Effects of MK801 on Fos expression in the rat brainstem after unilateral labyrinthectomy

doi:10.1016/0006-8993(95)00950-U

Brain Research

Volume 700, Issues 1–2, 27 November 1995, Pages 182-190

https://doi.org/10.1016/0006-8993(95)00950-U Get rights and content

Abstract

Unilateral labyrinthectomy (UL) causes ocular and postural asymmetries, which disappear over time in the processes of equilibrium recovery known as vestibular compensation. It has been reported that N-methyl- d-aspartate (NMDA) receptors are involved in vestibular compensation. In the present study, in order to elucidate the NMDA receptor-mediated neural circuit responsible for the development of vestibular compensation, we used Fos expression as a marker of neural activation and examined the effects of MK801, a specific antagonist of NMDA receptors, on UL-induced Fos expression in the rat brainstem. After UL, Fos-like immunoreactive (-LIR) neurons were observed in the ipsilateral medial vestibular nucleus (ipsi-MVe), the contralateral prepositus hypoglosal nucleus (contra-PrH) and the contralateral inferior olive beta subnucleus (contra-IOb). Fos-LIR neurons then gradually disappeared in the processes of vestibular compensation. It is suggested that the activation of the ipsi-MVe, the contra-PrH and the contra-IOb neurons after UL are the initial event of vestibular compensation. Intraperitoneal injection of MK801 in the processes of vestibular compensation caused reappearance of UL-induced behavioral deficits. During the decompensation induced by MK801, Fos-LIR neurons appeared in the contra-MVe, the ipsi-PrH and the bilateral-IOb. It is suggested that the contra-MVe, the ipsi-PrH and the bilateral-IOb neurons are inhibited by glutamatergic synapses driving inhibitory neurons via NMDA receptors in the processes of vestibular compensation and that disinhibition of these nuclei induced by MK801 causes decompensation. However, MK801 caused neither Fos expression nor behavioral decompensation after vestibular compensation is accomplished. All these findings suggest that the NMDA receptor-mediated inhibitory modulation in the central vestibular system plays an important role for the initial processes of the development of vestibular compensation.

