, Kurth S, Griebel H, Kuenzel T. (2018) Cholinergic innervation of principal neurons in the cochlear nucleus of the Mongolian gerbil. J Comp Neurol. 526:1647-1661.