Preventive effects of genistein on motor dysfunction following 6-hydroxydopamine injection in ovariectomized rats.

Estrogen and phytoestrogens such as the isoflavones have received considerable attention in Parkinson's disease (PD) research. Because they have been reported to possess neuroprotective effects on dopaminergic neurons in the substantia nigra (SN), isoflavones appear particularly promising for post-menopausal women at risk for PD. However, most previous studies were limited to morphological investigation, and the preventive effects of isoflavones on motor function have not been evaluated. The aim of the present study was to elucidate the prevention by an isoflavone against motor dysfunction after injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of ovariectomized rats, which mimics post-menopausal status in women. Pretreatment with genistein, an isoflavone, significantly preserved motor function in rats injected with low-dose 6-OHDA, as evaluated by the stepping and cylinder tests. An estrogen receptor antagonist, ICI182780, reversed the effects of genistein, indicating that this effect of genistein is mediated through estrogen receptors. The functional effects of genistein were accompanied by preservation of tyrosine hydroxylase-immunoreactive neurons in the SN after injection of low-dose 6-OHDA. These findings suggest that genistein may be useful for the prevention of PD in post-menopausal women.

Fast cortical oscillation after thalamic degeneration: pivotal role of NMDA receptor.

We examined electrophysiological and molecular changes of the thalamocortical system after thalamic degeneration in Purkinje cell degeneration (pcd) mice. In pcd mice, neurons in specific thalamic nuclei including the ventral medial geniculate nucleus began to degenerate around postnatal day 50, whereas the visual thalamic nucleus and nonspecific thalamic nuclei remained almost intact. In association with the morphological changes, auditory evoked potentials in the primary auditory cortex (AC) began to decrease gradually. Fast Fourier transform analysis of spontaneous cortical field potentials revealed that fast oscillation (FO) around 25 Hz occurred in the AC but not in the visual cortex. Quantitative mRNA analysis demonstrated that expression of the N-methyl-D-aspartate (NMDA) receptor was up-regulated in the AC but not in the visual cortex. Systemic administration of an NMDA antagonist abolished the FO in the AC. These results indicate that increased NMDA activity may cause the FO in the AC of pcd mice.

Emergence of endoplasmic reticulum stress and activated microglia in Purkinje cell degeneration mice.

In the current studies, we characterized the molecular and cellular mechanism of cell death in Purkinje cell degeneration (pcd) mice using real-time quantitative PCR, immunohistochemistry, and Western blotting. It appears that endoplasmic reticulum (ER) stress is involved in this degeneration of Purkinje cells because ER stress-related substrates, such as CHOP and caspase 12, were strongly activated in Purkinje cells of pcd mice during the third postnatal (P) week. A significant increase in the expression of the ER-specific chaperone BiP suggested that unfolded protein responses were induced. We also found that Purkinje cells underwent apoptosis via the activation of caspase 3 and subsequent fragmentation of DNA. In addition to the activation of apoptosis in Purkinje cells, many activated microglial cells are found to be present in the molecular layer of the cerebellar cortex. In the later phase of degeneration, there was conspicuous expression of inducible nitric oxide synthase (iNOS), and some Purkinje cells were strongly labeled with an antibody to nitrotyrosine, suggesting that Purkinje cells in pcd mice are damaged by nitric oxide released from microglial cells. Administration of minocycline, which may inhibit iNOS expression, delayed the death of Purkinje cells in pcd mice and mildly improved their motor abilities. These findings suggest that ER stress participates in the degeneration of Purkinje cells and that activation of microglia accelerates Purkinje cell death in pcd mice.

Thalamo-cortical projections to the posterior parietal cortex in the monkey.

Thalamo-cortical projections to the posterior parietal cortex (PPC) were investigated electrophysiologically in the monkey. Cortical field potentials evoked by the thalamic stimulation were recorded with electrodes chronically implanted on the cortical surface and at a 2.0-3.0 mm cortical depth in the PPC. The stimulation of the nucleus lateralis posterior (LP), nucleus ventralis posterior lateralis pars caudalis (VPLc), and nucleus pulvinaris lateralis (Pul.l) and medialis (Pul.m) induced surface-negative, depth-positive potentials in the PPC. The LP and VPLc projected mainly to the superior parietal lobule (SPL) and the anterior bank of the intraparietal sulcus (IPS), and the Pul.m mainly to the inferior parietal lobule (IPL) and the posterior bank of the IPS. The Pul.l had projections to all of the SPL, the IPL and both the banks. The significance of the projections is discussed in connection with motor functions.

Perirhinal cortex relays auditory information to the frontal motor cortices in the rat.

Auditory evoked potentials (AEPs) were recorded in the motor cortices (MC) with chronically implanted electrodes in the rat. Some of the AEPs in the MC, namely negative potentials on the surface and positive ones at a depth of 2 mm at latencies of about 50-150 ms, were abolished by limited bilateral lesions of the anterior perirhinal cortex (PERa) which was responsive to auditory stimulus, indicating that the AEPs in the MC were at least partially relayed in the PERa. The auditory response in the MC was prominently enhanced when water was supplied or the medial forebrain bundle was stimulated after auditory stimulus. These results indicate that the MC receives the reward associated auditory information from the PERa.

Cortical field potentials preceding self-paced forelimb movements and influences of cerebellectomy upon them in rats.

Seven rats were well trained to move lever to the left by right forelimb at self-pace (self-paced forelimb movements). Cortical field potentials associated with self-paced forelimb movements were recorded by electrodes implanted chronically on the surface and at a 2.0 mm depth in the forelimb motor cortex on the left side. A surface-negative, depth-positive potential starting about 1.0 s prior to the movement was recorded in the rostral part of the forelimb motor cortex. Further we found that the premovement potential was eliminated by the cerebellar hemispherectomy on the right side. This suggests the participation of the cerebellar hemisphere in preparing the activity of the motor cortex before self-paced forelimb movements in rats, by cerebello-thalamo-cortical projections.

Projection from the perirhinal cortex to the frontal motor cortex in the rat.

Stimulation of the anterior perirhinal cortex (PERa) induced marked surface-negative and depth-positive field potentials in the rat frontal motor cortex (MC) including the rostral and caudal forelimb areas. Injection of biotinylated dextran into the PERa densely labeled axon terminals in the superficial layers of the MC, where vigorous unit responses were evoked after PERa stimulation, indicated that the perirhinal-frontal projection preferentially activates the superficial layer neurons of the MC.