Reconsidering the Role of Neuronal Intrinsic Properties and Neuromodulation in Vestibular Homeostasis

The sensorimotor transformations performed by central vestibular neurons constantly adapt as the animal faces conflicting sensory information or sustains injuries. To ensure the homeostasis of vestibular-related functions, neural changes could in part rely on the regulation of 2° VN intrinsic properties. Here we review evidence that demonstrates modulation and plasticity of central vestibular neurons’ intrinsic properties. We first present the partition of Rodents’ vestibular neurons into distinct subtypes, namely type A and type B. Then, we focus on the respective properties of each type, their putative roles in vestibular functions, fast control by neuromodulators and persistent modifications following a lesion. The intrinsic properties of central vestibular neurons can be swiftly modulated by a wealth of neuromodulators to adapt rapidly to temporary changes of ecophysiological surroundings. To illustrate how intrinsic excitability can be rapidly modified in physiological conditions and therefore be therapeutic targets, we present the modulation of vestibular reflexes in relation to the variations of the neuromodulatory inputs during the sleep/wake cycle. On the other hand, intrinsic properties can also be slowly, yet permanently, modified in response to major perturbations, e.g., after unilateral labyrinthectomy (UL). We revisit the experimental evidence, which demonstrates that drastic alterations of the central vestibular neurons’ intrinsic properties occur following UL, with a slow time course, more on par with the compensation of dynamic deficits than static ones. Data are interpreted in the framework of distributed processes that progress from global, large-scale coping mechanisms (e.g., changes in behavioral strategies) to local, small-scale ones (e.g., changes in intrinsic properties). Within this framework, the compensation of dynamic deficits improves over time as deeper modifications are engraved within the finer parts of the vestibular-related networks. Finally, we offer perspectives and working hypotheses to pave the way for future research aimed at understanding the modulation and plasticity of central vestibular neurons’ intrinsic properties

No Gain No Pain: Relations Between Vestibulo-Ocular Reflexes and Motion Sickness in Mice

Motion sickness occurs when the vestibular system is subjected to conflicting sensory information or overstimulation. Despite the lack of knowledge about the actual underlying mechanisms, several drugs, among which scopolamine, are known to prevent or alleviate the symptoms. Here, we aim at better understanding how motion sickness affects the vestibular system, as well as how scopolamine prevents motion sickness at the behavioral and cellular levels. We induced motion sickness in adult mice and tested the vestibulo-ocular responses to specific stimulations of the semi-circular canals and of the otoliths, with or without scopolamine, as well as the effects of scopolamine and muscarine on central vestibular neurons recorded on brainstem slices. We found that both motion sickness and scopolamine decrease the efficacy of the vestibulo-ocular reflexes and propose that this decrease in efficacy might be a protective mechanism to prevent later occurrences of motion sickness. To test this hypothesis, we used a behavioral paradigm based on visuo-vestibular interactions which reduces the efficacy of the vestibulo-ocular reflexes. This paradigm also offers protection against motion sickness, without requiring any drug. At the cellular level, we find that depending on the neuron, scopolamine can have opposite effects on the polarization level and firing frequency, indicating the presence of at least two types of muscarinic receptors in the medial vestibular nucleus. The present results set the basis for future studies of motion sickness counter-measures in the mouse model and offers translational perspectives for improving the treatment of affected patients

Long-Lasting Visuo-Vestibular Mismatch in Freely-Behaving Mice Reduces the Vestibulo-Ocular Reflex and Leads to Neural Changes in the Direct Vestibular Pathway

International audienceCalibration of the vestibulo-ocular reflex (VOR) depends on the presence of visual feedback. However, the cellular mechanisms associated with VOR modifications at the level of the brainstem remain largely unknown. A new protocol was designed to expose freely behaving mice to a visuo-vestibular mismatch during a 2-week period. This protocol induced a 50% reduction of the VOR. In vivo pharmacological experiments demonstrated that the VOR reduction depends on changes located outside the flocculus/paraflocculus complex. The cellular mechanisms associated with the VOR reduction were then studied in vitro on brainstem slices through a combination of vestibular afferent stimulation and patch-clamp recordings of central vestibular neurons. The evoked synaptic activity demonstrated that the efficacy of the synapses between vestibular afferents and central vestibular neurons was decreased. In addition, a long-term depression protocol failed to further decrease the synapse efficacy, suggesting that the VOR reduction might have occurred through depression-like mechanisms. Analysis of the intrinsic membrane properties of central vestibular neurons revealed that the synaptic changes were supplemented by a decrease in the spontaneous discharge and excitability of a subpopulation of neurons. Our results provide evidence that a long-lasting visuo-vestibular mismatch leads to changes in synaptic transmission and intrinsic properties of central vestibular neurons in the direct VOR pathway. Overall, these results open new avenues for future studies on visual and vestibular interactions conducted in vivo and in vitro

Control of Local Intracellular Calcium Concentration with Dynamic-Clamp Controlled 2-Photon Uncaging

The variations of the intracellular concentration of calcium ion ([Ca 2+]i) are at the heart of intracellular signaling, and their imaging is therefore of enormous interest. However, passive [Ca 2+] i imaging provides no control over these variations, meaning that a full exploration of the functional consequences of [Ca 2+]i changes is difficult to attain. The tools designed so far to modify [Ca 2+]i, even qualitatively, suffer drawbacks that undermine their widespread use. Here, we describe an electrooptical technique to quantitatively set [Ca 2+]i, in real time and with sub-cellular resolution, using two-photon Ca 2+ uncaging and dynamic-clamp. We experimentally demonstrate, on neurons from acute olfactory bulb slices of Long Evans rats, various capabilities of this technique previously difficult to achieve, such as the independent control of the membrane potential and [Ca 2+]i variations, the functional knocking-in of user-defined virtual voltage-dependent Ca 2+ channels, and the standardization of [Ca 2+]i patterns across different cells. Our goal is to lay the groundwork for this technique and establish it as a new and versatile tool for the study of cell signaling