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After unilateral peripheral vestibular lesions, the neural activity of neurons in the ipsi-lesional medial vestibular nucleus (ipsi-MVe) are markedly decreased, resulting in static and dynamic asymmetries of the vestibulo-ocular and vestibulo-spinal reflexes. Consequently, static vestibular symptoms such as spontaneous nystagmus and postural deviation and dynamic vestibular symptoms such as oscillopsia and swaying gait are induced. However, these behavioral asymmetries gradually recover after the lesion. Progressive balance restoration is termed vestibular compensation, which is divided into two phases: static and dynamic. Static vestibular compensation is further divided into initial and late processes.
In the initial process of static vestibular compensation after unilateral labyrinthectomy (UL) in rats, plastic changes in the cerebello-vestibular and vestibular commissural inhibitory pathways suppress neurons in the contra-lesional MVe (contra-MVe), resulting in the restoration of symmetrical resting activity of MVe neurons on both sides at low levels. The declining frequency of spontaneous nystagmus after UL is an index of the initial process, and short-term administration of diazepam, a GABA_A receptor agonist, has been shown to accelerate the initial process in rats. Accordingly, short-term administration of diazepam is recommended for the treatment of acute vertigo in patients with unilateral vestibular dysfunction.
In the late process of static vestibular compensation after UL in rats, the resting activity of ipsi-MVe neurons gradually recovers due to changes in cell membrane properties, resulting in the reinforcement of balanced intervestibular nuclear activities to nearly normal levels without the suppression of contra-MVe neurons. The declining number of MK801-induced Fos-positive neurons in contra-MVe after UL is an index of the late process, and long-term administration of betahistine, a histamine H₃ receptor antagonist, has been shown to accelerate the late process in rats. Accordingly, long-term administration of betahistine is recommended for the treatment of subacute vertigo in patients who were not compensated for unilateral vestibular dysfunction.
In the process of dynamic vestibular compensation after UL, the sensitivity of ipsi-MVe neurons to head velocity and acceleration is restored due to synaptic changes such as long-term potentiation and sprouting of commissures, resulting in the restoration of the dynamic vestibulo-ocular and vestibulo-spinal reflexes. To facilitate dynamic vestibular compensation, early ambulation and subsequent vestibular rehabilitation exercise are recommended for the treatment of chronic vertigo in patients with uncompensated unilateral vestibular dysfunction.
Although vestibular compensation after bilateral vestibular loss is not expected, vestibular rehabilitation with a sensory-substitution strategy can improve imbalance in patients with bilateral vestibular lesions.
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Citation Excerpt :
Initially, this injurious procedure results in a syndrome of severe oculomotor and postural disorder. Studies that explored the mechanism of compensation processes demonstrate that this pathology can be replicated by NMDA receptor antagonists [16,17], postulating involvement of NMDA receptor-mediated inhibitory systems in the process of vestibular compensation [18]. Nonetheless, electrophysiologic and histologic evidence has proven that vestibular compensation is not due to regeneration of the vestibular receptors nor of a recovery of the VIIIth nerve [19–21].
Transient vestibular organ deafferentation, such that is caused by traumatic tissue injury, is presently addressed by corticosteroid therapy. However, restoration of neurophysiological properties is rarely achieved. Here, it was hypothesized that the tissue-protective attributes of α1-antityrpsin (AAT) may promote restoration of neuronal function. Inner ear injury was inflicted by unilateral labyrinthotomy in wild-type mice and in mice overexpressing human AAT. A 2-week–long assessment of vestibular signs followed. All animals responded with peak vestibular dysfunction scores within 4 h after local trauma. While wild-type animals displayed partial or no recovery across 7 days post-injury, AAT-rich group exhibited early recovery: from behavioral score 9-out-of-9 at peak to 4.8 ± 0.44 (mean ± SD) within 8 h from injury, a time when wild-type mice scored 8.6 ± 0.54 (p < 0.0001), and from vestibular score 15-out-of-15 to 7.8 ± 2.2 within 24 h, when wild-type mice scored 13.0 ± 2.0 (p < 0.01). Thus, recovery and functional normalisation of an injured vestibular compartment is achievable without corticosteroid therapy; expedited tissue repair processes appear to result from elevated circulating AAT levels. This study lays the foundation for exploring the molecular and cellular mediators of AAT within the repair processes of the delicate microscopic structures of the vestibular end organ.
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Vestibular compensation is the process by which the central nervous system (CNS) attempts to adapt to the loss of unilateral or bilateral peripheral vestibular sensory inputs. Although it is well accepted that the bilateral vestibular nuclei are critical for the compensation, it has been suspected for decades that the full spectrum of compensatory processes involves many different areas of the CNS, and that therefore vestibular compensation is a “distributed process”. This concept, originally advanced by Llinas and Walton (1979), has been supported by numerous studies over the last decades, including recent positron-emission tomography and functional magnetic resonance imaging studies.
Changes in beta-2 adrenergic receptor and AMP-activated protein kinase alpha-2 subunit in the rat vestibular nerve after labyrinthectomy
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In the present study, to elucidate the role of vestibular ganglion (VG) after the unilateral labyrinthine damage, we examined quantitative changes in mRNA expression of beta-adrenergic receptors (bARs) and AMP-activated protein kinase alpha catalytic subunits (aAMPKs) in VG after unilateral labyrinthectomy (UL) in rats. Using the real-time PCR method, beta2 AR mRNA expression in bilateral VG and AMPK alpha2 mRNA expression in the ipsilateral VG were significantly up-regulated with the maximum increase at the postoperative 7 day and 1 day, respectively. The up-regulation of beta2 AR in bilateral VG was long-lasting until 28 days after UL and that of AMPK alpha2 in the ipsilateral VG was just transient within 7 days after UL. These mRNA changes were supported by immunohistochemical data. According to previous reports, both of bARs and aAMPKs could regulate mitochondrial uncoupling protein (UCP) mRNA expression in several kinds of tissues and therefore might have thermogenic neurotransmission and antioxidant neuroprotective roles in neuronal tissues. UL requires not only long-lasting response of VG for central vestibular neuro-plasticity around 2–4 weeks but rapid response of VG against apoptosis of peripheral vestibular epithelia-neuronal synapses. The present findings suggest that beta2 AR in bilateral VG and AMPK alpha2 in the ipsilateral VG might play important signaling roles after the unilateral labyrinthine damage.
Decreased Fos protein expression in rat caudal vestibular nucleus is associated with motion sickness habituation
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We investigated the temporal change of Fos protein expression in the caudal vestibular nucleus of rats exposed to daily 2-h Ferris-wheel like (FWL) rotation. Repeated rotation (2 h daily for 14 consecutive days) caused an initial increase in defecation, followed by a gradual decline back to the baseline level after 8 rotation sessions. Unlike defecation, the Kaolin consumption of rats showed a bitonic function during the daily rotation sessions (2 h daily for 33 consecutive days) and finally recovered to the baseline after about 31 sessions. Immunohistochemistry study revealed increased Fos immunolabeled (Fos-LI) neurons in the medial vestibular nucleus and spinal vestibular nucleus during the initial 7 rotation sessions, and it decreased to the baseline level after 10 rotation sessions. There was a strong linear relationship between the amount of Fos-LI neurons and rat defecation level throughout the whole rotation sessions. These results suggest that the change of neuronal plasticity in the caudal vestibular nucleus might contribute to attenuation of gastrointestinal symptoms during motion sickness habituation process.
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In the present study, to elucidate the role of mitochondrial uncoupling proteins (UCPs) in inner ear, we examined quantitative changes in the mRNA expression in vestibular ganglion (VG) after unilateral labyrinthectomy (UL) in rats. Using real-time PCR methods, UCP2, 3 and 4 mRNA expressions in the ipsilateral VG were significantly up-regulated with the maximum increase at the post-operative 1 day and all but UCP2 returned to the control level 1 week after UL. UCP2 mRNA expression was significantly up-regulated even 4 weeks after UL. Only UCP2 mRNA expression in the contralateral VG was gradually up-regulated between 1 and 4 weeks after UL. According to previous reports, UCP2 and 3 as well as UCP1 were thermogenic in yeast and brain UCP2 was suggested to modulate pre- and post-synaptic events by axonal thermogenesis. It was also reported that UCP1, 2 and 3 responses to superoxide application were an antioxidant protective mechanism. These findings suggest that mitochondrial UCPs could play both a neuro-protective role against oxidative damage and a thermal signaling role for neuro-modulation in vestibular nerve.

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Effects of MK801 on Fos expression in the rat brainstem after unilateral labyrinthectomy

Abstract

Neuroscience

Brain Res.

Neurosci. Lett.

J. Physiol.

Brain Res.

Brain Res.

Mol. Brain Res.

Brain Res.

Mol. Brain Res.

Neuropharmacology

Eur. J. Pharmacol.

Brain Res.

Brain Res.

Brain Res. Rev.

Neurosci. Lett.

Brain Res. Rev.

Neurosci. Lett.

Brain Res.

Cerebro cerebellar communication systems

Physiol. Rev.

Long-term potentiation and NMDA receptors in rat visual cortex

Nature

Ultrastructural description of glutamate-, aspartate-, taurine- and glycine-like immunoreactive terminals from five rat brain regions

J. Electron Microsc. Techn.