Role of the flocculus in mediating vestibular nucleus neuron plasticity during vestibular compensation in the rat

Abstract

We investigated the role of the cerebellar flocculus in mediating the adaptive changes that occur in the intrinsic properties of brainstem medial vestibular nucleus (MVN) neurons during vestibular compensation. Ipsi-lesional, but not contra-lesional, flocculectomy prevented the compensatory increase in intrinsic excitability (CIE) that normally occurs in the de-afferented MVN neurons within 4 h after unilateral labyrinthectomy (UL). Flocculectomy did not, however, prevent the down-regulation of efficacy of GABA receptors that also occurs in these neurons after UL, indicating that these responses of the MVN neurons to deafferentation are discrete, parallel processes. CIE was also abolished by intra-floccular microinjection of the metabotropic glutamate receptor (mGluR) antagonist AIDA, and the protein kinase C inhibitor bisindolymaleimide I (BIS-I). The serene-threonine kinase inhibitor H-7 had no effect when microinjected at the time of de-afferentation, but abolished CIE if microinjected 2 h later. These cellular effects are in line with the recently reported retardatory effects of BIS-I and H-7 on behavioural recovery after UL. They demonstrate that the increase in intrinsic excitability in MVN neurons during vestibular compensation is cerebellum dependent, and requires mGluR activation and protein phosphorylation in cerebellar cortex. Furthermore, microinjection of the glucocorticoid receptor (GR) antagonist RU38486 into the ipsi-lesional flocculus also abolished CIE in MVN neurons. Thus an important site for glucocorticoids in facilitating vestibular compensation is within the cerebellar cortex. These observations ascribe functional significance to the high levels of GR and 11-beta-HSD Type 1 expression in cerebellum.

Asymmetric Recovery in Cerebellar-Deficient Mice Following Unilateral Labyrinthectomy

“…Overall, our results agree with the proposal that the vestibular compensation process consists of independent cellular plastic mechanisms, which display different dependencies on cerebellar inputs (Johnston et al 2002;see Paterson et al 2006 for a review).…”

“…While the vestibular cerebellum's role in motor leaning is well established, only a few investigations have explicitly addressed whether this region plays a comparable role in the vestibular compensation process following peripheral lesions (Johnston et al 2002;Kitahara et al 1998a). Nevertheless, the evidence that is available to date supports the proposal that the floccular complex plays a comparable role during VOR postlesional recovery and motor learning.…”

Cellular Mechanisms of Vestibular Compensation

“…An important role for the flocculus is also indicated by the finding that in a knockout mouse lacking the delta-2 subunit of the glutamate receptor, which is selectively localized in cerebellar Purkinje cells and which is essential for cerebellar cortical plasticity, the severity of ocular nystagmus after UVD is exaggerated, and the time course of recovery is prolonged [45] . Consistent with this are the findings that indicate that cerebellar cortical plasticity in the flocculus occurs after UVD, and is required for compensation [46][47][48][49][50] . However, the flocculus is not essential for VC, as even in flocculectomized animals the ocular nystagmus eventually disappears completely; thus, other processes, such as the changes in intrinsic properties of MVN neurons, and synaptic reorganization of the brainstem vestibular pathways, may be sufficient to achieve compensation but over a longer recovery time.…”

Neurobiological Mechanisms of Acute Vertigo

“…Early after UVD inhibitory signals from the flocculus to the VN are in fact decreased ipsilesional and increased contralesional in rats [49,50]. Yet, the specific role of the vestibulo-cerebellum itself remains nevertheless speculative, since some studies have reported no changes in recovery from UVD despite a deficient nodulus, flocculus or uvula [51,52], while others have observed delayed (but not abolish) VC in case of preexisting cerebellar lesions affecting the nodulus, uvula [53] or flocculus [50,54,55].…”