Propriétés électrophysiologiques intrinsèques et modélisation des neurones responsables de l'intégration mathématique dans le noyau prepositus hypoglossi

Cette thèse concerne les mécanismes neuronaux impliqués dans l intégration mathématique d un signal de vitesse en signal de position. Dans le cadre du contrôle des mouvements horizontaux de l œil, cette intégration est réalisée par les neurones du noyau prepositus hypoglossi (nNPH). Les nNPH ont été classés, selon leur profil électrophysiologique, en 3 types (A, B et D) et modélisés. Contrairement aux neurones de type A et B présents aussi dans les noyaux vestibulaires médian et latéral, les neurones de type D sont spécifiques du NPH et leur potentiel de membrane présente des oscillations. De plus, la conductance sodique persistante est cruciale pour l électrophysiologie de tous les nNPH, quoique son impact et sa localisation diffèrent selon les types cellulaires. Enfin, les propriétés intrinsèques des neurones du NPH et des noyaux vestibulaires ont été comparées afin de comprendre le lien entre les fonctions de ces noyaux et les propriétés intrinsèques spécifiques de leurs neurones.The rationale behind this thesis is the understanding of the neural mechanisms involved in the mathematical integration of a velocity signal into a position signal. For eye movements in the horizontal plane, neurons of the prepositus hypoglossi nucleus (PHNn) are responsible for this integration. Here, PHNn have been classified in 3 types (A, B and D) according to their electrophysiological profile and then modeled. Unlike type A and B neurons, which are also found in the medial and lateral vestibular nuclei, type D neurons are specific to the NPH and their membrane potential shows subthreshold oscillations. Besides, persistent sodium conductance is crucial to the electrophysiology of the PHNn, however its impact and location are type-dependant. The intrinsic properties of neurons of the PHN and the vestibular nuclei have been compared to understand the link between the functions of these nuclei and the specific intrinsic properties of their respective neurons.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

No Gain No Pain: Relations Between Vestibulo-Ocular Reflexes and Motion Sickness in Mice

International audienceMotion sickness occurs when the vestibular system is subjected to conflicting sensory information or overstimulation. Despite the lack of knowledge about the actual underlying mechanisms, several drugs, among which scopolamine, are known to prevent or alleviate the symptoms. Here, we aim at better understanding how motion sickness affects the vestibular system, as well as how scopolamine prevents motion sickness at the behavioral and cellular levels. We induced motion sickness in adult mice and tested the vestibulo-ocular responses to specific stimulations of the semi-circular canals and of the otoliths, with or without scopolamine, as well as the effects of scopolamine and muscarine on central vestibular neurons recorded on brainstem slices. We found that both motion sickness and scopolamine decrease the efficacy of the vestibulo-ocular reflexes and propose that this decrease in efficacy might be a protective mechanism to prevent later occurrences of motion sickness. To test this hypothesis, we used a behavioral paradigm based on visuo-vestibular interactions which reduces the efficacy of the vestibulo-ocular reflexes. This paradigm also offers protection against motion sickness, without requiring any drug. At the cellular level, we find that depending on the neuron, scopolamine can have opposite effects on the polarization level and firing frequency, indicating the presence of at least two types of muscarinic receptors in the medial vestibular nucleus. The present results set the basis for future studies of motion sickness countermeasures in the mouse model and offers translational perspectives for improving the treatment of affected patients

Experimental diagram and design.

<p>A. Schematic of the optical setup for DTC. Uncaging was performed by a mode-locked Ti:sapph laser beam (734 nm), the power of which was controlled by an electronic-optic modulator (EOM, Conoptics M350-80). The laser focus was scanned in a closed, curvilinear path along the inner membrane surface of the patched neuron. The patch electrode delivers caged Ca²⁺ (Ca²⁺-laden DM-nitrophen, 1.51 mM) and fluo-4 (77 µM, fluorescent Ca²⁺ sensor). ΔF/F is monitored using a 491 nm DPSS laser (Cobolt Calypso) or a 488 nm argon laser (JDS Uniphase), co-aligned with the uncaging laser through dichroic mirror 1 (see Methods). B. Control case with no uncaging: the reference membrane potential V₀(t) and fluorescence F₀(t) are recorded. C. Application 1: V₀(t), the membrane potential sequence recorded in B. , is used as the input command in RTXI to compute the laser power required for the desired Ca²⁺ uncaging, while the cell is maintained hyperpolarized to prevent endogenous [Ca²⁺]_i variations. V₁(t) and F₁(t) are recorded by DTC. D. Application 2_a: To test for residual endogenous Ca²⁺ influx, V₀(t) is played back into the cell without any uncaging. Since the amplifier is in voltage-clamp mode, V_2a(t) is recorded and should be identical to V₀(t). E. Application 2_b: Similarly, V₀(t) is played back, but the uncaging is driven by the measured membrane potential of the neuron (V_2b(t)).</p

Complete set of <i>parameters for power modulation</i>.

<p>Complete set of <i>parameters for power modulation</i>.</p

Conductance parameters.

<p>Conductance parameters.</p