INFLUENCE OF LONG-TERM VIBRATION ON THE ACTIVITY OF THE SUPERIOR VESTIBULAR NUCLEUS NEURONS UNDER THE CONDITIONS OF STIMULATION OF THE HYPOTHALAMUS NUCLEI.

Prolonged vibration exposure leads to alterations of the central control mechanisms of both the vestibulo-ocular and the vestibulo-autonomic systems, including a change in the hypothalamic-vestibular relationships associated, in particular, with the supraoptic nucleus and paraventricular nucleus. Post-vibration disturbances of the vestibular function are largely due to adaptive changes in neurotransmitter activity. The dynamics of spike activity of single neurons of the superior vestibular nucleus (SVN) in response to high-frequency stimulation of the paraventricular and supraoptic hypothalamic nuclei after long-term vibration exposure were analyzed. Analysis of impulse activity revealed the prevalence of tetanic potentiation in the responses of SVN neurons to high-frequency stimulation of paraventricular and supraoptic nuclei of rats. Exposure of animals to vibration led to a decrease in the number of neurons with tetanic potentiations and significant dominance of post-tetanic potentiation. Morphological and histochemical results showed that under hypothalamic stimulation in the SVN neurons of rats exposed to vibration, there is an increase in metabolism and dephosphorylation processes in the cellular structures of the studied brain area, which ultimately provides optimal conditions for the processes of cell survival and regeneration.

Integrated metabolomics and network pharmacology approach to exploring the potential mechanism of tianxiang capsule for treating motion sickness.

ETHNOPHARMACOLOGICAL RELEVANCE: Motion sickness is a multi-system syndrome caused by abnormal spatial environmental sensory conflicts. Tianxiang Capsule (TXC) is a traditional Chinese medicine (TCM) formula for the prevention and treatment of motion sickness for years. However, the main active components of TXC and mechanism of its therapeutic effects on motion sickness are still unclear. AIM OF THE STUDY: The purpose of this work is to investigate the mechanism of TXC in preventing motion sickness based on serum metabolomics and network pharmacology. On the basis of the clear validation of the anti-motion sickness effect of TXC, we used the strategy of combined GC-MS metabolomics and network pharmacology to screen 60 differential metabolites regulated by TXC. MATERIALS AND METHODS: The rat models of motion sickness were stimulated by biaxial rotational acceleration, spontaneous activity was used to evaluate the efficacy of TXC on motion sickness. Serum metabolomics-based analysis was conducted to screen the differential metabolites related to motion sickness. Then, network pharmacology analysis was used to integrate the information of differential metabolites with target proteins and chemical components, and the "components-target protein-metabolite related protein-metabolite" network was constructed to explore the mechanism of the protective effect of TXC against motion sickness. RESULTS: The results of network integration analysis showed that the 50 TXC potential active ingredients mediated the differential expression of 49 metabolic biomarkers by targeting 25 target protein and regulated arachidonic acid metabolism, calcium signaling pathways, etc. In addition, we found that TXC can promote the secretion of insulin mediated by arachidonic acid pathway metabolites, regulate the levels of adrenaline and leptin, maintain blood glucose balance, and achieve the therapeutic effect of motion sickness. CONCLUSIONS: Our results indicated that the arachidonic acid metabolic pathway and related targets are the key ways for TXC to exert its efficacy, and its target protein and anti-motion sickness mechanism deserve further study. Our work proved that the integrated strategy of metabolomics and network pharmacology can well explain the "multi-component - multi-target" mechanism of complex TCM in vivo, which is a practical approach for the study of TCM formula.

Electrical Stimulation Normalizes c-Fos Expression in the Deep Cerebellar Nuclei of Depressive-like Rats: Implication of Antidepressant Activity.

The electrical stimulation of specific brain targets has been shown to induce striking antidepressant effects. Despite that recent data have indicated that cerebellum is involved in emotional regulation, the mechanisms by which stimulation improved mood-related behaviors in the cerebellum remained largely obscure. Here, we investigated the stimulation effects of the ventromedial prefrontal cortex (vmPFC), nucleus accumbens (NAc), and lateral habenular nucleus on the c-Fos neuronal activity in various deep cerebellar and vestibular nuclei using the unpredictable chronic mild stress (CMS) animal model of depression. Our results showed that stressed animals had increased number of c-Fos cells in the cerebellar dentate and fastigial nuclei, as well as in the spinal vestibular nucleus. To examine the stimulation effects, we found that vmPFC stimulation significantly decreased the c-Fos activity within the cerebellar fastigial nucleus as compared to the CMS sham. Similarly, there was also a reduction of c-Fos expression in the magnocellular part of the medial vestibular nucleus in vmPFC- and NAc core-stimulated animals when compared to the CMS sham. Correlational analyses showed that the anxiety measure of home-cage emergence escape latency was positively correlated with the c-Fos neuronal activity of the cerebellar fastigial and magnocellular and parvicellular parts of the interposed nuclei in CMS vmPFC-stimulated animals. Interestingly, there was a strong correlation among activation in these cerebellar nuclei, indicating that the antidepressant-like behaviors were possibly mediated by the vmPFC stimulation-induced remodeling within the forebrain-cerebellar neurocircuitry.

