Neuroscience
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Evidence suggests that cerebrovascular hemodynamic disturbances underlie cognitive deterioration secondary to cardiovascular disease (CVD), including manifestations other than stroke, but the mechanisms remain unclear. To date, the majority of studies have used neuropsychological measures validated for the detection of clinically significant cognitive decline but lack the sensitivity to accurately detect subclinical or subtle cognitive changes. The N2 and P3 components of the event-related potential are sensitive markers of attention and cognitive processing, and are valuable in the assessment of age-related cognitive changes and neurodegenerative disease. ⋯ Further, MCAv and PI were strongly associated with N2 amplitude in the CVD group, such that greater MCAv was associated with reductions in N2 amplitude (b = -0.58, p = .018), whilst PI was associated with increases in N2 amplitude (b = 0.66, p = .006). No relationships between MCAv or PI with N2 or P3 ERP components were observed in the healthy control group. The data reported here suggest that a reduction in N2 amplitude may be an important objective indicator of subclinical cognitive and attentional alterations in non-stroke CVD, and support the notion that cerebrovascular hemodynamic disturbances play a role in the pathogenesis of cognitive deterioration secondary to non-stroke CVD.
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Status epilepticus (SE) is a life-threatening condition needing immediate care to prevent brain damage. SE with electrographic and behavioral features similar to those seen in humans is reproduced in rodents by i.p. pilocarpine injection, and can be terminated by diazepam and ketamine treatment but only behaviourally, not electrographically. Little is known on the behavioral and EEG effects induced by a delayed administration of ketamine (25 mg/kg) after diazepam (10 mg/kg) or vice versa. ⋯ However, diazepam administration before ketamine significantly shortened the time of behavioral recovery compared to when ketamine was administered before diazepam (p < 0.05). The two protocols were also associated to distinct EEG changes in gamma and high frequency oscillations. In conclusion, although diazepam and ketamine are not effective in stopping EEG SE, diazepam administration one hour before ketamine shortens behavioral recovery in pilocarpine-treated mice.
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A prominent feature of the hypothalamic neuropeptides orexins/hypocretins is their role in the regulation of sleep-wake behavior. While there is strong evidence for a diurnal (i.e. 24-h) rhythmicity of the expression of prepro-orexin (PPO) and its cleavage products, orexin A and B, it is not known whether orexin receptors are also subject to diurnal regulation. Here we ask whether besides the regulation of PPO the expression of the orexin receptor subtypes OX1R and OX2R varies over 24 hours in the mouse brain. ⋯ The expression of both orexin receptor subtypes significantly correlated with that of clock genes. Remarkably, the expression pattern of OX2R showed a strong and highly significant correlation with that of the clock gene Bmal1 in the cortex and hypothalamus. These results suggest that the rhythmic expression of orexin receptors is linked to clock gene expression and that OX2R may potentially play a role in the timing of sleep-wake behavior.
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In central synapses, synaptobrevin-2 (also called VAMP-2) is the predominant synaptic vesicle SNARE protein that interacts with the plasma membrane SNAREs, SNAP-25 and syntaxin-1 to execute exocytosis. Mice deficient in synaptobrevin-2 or SNAP-25 show embryonic lethality, which precludes investigation of the complete loss-of-function of these proteins in the adult nervous system. However, mice that carry heterozygous null mutations survive into adulthood and are fertile. ⋯ This analysis revealed only mild phenotypes, SNAP-25 (+/-) mice exhibited marked hypoactivity, whereas synaptobrevin-2 (+/-) mice showed enhanced performance on the rotarod. The two mouse lines did not manifest significant deficits in anxiety-related behaviors, learning and memory measures, or prepulse inhibition. The rather mild behavioral deficits indicate that these key proteins, SNAP25 and synaptobrevin-2, are expressed in excess to circumvent the impact of potential fluctuations in expression levels on nervous system function.
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The endocannabinoid system modulates synaptic transmission, controls neuronal excitability, and is involved in various brain functions including learning and memory. 2-arachidonoylglycerol, a major endocannabinoid produced by diacylglycerol lipase-α (DGLα), is released from postsynaptic neurons, retrogradely activates presynaptic CB1 cannabinoid receptors, and induces short-term or long-term synaptic plasticity. To examine whether and how the endocannabinoid system contributes to reward-based learning of a motor sequence, we subjected male CB1-knockout (KO) and DGLα-KO mice to three types of operant lever-press tasks. First, we trained mice to press one of three levers labeled A, B, and C for a food reward (one-lever task). ⋯ In the three-lever task, both strains of knockout mice showed a slower rate of learning of the motor sequence. In the reverse three-lever task, both strains of knockout mice needed more lever presses for reversal learning. These results suggest that the endocannabinoid system facilitates reward-based learning of a motor sequence by conferring the flexibility with which animals can switch between strategies.