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Efferent-mediated fluctuations in vestibular nerve discharge: a novel, positive-feedback mechanism of efferent control.

ABSTRACT: We compared the background discharge of vestibular nerve afferents in barbiturate-anesthetized and unanesthetized, decerebrate chinchillas. Based on their interspike-interval statistics, units were categorized as regular, intermediate, or irregular. Background discharge rates were higher in irregular units from decerebrates compared to anesthetized preparations; no such difference was observed for regular or intermediate units. Large fluctuations in discharge rate were confined to intermediate and irregular units in decerebrates, but were not seen at all in anesthetized animals. The most prominent examples of fluctuations consisted of oscillations with periods exceeding 500 s and peak-to-peak amplitudes as large as 300 spikes/s. Several observations show that the fluctuations are mediated by the efferent vestibular system (EVS): (1) they are abolished when the vestibular nerve is cut proximal to the recording electrode; (2) their amplitude is correlated with the size of efferent-mediated rotational responses in individual units; and (3) they occur even when vital signs are stable. Previous studies had provided evidence that the EVS involves positive feedback: vestibular nerve afferents and EVS neurons excite one another. To study how oscillations could be produced, we developed a nonlinear model of positive feedback in which afferent feed-forward discharge was nonlinearly related to its inputs from hair cells and the EVS, while these inputs declined (adapted) as discharge was prolonged. Provided that the gain of the efferent feedback loop was sufficiently large, the model showed oscillations similar to those observed experimentally. Although large fluctuations in afferent discharge are unlikely to occur under physiological circumstances, positive feedback may be a normal feature that can amplify the influence of the EVS.

SUBMITTER: Plotnik M

PROVIDER: S-EPMC2504623 | biostudies-other | 2005 Dec

REPOSITORIES: biostudies-other

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Project description:Stimulation of vestibular efferent neurons excites calyx and dimorphic (CD) afferents. This excitation consists of fast and slow components that differ >100-fold in activation kinetics and response duration. In the turtle, efferent-mediated fast excitation arises in CD afferents when the predominant efferent neurotransmitter acetylcholine (ACh) activates calyceal nicotinic ACh receptors (nAChRs); however, it is unclear whether the accompanying efferent-mediated slow excitation is also attributed to cholinergic mechanisms. To identify synaptic processes underlying efferent-mediated slow excitation, we recorded from CD afferents innervating the turtle posterior crista during electrical stimulation of efferent neurons, in combination with pharmacological probes and mechanical stimulation. Efferent-mediated slow excitation was unaffected by nAChR compounds that block efferent-mediated fast excitation, but were mimicked by muscarine and antagonized by atropine, indicating that it requires ACh and muscarinic ACh receptor (mAChR) activation. Efferent-mediated slow excitation or muscarine application enhanced the sensitivity of CD afferents to mechanical stimulation, suggesting that mAChR activation increases afferent input impedance by closing calyceal potassium channels. These observations were consistent with suppression of a muscarinic-sensitive K+-current, or M-current. Immunohistochemistry for putative M-current candidates suggested that turtle CD afferents express KCNQ3, KCNQ4, and ERG1-3 potassium channel subunits. KCNQ channels were favored as application of the selective antagonist XE991 mimicked and occluded efferent-mediated slow excitation in CD afferents. These data highlight an efferent-mediated mechanism for enhancing afferent sensitivity. They further suggest that the clinical effectiveness of mAChR antagonists in treating balance disorders may also target synaptic mechanisms in the vestibular periphery, and that KCNQ channel modulators might offer similar therapeutic value.SIGNIFICANCE STATEMENT Targeting the efferent vestibular system (EVS) pharmacologically might prove useful in ameliorating some forms of vestibular dysfunction by modifying ongoing primary vestibular input. EVS activation engages several kinetically distinct synaptic processes that profoundly alter the discharge rate and sensitivity of first-order vestibular neurons. Efferent-mediated slow excitation of vestibular afferents is of considerable interest given its ability to elevate afferent activity over an extended time course. We demonstrate for the first time that efferent-mediated slow excitation of vestibular afferents is mediated by muscarinic acetylcholine receptor (mAChR) activation and the subsequent closure of KCNQ potassium channels. The clinical effectiveness of some anti-mAChR drugs in treating motion sickness suggest that we may, in fact, already be targeting the peripheral EVS.

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Efferent-mediated fluctuations in vestibular nerve discharge: a novel, positive-feedback mechanism of efferent control.

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