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Pael receptor (Pael-R) has been identified as one of the substrates of Parkin, a ubiquitin ligase responsible for autosomal recessive juvenile Parkinsonism (AR-JP). When Parkin is inactivated, unfolded Pael-R accumulates in the endoplasmic reticulum and results in neuronal death by unfolded protein stress, suggesting that Pael-R has an important role in the pathogenesis of AR-JP. Here we report the analyses on Pael-R-deficient (KO) and Pael-R-transgenic (Tg) mice. The striatal dopamine (DA) level of Pael-R KO mice was only 60% of that in normal mice, while in Pael-R Tg mice, striatal 3,4-dihydroxyphenylacetic acid (DOPAC) as well as vesicular DA content increased. Moreover, the nigrostriatal dopaminergic neurons of Pael-R Tg mice are more vulnerable to Parkinson's disease-related neurotoxins while those of Pael-R KO mice are less. These results strongly suggest that the Pael-R signal regulates the amount of DA in the dopaminergic neurons and that excessive Pael-R expression renders dopaminergic neurons susceptible to chronic DA toxicity.

Systemic administration of a dopamine D2 receptor blocker, haloperidol, but not vehicle, significantly increased the number of c-Fos-immunoreactive neurons in the globus pallidus (GP) in rats. Dual immunohistochemistry, a combination of c-Fos immunohistochemistry and retrograde tracing experiments with cholera toxin B (ChB), revealed that a subset of the c-Fos-immunoreactive GP neurons was pallidostriatal feedback neurons. Lesioning of the subthalamic nucleus (STN) by local injection of ibotenic acid inhibited the haloperidol-induced c-Fos expression in the GP neurons, suggesting that the activation of GP neurons is a result of increased excitatory drives from the STN. Therefore, the present findings are evidence of the existence of the subthalamo-pallido-striatal axis as a feedback system in the internal circuits of the basal ganglia.

The regional distribution of c-Fos expression in the brain after the administration of two tremorgenic agents was studied. In both the harmaline- and oxotremorin-treated rats, c-Fos-positive neurons were extensively distributed in the basal ganglia nuclei and the cerebellum. Additionally, in the harmaline-treated rats, numerous c-Fos-positive neurons were also distributed throughout the inferior olivary nucleus. In the oxotremorine-treated rats, while the inferior olive was not involved, c-Fos was strongly expressed in the neurons of the reticular thalamic nucleus, possibly due to the muscarinic effects of oxotremorine. The present study revealed that the inferior olive is selectively activated in the harmaline-administered animals and that the basal ganglia are involved in both harmaline- and oxotremorine-induced tremors.

This study examined the induction of c-Fos expression in the substantia nigra pars reticulata (SNr) and entopeduncular nucleus (EP) in the rats with a globus pallidus (GP) lesion, following the administration of haloperidol. After a GP lesion was made unilaterally by stereotaxic administration of ibotenic acid, haloperidol was administered systemically, and the number of cells expressing c-Fos was quantitatively assessed. Haloperidol induced a high level of the expression of c-Fos in neurons of the SNr and EP, and the GP lesion significantly decreased the expression of c-Fos in the ipsilateral SNr and EP. Since it has been suggested that c-Fos expression in the SNr/EP is caused by increased excitatory inputs from the subthalamic nucleus (STN), the present results provide functional evidence indicating that neuronal activities of the basal ganglia output nuclei are not increased by GP ablation, unlike D2 receptor blockade, supporting the recently proposed hypothesis that overactivity of the STN resulting from dopamine depletion is not solely a result of disinhibition from inhibitory GP efferents.

c-Fos is one of the transcription factors contributing to the regulation of the downstream gene expression. Administration of dopamine D1 receptor agonist or D2 receptor antagonist have been known to induce c-Fos expressions in striatal projection neurons. We examined the effects of unilateral ablation of the globus pallidus (GP) on apomorphine- or haloperidol-induced expression of c-Fos in the striatum. Haloperidol induced a high level of c-Fos expression in the striatal neurons, predominantly those in the dorsal part, and the unilateral GP lesion caused by ibotenic acid increased the number of neurons exhibiting haloperidol-induced c-Fos expression in the striatum on the side with the GP lesion by about 2- or 3-fold. On the other hand, the unilateral GP lesion had no significant effect on the apomorphine-induced c-Fos expression in the striatal neurons. The present study provides evidence indicating that the activity of GP neurons may have an inhibitory influence on the induction of the immediate early genes by haloperidol in the striatal neurons, suggesting a function of the pallido-striatal feedback loops which have been identified anatomically.

THE ipsilateral and contralateral corticocortical connections to the fifth somatosensory area (SV) in the feline cortex were determined from the location of retrogradely labelled cells following a single injection of HRP into SV. The injection was made into physiologically defined components of the body representation in SV. After injection of HRP into the face regions of SV, HRP-labelled cells were located ipsilaterally in areas 6 beta, 3b and 1-2 of the primary somatosensory (SI), in the second somatosensory (SII), third somatosensory (SIII), and fourth somatosensory (SIV) areas, along the ansate sulcus, and in areas 5a and 6a beta of the ipsilateral cortex, as well as in area 1-2 of SI and in SV of the contralateral cortex. On the other hand, after HRP had been injected into the trunk/hindlimb area, HRP-labelled cells were located in areas 3a, 1-2 of SI, in area 5, in SII, in SIII and in SIV of the ipsilateral cortex, as well as in area 1-2 of SI, and in SV of the contralateral cortex. The extent of these interconnections suggests that SV receives multiple sensory inputs and may function to integrate this information.

To analyze the descending pathways of the paralemniscal pontine reticular formation (PLRF), a technique was used for the selective activation of cell bodies by localized injection of putative neurotransmitters in the PLRF. When a small amount (less than 0.1 microliter) of 0.1 M glutamate was injected into the PLRF unilaterally in thalamic cats, the forelimb contralateral (c-forelimb) to the injection was extended, and occasionally the ipsilateral forelimb was flexed. These responses were similar to those obtained by electrical stimulation of the PLRF, but were relatively weaker. Unit spikes of PLRF neurons were increased in frequency following administration of glutamate. The latent periods and durations of increases in spike frequency varied depending on the concentration and quantity of the glutamate solution, and were roughly similar to those of the extensor EMG in the c-forelimb. Since the firing of PLRF neurons preceded the EMG with 11 ms latency, the unit spike of PLRF neurons could be used as a triggering signal to observe a spike triggered averaged EMG response in the extensor muscle of the c-forelimb. Results similar to those with glutamate were observed upon administration of quisqualate, kainate and aspartate. The most effective compound was quisqualate. Application to the PLRF of 1-naphthylacetyl spermine (1-NA-Spm), an analogue of the natural spider toxin JSTX-3 and an antagonist of glutamate, suppressed both the PLRF neuron activity and the extensor EMG of the c-forelimb. These observations suggest that extensor muscles of the forelimb are excited by the contralateral PLRF, perhaps via the crossed reticulospinal tract from the PLRF. PLRF neurons may be activated by glutamate (quisqualate) receptors.