Yiwen Zheng

Move it or lose it—Is stimulation of the vestibular system necessary for normal spatial memory?

Studies in both experimental animals and human patients have demonstrated that peripheral vestibular lesions, especially bilateral lesions, are associated with spatial memory impairment that is long‐lasting and may even be permanent. Electrophysiological evidence from animals indicates that bilateral vestibular loss causes place cells and theta activity to become dysfunctional; the most recent human evidence suggests that the hippocampus may cause atrophy in patients with bilateral vestibular lesions. Taken together, these studies suggest that self‐motion information provided by the vestibular system is important for the development of spatial memory by areas of the brain such as the hippocampus, and when it is lost, spatial memory is impaired. This naturally suggests the converse possibility that activation of the vestibular system may enhance memory. Surprisingly, there is some human evidence that this may be the case. This review considers the relationship between the vestibular system and memory and suggests that the evolutionary age of this primitive sensory system as well as how it detects self‐motion (i.e., detection of acceleration vs. velocity) may be the reasons for its unique contribution to spatial memory.

From ear to uncertainty: vestibular contributions to cognitive function

In addition to the deficits in the vestibulo-ocular and vestibulo-spinal reflexes that occur following vestibular dysfunction, there is substantial evidence that vestibular loss also causes cognitive disorders, some of which may be due to the reflexive deficits and some of which are related to the role that ascending vestibular pathways to the limbic system and neocortex play in spatial orientation. In this review we summarize the evidence that vestibular loss causes cognitive disorders, especially spatial memory deficits, in animals and humans and critically evaluate the evidence that these deficits are not due to hearing loss, problems with motor control, oscillopsia or anxiety and depression. We review the evidence that vestibular lesions affect head direction and place cells as well as the emerging evidence that artificial activation of the vestibular system, using galvanic vestibular stimulation (GVS), can modulate cognitive function.

Long‐term deficits on a foraging task after bilateral vestibular deafferentation in rats

Animal studies have shown that bilateral vestibular deafferentation (BVD) causes deficits in spatial memory that may be related to electrophysiological and neurochemical changes in the hippocampus. Recently, human studies have also indicated that human patients can exhibit spatial memory impairment and hippocampal atrophy even 8–10 yr following BVD. Our previous studies have shown that rats with unilateral vestibular deafferentation (UVD) showed an impairment at 3 months after the surgery on a food foraging task that relies on hippocampal integration of egocentric cues, such as vestibular information; however, by 6 months postop, they showed a recovery of function. By contrast, the long‐term effects of BVD on spatial navigation have never been well studied. In this study, we tested BVD or sham rats on a food foraging task at 5 months postop. Under light conditions, BVD rats were able to use visual cues to guide themselves home, but did so with a significantly longer homing time. However, in darkness, BVD rats were severely impaired in the foraging task, as indicated by a significantly longer homing distance and homing time, with more errors and larger heading angles when compared with sham rats. These results suggest that, unlike UVD, BVD causes long‐term deficits in spatial navigation that are unlikely to recover, even with repeated T‐maze training.

Locomotor and exploratory behavior in the rat following bilateral vestibular deafferentation.

Despite many studies of the postural and ocular reflex deficits caused by chronic bilateral vestibular loss in rats and guinea pigs, there have been few systematic studies of the effects of vestibular loss on locomotor activity and exploratory behavior over a period of several months following the lesion. In this study, the authors quantified locomotor and exploratory behavior in an open field maze at 3 weeks, 3 months, and 5 months following bilateral vestibular loss in rats. As a result of bilateral surgical vestibular lesions, rats exhibited a persistent increase in locomotor velocity, duration, and distance traveled, with a marked tendency for increased inner field activity and reduced thigmotaxis. Rats without balance-sense were also found to spend less time exploring the environment, as indicated by a decreased frequency and duration of wall-supported rearings. These results suggest that sudden and complete loss of balance-sense has persistent and complex effects on the way that rats navigate through and explore the environment.

Role of brain nitric oxide in (±)3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity in rats

The role of nitric oxide (NO) in the long-term serotoninergic neurotoxicity induced by (+/-)3,4-methylenedioxymethamphetamine (MDMA) in rats was investigiated. Pretreatment with Nomega-nitro-L-arginine (L-NOARG) (10 mg kg-1), a nitric oxide synthase (NOS) inhibitor, partially protected against long-term serotonin (5-HT) depletion induced by MDMA (40 mg kg-1) in frontal cortex and parietal cortex, but not in other brain regions examined. Brain NOS activities in these two regions were significantly elevated at 6 h after MDMA administration. Moreover, L-NOARG pretreatment caused significant inhibition of brain NOS activity but did not affect the acute 5-HT and dopamine (DA) changes or the hyperthermia induced by MDMA. These results suggest that it is the NOS inhibitory properties of L-NOARG, rather than its effects on the acute monoamine changes or the hyperthermia induced by MDMA, that are responsible for the prevention of neurotoxicity. The regional differences on the protection of L-NOARG and on the activation of NOS by MDMA indicate the unequal role that NO may play in MDMA-induced neurotoxicity in different brain regions.

