Cellular correlates of sensory processing in the mammalian audio-vestibular brainstem

Abstract

Efferent projections to the vestibular inner ear organs have remained elusive. To shed light on their physiological role, a first investigation of the vestibular efferent (VE) neurons in the brainstem was undertaken by using a transgenic mouse which expresses a fluorescent marker in the VE neurons. The intrinsic electrical properties of VE neurons were compared to those of the lateral olivocochlear (LOC) brainstem neurons, which innervate the cochlea. The study demonstrated that, due to more complex expression of potassium-based conductances, VE neurons display a more bimodal firing pattern than LOC neurons, which indicates that their role may be more widespread and control both motion and gravity sensors (Paper I).

This thesis next investigated the cellular properties of the superior paraolivary nucleus (SPON) neurons in normal (Paper II and III) and congenitally deaf (Paper IV) mice. This evolutionary conserved mammalian brainstem structure has been implicated in the processing of speech cues by extracting the temporal signal in coarse sound amplitude fluctuations or brief sound segments, by responding abruptly to the offset of a tone stimulus or by entrainment to slow amplitude modulations of the same tone. Patch-clamp recordings in brain slices revealed that all SPON neurons exhibit postinhibitory rebound spiking, generated by the subthreshold-activated h current and low voltage-activated calcium current of the T-type. Pharmacological blockade of these currents in vivo abolished the sound-induced offset response and sensitivity to amplitude modulated tones, providing evidence that rebound spiking is the mechanism for offset-spiking in SPON (Paper II).

In addition to a powerful inhibitory input, SPON was also confirmed to receive a single excitatory input from the octopus cells (Paper III) – held to be the most temporally precise neurons in the brain, responding with extremely high precision to complex sounds. A selective, strong projection from the octopus cells can also explain why SPON responds to the onset of sounds and is compatible with the idea that there are specialized brain circuits that encode the slow temporal rhythm contained in natural sounds, such as speech. The robustness of these brain circuits was demonstrated in SPON of congenitally deaf mice. Despite the absence of input activity, the deaf SPON neurons developed normal capacity for well-timed rebound spiking. This remarkable rescue of the SPON cellular function may have been possible due to up-regulation of the neuroprotective factor neuritin, prolonging the developmental time window (Paper IV).

In summary, this thesis demonstrates, on a cellular level, how combinations of different voltage-gated ion channels that are activated by excitation or inhibition or both, can create distinct firing patterns in sensory neurons that encode selective features of the incoming afferent signal. This code will either project back to control the sensory receptors or feed into higher order brain areas where it contributes to the hierarchical processing that enable us to perceive and comprehend a sensation