Portable microstimulator for chronic deep brain stimulation in freely moving rats.

In the last decades, deep brain stimulation (DBS) has been widely used as a functional surgical strategy for the treatment of a variety of neurological and psychiatric disorders, including Parkinson's disease (PD), dystonia, epilepsy, depression or obsessive-compulsive disorder. While the therapeutic benefits of DBS are now recognized, experimental data on its mechanisms and impact at long term remain poor. This is mainly due to the lack of a microstimulation system adapted for chronic DBS in small laboratory animals. In this context, we have developed a microstimulator for DBS adapted to rat. This device, which has a size and weight compatible for use in freely moving rat, can be clipped to a support fixed on the animal's head. This easy "removal" property is crucial because it enables removing or even switching the microstimulator during the experiments without having to anaesthetize or to operate the animal, thus minimizing stress. The design of the microstimulator allows to set the DBS parameters easily (intensity, frequency and pulse width) and to replace the battery for long-term DBS. To validate our device, we performed continuous DBS of the subthalamic nucleus (known to improve motor deficits in clinic) in a classical rat model of PD during 5 weeks. We show that this long duration stimulation reduces significantly PD-induced akinesia without inducing animal discomfort and tissue damage. These first data demonstrated that long term DBS procedure in behaving rat is now workable.

Sleep disorders in Parkinson's disease: the contribution of the MPTP non-human primate model.

To replicate the sleep-wake disorders of Parkinson's disease (PD) and to understand the temporal relationship between these sleep disturbances and the occurrence of parkinsonism, we performed long-term continuous electroencephalographic monitoring of vigilance states in unrestrained rhesus monkeys using an implanted miniaturized telemetry device and tested the effect of MPTP intoxication on their sleep-wake organization. MPTP injection yielded a dramatic disruption of sleep-wake architecture with reduced sleep efficacy that persisted years after MPTP administration. Primary deregulation of REM sleep and increased daytime sleepiness occurring before the emergence of motor symptoms were a striking feature of the MPTP effect. This was concomitant with a breakdown of dopaminergic homeostasis, as evidenced by decreased dopamine turnover measured after a single MPTP injection. In the long term, partial re-emergence of REM sleep paralleled the partial adaptation to parkinsonism, the latter being known to result from compensatory mechanisms within the dopaminergic system. Altogether, these findings highlight the suitability of the MPTP model of PD as a tool to model the sleep/wake disturbances of the human disease. Ultimately, this may help in deciphering the specific role of dopamine depletion in the occurrence of these disorders.

Bilateral high-frequency stimulation of the subthalamic nucleus on attentional performance: transient deleterious effects and enhanced motivation in both intact and parkinsonian rats.

It is now well established that subthalamic nucleus high-frequency stimulation (STN HFS) alleviates motor problems in Parkinson's disease. However, its efficacy for cognitive function remains a matter of debate. The aim of this study was to assess the effects of STN HFS in rats performing a visual attentional task. Bilateral STN HFS was applied in intact and in bilaterally dopamine (DA)-depleted rats. In all animals, STN HFS had a transient debilitating effect on all the variables measured in the task. In DA-depleted rats, STN HFS did not alleviate the deficits induced by the DA lesion such as omissions and latency to make correct responses, but induced perseverative approaches to the food magazine, an indicator of enhanced motivation. In sham-operated controls, STN HFS significantly reduced accuracy and induced perseverative behaviour, mimicking partially the effects of bilateral STN lesions in the same task. These results are in line with the hypothesis that STN HFS only partially mimics inactivation of STN produced by lesioning and confirm the motivational exacerbation induced by STN inactivation.

High frequency stimulation of the subthalamic nucleus has beneficial antiparkinsonian effects on motor functions in rats, but less efficiency in a choice reaction time task.

Chronic subthalamic nucleus high frequency stimulation (STN HFS) improves motor function in Parkinson's disease. However, its efficacy on cognitive function and the mechanisms involved are less known. The aim of this study was to assess the effects of STN HFS in hemiparkinsonian awake rats performing different specific motor tests and a cognitive operant task. Unilateral STN HFS applied in unilaterally DA-depleted rats decreased the apomorphine-induced circling behaviour and reduced catalepsy induced by the neuroleptic haloperidol. DA-depleted rats exhibited severe deficits in the operant task, among which the inability to perform the task was not alleviated by STN HFS. However, in a few animals showing less impairment, STN HFS significantly reduced the contralateral neglect induced by the lesion. These results are the first to demonstrate a beneficial effect of STN HFS applied in awake rats on basic motor functions. However, STN HFS appears to be less effective on impaired cognitive functions.

Myelin basic protein-reactive T cells induce conduction failure in vivo but not in vitro.

The ability of myelin basic protein (MBP)-reactive T cells to induce conduction failure was investigated and. With the model, somatosensory evoked potentials (SEP) were recorded before and during adoptively transferred experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Maximum amplitude SEP were reached within 15 min of anesthesia. During EAE, the SEP decreased considerably and their onset was delayed. However, the compound action potentials (CAPs) recorded from Lewis rat optic nerves incubated with encephalitogenic T cells were not affected, emphasizing the importance of environmental factors. This study shows that the model described here is an useful means of investigating the neurological disorders associated with EAE.

High-frequency stimulation of the subthalamic nucleus selectively reverses dopamine denervation-induced cellular defects in the output structures of the basal ganglia in the rat.

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is now recognized as an effective treatment for advanced Parkinson's disease, but the molecular basis of its effects remains unknown. This study examined the effects of unilateral STN HFS (2 hr of continuous stimulation) in intact and hemiparkinsonian awake rats on STN neuron metabolic activity and on neurotransmitter-related gene expression in the basal ganglia, by means of in situ hybridization histochemistry and immunocytochemistry. In both intact and hemiparkinsonian rats, this stimulation was found to induce c-fos protein expression but to decrease cytochrome oxidase subunit I mRNA levels in STN neurons. STN HFS did not affect the dopamine lesion-mediated overexpression of enkephalin mRNA or the decrease in substance P in the ipsilateral striatum. The lesion-induced increases in intraneuronal glutamate decarboxylase 67 kDa isoform (GAD67) mRNA levels on the lesion side were reversed by STN HFS in the substantia nigra, partially antagonized in the entopeduncular nucleus but unaffected in the globus pallidus. The stimulation did not affect neuropeptide or GAD67 mRNA levels in the side contralateral to the dopamine lesion or in intact animals. These data furnish the first evidence that STN HFS decreases the metabolic activity of STN neurons and antagonizes dopamine lesion-mediated cellular defects in the basal ganglia output structures. They provide molecular substrate to the therapeutic effects of this stimulation consistent with the current hypothesis that HFS blocks STN neuron activity. However, the differential impact of STN HFS on the effects of dopamine lesion among structures receiving direct STN inputs suggests that this stimulation may not cause simply interruption of STN outflow.