Long-term changes in hippocampal n-methyl-D-aspartate receptor subunits following unilateral vestibular damage in rat.

Previous studies have indicated that damage to the peripheral vestibular system results in dysfunction of hippocampal place cells and an impairment of spatial learning and memory. The aim of this study was to determine whether lesions of one vestibular labyrinth (unilateral vestibular deafferentation, UVD) result in changes in the expression of the NR1 and NR2A subunits of the N-methyl-D-aspartate (NMDA) receptor, and the GluR2 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor, in subregions of the rat hippocampus (CA1, CA2/3 and the dentate gyrus) at 10 h or 2 weeks following UVD. Compared with sham surgery controls and anaesthetic controls, the expression of the NR1 subunit was significantly reduced in the ipsilateral CA2/3 region at 2 weeks post-UVD. The expression of the NR2A subunit was also significantly reduced in the ipsilateral CA2/3 and, to a smaller extent, in the contralateral CA2/3 region, at 2 weeks post-UVD. The only other change in NR2A expression was an increase in the ipsilateral CA1 at 10 h post-UVD. No other changes in NR1, NR2A or GluR2 expression were observed in any hippocampal subregion, at any time point, or in cortical tissue at any time point. These results suggest that UVD may result in long-term changes in NMDA receptor subunit expression in the rat hippocampus.

Modulation of Memory by Vestibular Lesions and Galvanic Vestibular Stimulation

For decades it has been speculated that there is a close association between the vestibular system and spatial memories constructed by areas of the brain such as the hippocampus. While many animal studies have been conducted which support this relationship, only in the last 10 years have detailed quantitative studies been carried out in patients with vestibular disorders. The majority of these studies suggest that complete bilateral vestibular loss results in spatial memory deficits that are not simply due to vestibular reflex dysfunction, while the effects of unilateral vestibular damage are more complex and subtle. Very recently, reports have emerged that sub-threshold, noisy galvanic vestibular stimulation can enhance memory in humans, although this has not been investigated for spatial memory as yet. These studies add to the increasing evidence that suggests a connection between vestibular sensory information and memory in humans.

Cannabinoid CB2 receptor expression in the rat brainstem cochlear and vestibular nuclei

Conclusion. This evidence suggests that both CB1 and CB2 receptors are important in the control of balance and hearing. Objective. Although the cannabinoid CB1 receptor has been identified in the brainstem vestibular and cochlear nuclei, the existence of the second cannabinoid receptor subtype, the CB2 receptor, has been more controversial. The aim of this study was to determine whether or not CB2 receptors are expressed in the vestibular and cochlear nuclei. Materials and methods. Data were obtained from four young male Wistar rats In analyzing the presence of CB2 receptors in the vestibular and cochlear nuclei, the immunohistochemical complex was visualized by exposure to diaminobenzidine for 20 min. Positive immunoreactivity to CB2 was expressed as brown staining in the cytoplasm, nucleus, nuclear membrane and cell membrane. Results. We confirmed the existence of the CB2 receptor in the vestibular and cochlear nuclei in the brainstem of Wistar rats.

Bilateral labyrinthectomy causes long-term deficit in object recognition in rat.

It has been reported that patients with vestibular disorders experience a wide range of cognitive disorders, including memory loss. However, to our knowledge, no study has investigated the contribution of vestibular information to episodic memory in experimental animals using vestibular deafferentation. In the present study, the effects of a complete unilateral or bilateral surgical lesion of the vestibular labyrinths in a spontaneous object recognition task were evaluated in Wistar rats 3 and 6 months following the surgery. We found that rats with bilateral vestibular deafferentation, but not those with unilateral vestibular deafferentation were impaired on the task at both time points. These results suggest for the first time that vestibular information may contribute to non-spatial memory to some extent.

Immunohistochemical characterisation and localisation of cannabinoid CB1 receptor protein in the rat vestibular nucleus complex and the effects of unilateral vestibular deafferentation

CB1 receptor expression has been reported to be low in the brainstem compared with the forebrain, and low in the vestibular nucleus complex (VNC) compared with other regions in the brainstem. However, a frequent effect of cannabis is dizziness and loss of balance. This may be due to the activation of cannabinoid receptors in the central vestibular pathways. We used immunohistochemistry to study the distribution of CB1 receptor protein in the VNC, and Western blotting to measure CB1 receptor expression in the VNC following unilateral vestibular deafferentation (UVD); the hippocampal CA1, CA2/3 and dentate gyrus (DG) regions were also analysed for comparison. This study confirms a previous electrophysiological demonstration that CB1 receptors exist in significant densities in the VNC and are likely to contribute to the neurochemical control of the vestibular reflexes. Nonetheless, CB1 receptor expression did not change significantly in the VNC during vestibular compensation. In addition, despite some small but significant changes in CB1 receptor expression in the CA2/3 and the DG following UVD, in no case were these differences statistically significant in comparison to both control groups.