Lesion-induced plasticity in rat vestibular nucleus neurones dependent on glucocorticoid receptor activation

Abstract

1. We have recently shown that neurones in the rostral region of the medial vestibular nucleus (MVN) develop a sustained increase in their intrinsic excitability within 4 h of a lesion of the vestibular receptors of the ipsilateral inner ear. This increased excitability may be important in the rapid recovery of resting activity in these neurones during 'vestibular compensation', the behavioural recovery that follows unilateral vestibular deafferentation. In this study we investigated the role of the acute stress that normally accompanies the symptoms of unilateral labyrinthectomy (UL), and in particular the role of glucocorticoid receptors (GRs), in the development of the increase in excitability in the rostral MVN cells after UL in the rat. 2. The compensatory increase in intrinsic excitability (CIE) of MVN neurones failed to occur in animals that were labyrinthectomized under urethane anaesthesia and kept at a stable level of anaesthesia for either 4 or 6 h after UL, so that they did not experience the stress normally associated with the vestibular deafferentation syndrome. In these animals, 'mimicking' the stress response by administration of the synthetic GR agonist dexamethasone at the time of UL, restored and somewhat potentiated CIE in the MVN cells. Administration of dexamethasone in itself had no effect on the intrinsic excitability of MVN cells in sham-operated animals. 3. In animals that awoke after labyrinthectomy, and which therefore experienced the full range of oculomotor and postural symptoms of UL, there was a high level of Fos-like immunoreactivity in the paraventricular nucleus of the hypothalamus over 1.5-3 h post-UL, indicating a strong activation of the stress axis. 4. The GR antagonist RU38486 administered at the time of UL abolished CIE in the rostral MVN cells, and significantly delayed behavioural recovery as indicated by the persistence of circular walking. The mineralocorticoid receptor (MR) antagonist spironolactone administered at the time of UL had no effect. 5. Vestibular compensation thus involves a novel form of 'metaplasticity' in the adult brain, in which the increase in intrinsic excitability of rostral MVN cells and the initial behavioural recovery are dependent both on the vestibular deafferentation and on the activation of glucocorticoid receptors, during the acute behavioural stress response that follows UL. These findings help elucidate the beneficial effects of neuroactive steroids on vestibular plasticity in various species including man, while the lack of such an effect in the guinea-pig may be due to the significant differences in the physiology of the stress axis in that species.

Figures

Figure 1. Compensatory increase in intrinsic excitability of rostral MVN cells after UL under various experimental conditions

Mean (±s.e.m.) spontaneous firing rates of rostral MVN neurones in slices of the ipsilateral medial vestibular nucleus in vitro, under various experimental conditions. A, mean spontaneous firing rates of rostral MVN neurones in slices from control animals and animals that were sham operated (Avertin-sham) or labyrinthectomized (Avertin-UL) under avertin anaesthesia. Note the significant increase in the mean spontaneous firing rate of MVN cells in the avertin-UL group compared with the avertin-sham controls (* P < 0.05, Student's t test). B, mean spontaneous firing rates of rostral MVN cells in slices from urethane-anaesthetized animals that underwent a sham operation (urethane-Sham), or a left labyrinthectomy either 4 h earlier (‘urethane-UL, 4 h’ group) or 6 h earlier (‘urethane-UL, 6 h’ group). There was no significant change in the spontaneous discharge rate of the rostral MVN cells after UL in these animals. C, mean spontaneous firing rates of rostral MVN cells in slices from urethane-anaesthetized animals that were treated with the glucocorticoid receptor agonist dexamethasone, and subjected either to a sham operation (‘urethane-Sham, Dex-treated’ group) or to a left labyrinthectomy (‘urethane-UL, Dex-treated’ group) 4 h earlier. The significant increase in the spontaneous firing rate of rostral MVN cells after UL is restored in the urethane-anaesthetized animals by dexamethasone. D, mean spontaneous firing rates of rostral MVN cells in slices from animals labyrinthectomized under avertin anaesthesia 4 h earlier, which were treated with either the GR antagonist RU38486 (‘avertin-UL, RU-treated’ group) or the mineralocorticoid receptor antagonist spironolactone (‘avertin-UL, Sp-treated’ group). The increase in spontaneous firing rate of the rostral MVN cells after UL is abolished by the GR antagonist, while the MR antagonist has no effect.

Figure 2. Effects the glucocorticoid receptor antagonist RU38486 on the incidence of circular walking in avertin-UL animals

□, control group, n = 12 animals; ▪, RU38486 treated group, n = 12 animals. The number of circular movements carried out by the labyrinthectomized animals over a 3 min period when placed in an open enclosure, were measured at hourly intervals after recovery from avertin anaesthesia. The bars show the mean (±s.e.m.) number of circular walks for the two groups at each time point. Asterisks indicate a significant difference between the RU38486-treated and control groups (P < 0.05, Mann-Whitney ranked sum test).

Figure 3. Evidence for the activation of the stress axis after unilateral labyrinthectomy

A, micrograph of the paraventricular nuclei of the hypothalamus showing immunoreactivity for Fos 1.5 h after an avertin-UL. Calibration bar, 100 μm. B, mean (±s.e.m.) numbers of Fos-immunoreactive cell bodies in the paraventricular nucleus of avertin-sham animals (□) and avertin-UL animals (▪), at various times post operation. The numbers of animals in each group are indicated at the foot of each column. Asterisks indicate significant differences between the avertin-UL and avertin-sham groups (P < 0.01, Mann-Whitney ranked sum test).