Projections from the vestibular nuclei to the hypothalamic paraventricular nucleus: morphological evidence for the existence of a vestibular stress pathway in the rat brain.

Although it has been reported by several laboratories that vestibular stress activates the hypothalamo-pituitary-adrenocortical axis (HPA), the existence of neuronal connections between vestibular and hypothalamic paraventricular neurons has not yet been demonstrated. By the use of a virus-based retrograde trans-synaptic tracing technique in the rat, here we demonstrate vestibular projections to the paraventricular nucleus (PVN). Pseudorabies virus (Bartha strain, type BDR62) was injected into the PVN, and the progression of the infection along synaptically connected neurons was followed in the pons and the medulla, 3 and 4 days post-inoculation. Virus-infected neurons were revealed mainly in the medial vestibular nucleus. Labeled cells were scattered in the spinal, and very rarely in the superior nuclei, but none of them in the lateral vestibular nucleus. Injections of cholera toxin B subunit, a monosynaptic retrograde tracer into the PVN failed to label any cells in the vestibular nuclei. These results provide anatomical evidence for the existence of a vestibulo-paraventricular polysynaptic pathway and support the view that the HPA axis is modulated by vestibular stress.

Optokinetic and vestibulo-ocular reflex adjustment by GABA antagonists.

We determined if high and low doses of anti-GABAergic drugs have opposite effects on the visuo-vestibular activity in pigmented rats and examined a possible correlation with the level of GABA in the related structures. First, the horizontal optokinetic and vestibulo-ocular reflexes of most animals were depressed by high doses of anti-GABAergic drugs (10(-3) M purified picrotoxin or 10(-6) M picrotoxin in unpurified vegetal extract). Simultaneously, a drop in GABA level in the cerebellum and posterior brainstem was detected. Second, after a subsequent injection (1 ml) of the diluted extract (10(-13) M picrotoxin), the reflexes returned to normal despite the fact that no correlation with the GABA level was found. These results demonstrate that small doses of anti-GABAergic drugs reverse the depressive effect created by large doses of these drugs on the oculomotor system, and even adjust the reflexes to the stimulation. This adjustment, without correlation with the GABA level, suggest a powerful effect of very low dose of the drug to modulate either the activity of the cerebellar inhibiting input or of the vestibular nuclei neurons or to trigger the adaptation by other neurotransmitter systems involved in the performances of the reflexes.

Cerebral glucose utilization: local changes after microinoculation of scrapie agent in hamster.

The effects of scrapie agent on local cerebral energy metabolism were studied by the [14C]2-deoxyglucose (2-DG) autoradiographic method of Sokoloff et al. after stereomicroinoculation (0.5 microliter, 10(-2) of scrapie suspension) in hamster left striatum. From a group of 20 hamsters inoculated, 2 animals were killed every 10 days from the 30th day after inoculation to the terminal stage of the disease. Experiments were carried out according to the qualitative 2-DG procedure and cerebral autoradiographs of inoculated animals were compared to those of 3 controls. The results show changes of local cerebral glucose utilization in some discrete brain regions, ipsilateral to the side of inoculation, and their sequential spreading to other cerebral structures with a definite order: left anterior thalamus, left posterior thalamus, then medial geniculate body (ipsilateral, then controlateral), and finally some brainstem nuclei (inferior colliculus, superior olivary nucleus); the inoculated striatum is affected very late, after clinical signs. Metabolic changes which first occur ipsilaterally to the side of inoculation precede the clinical symptoms, while their contralateral spreading is concomitant with the clinical signs. The data demonstrate a rostral--caudal sequence of the cerebral metabolic changes, ipsilateral to the side of inoculation, which may reflect in part the slow spread of agent in the central nervous system from the inoculation site.

[The auditory pathway in guinea pigs. A [14C]2-deoxyglucose study (author's transl)]. / Die zentrale Hörbahn beim Meerschweinchen. Eine Untersuchung mit [14C]2-Deoxyglucose.

The auditory pathway of guinea pigs was labeled with [14C]-deoxyglucose after mon- or binaural stimulation with farfield white noise in a sound-proof chamber. In the autoradiographs, all auditory nuclei were labeled. The highest metabolic effects were seen in the dorsal cochlear nucleus, the lateral superior olivary nucleus, and in the inferior colliculus. No selective labeling was observed in the auditory cortex. Monaural stimulation depressed the metabolic activity contralaterally in the ventral cochlear nucleus and ipsilaterally in the medial nucleus of the trapezoid body, the dorsomedial periolivary nucleus, and in the inferior colliculus.