Neuroscience
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Vascular dementia (VD), defined as a loss of memory and cognitive function resulting from vascular lesions in the brain, is the second-most-common cause of dementia in the elderly, after Alzheimer's disease. In recent years, research has focused on the pathogenesis of VD, and mitochondrial bioenergetic deficits have been suggested to contribute to VD onset. To further investigate the role of mitochondria in VD, we used a rat model of VD, which involved permanent bilateral occlusion of the common carotid arteries (with a 1-week interval between artery occlusion to avoid an abrupt reduction in cerebral blood flow) leading to chronic cerebral hypoperfusion. ⋯ The ischemia group mitochondria also exhibited decreased respiration coupled to decreased expression and activity of the electron transport chain complex IV (cytochrome c oxidase). These results indicate that the mitochondrial oxidative metabolism is inhibited in the hippocampi of rats following chronic ischemia-induced VD. As the mitochondrial oxidative metabolism deficits, namely mitochondrial bioenergetic deficits directly affect the functions of neurons, it may contribute to VD onset.
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As a widely used intravenous short-acting anesthetic, propofol is recently indicated by clinical and animal studies for its abuse potential, but the mechanism underlying propofol abuse is largely unknown. This study examined the contribution of dopamine receptor subtype (D1 and D2 receptors) and neuroanatomical locus (i.e. nuclear accumbens) in the maintenance of propofol self-administration in rats. ⋯ We demonstrated (i) systemic administration of SCH23390 (10, 30, 100 μg/kg, i.p.) dose-dependently decreased the rate of propofol-maintained self-administration, suggesting a critical role of the D1 receptor in mediating propofol self-administration; (ii) the blockade of the propofol self-administration by SCH23390 was specific since spiperone and eticlopride did not affect propofol self-administration and SCH23390 at these doses did not affect food-maintained responding under an FR5 schedule; (iii) intra-accumbenal injection of SCH23390 (2.5 μg/site) but not eticopride (3.0 μg/site) attenuated the propofol self-administration, localizing nuclear accumbal D1 receptors as a critical locus in the reinforcement of propofol. Together, these findings provide the first direct evidence that D1 receptors in nuclear accumbens play an important role in the maintenance of propofol self-administration.
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In this study, we assessed the effects of varying tetanus and test-pulse intensity on the magnitude of long-term potentiation (LTP) in the perforant path-dentate gyrus projection of urethane-anaesthetized rats. We developed a novel within-subjects procedure in which test-pulse-stimulation intensity (60-1000 μA) was varied quasi-randomly under computer control throughout the recording period. After a baseline period, we applied a high-frequency tetanus, the intensity of which was varied over the same range as test-pulse intensity, but between subjects. ⋯ After 1000-μA tetanization of the original ('upstream') site, fEPSPs were again depressed in response to test stimulation of the upstream site, but only potentiation was observed in response to stimulation of the downstream site. This is consistent with the idea that the depression induced by intense tetanization results from local changes at the stimulation site. In conclusion, while tetanus intensity must exceed the LTP induction threshold, intensities above 500 μA should be avoided; in the present study, tetanization at 250-500 μA yielded maximal levels of LTP.
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Neuronal electrical activity has been known to affect the viability of neurons in the central nervous system. Here we show that long-lasting membrane depolarization induced by elevated extracellular K(+) recruits nitric oxide (NO)/soluble guanylyl cyclase/protein kinase G signaling pathway, induces 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP)-mediated protein S-guanylation, and confers dopaminergic neuroprotection. Treatment of primary mesencephalic cell cultures with 1-methyl-4-phenylpyridinium (MPP(+)) for 72 h decreased the number of dopaminergic neurons, whereas the cell loss was markedly inhibited by elevated extracellular concentration of K(+) (+40 mM). ⋯ Zinc protoporphyrin IX also inhibited the neuroprotective effect of elevated extracellular K(+). On the other hand, KT5823 or Rp-8-Br-PET-cGMPS did not inhibit the induction of HO-1 protein expression by 8-nitro-cGMP, although these protein kinase G inhibitors abrogated the neuroprotective effect of 8-nitro-cGMP. These results suggest that protein S-guanylation (leading to HO-1 induction) as well as canonical protein kinase G signaling pathway plays an important role in NO-mediated, activity-dependent dopaminergic neuroprotection.
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Rett syndrome (RTT) is a disorder with a pronounced neurological phenotype and is caused mainly by mutations in the X-linked gene MECP2. A common feature of RTT is an abnormal electroencephalography and a propensity for seizures. In the current study we aimed to assess brain network excitability and seizure propensity in a mouse model of RTT. ⋯ Brain slices challenged with the GABA(A)-receptor antagonist bicuculline (0.1-10 μM) and the potassium channel blocker 4-aminopyridine (1-50 μM) also revealed differences between genotypes with hippocampal circuits from Mecp2(stop/y) mouse slices showing enhanced epileptiform burst duration and frequency. In contrast to these network level findings, single cell analysis of pyramidal cells by whole-cell patch clamp recording revealed no detectable differences in synaptic or biophysical properties between methyl-CpG-binding protein 2 (MeCP2)-containing and MeCP2-deficient neurons. These data support the proposal that loss of MeCP2 alters network level excitability in the brain to promote epileptogenesis.