Neuroscience
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Histamine H3 receptors are widely distributed Gi-coupled receptors whose activation reduces neuronal activity and inhibits release of numerous neurotransmitters. Although these receptors are abundantly expressed in the striatum, their modulatory role on activity-dependent dopamine release is not well understood. Here, we observed that histamine H3 receptor activation indirectly diminishes dopamine overflow in the ventral striatum by reducing cholinergic interneuron activity. ⋯ Resting membrane potential and number of spontaneous action potentials in ventral-striatal cholinergic interneurons were significantly reduced by α-methylhistamine. Acetylcholine release from isolated striatal synaptosomes, however, was not altered by α-methylhistamine. Together, these results indicate that histamine H3 receptors are important modulators of dopamine release, specifically in the ventral striatum, and that they do so by decreasing the firing rate of cholinergic neurons and, consequently, reducing cholinergic tone on dopaminergic axons.
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Comparative Study
Quantitative Comparison Of Vesicular Glutamate Transporters in rat Deep Cerebellar Nuclei.
The excitatory synapses of the rat deep cerebellar nuclei (DCN) were quantitatively analyzed by vesicular glutamate transporter 1 and 2 (vGluT1 and vGluT2) immunolabeling. We calculated the number and sizes of the labeled boutons and compared them between lateral/dentate nucleus (LN/DN), posterior interposed nucleus (PIN), anterior interposed nucleus (AIN), and medial nucleus (MN). The density of vGluT1+ boutons differs significantly within these nuclei. ⋯ The phylogenetically newer DCN (LN/DN and PIN) have a 39% higher density of vGluT1+ boutons than the phylogenetically older DCN (AIN and MN). The volume of vGluT1+ boutons does not differ between the DCN, however the average volume of vGluT2+ boutons is larger in MN. In summary, our current results confirm and extend our previous findings showing that the increase in dendritic and axonal wiring in phylogenetically newer DCN is associated with an increase in vGluT1+ bouton density.
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Central neuropathic pain (CNP) a significant problem for many people, is not well-understood and difficult to manage. Dysfunction of the central noradrenergic system originating in the locus coeruleus (LC) may be a causative factor in the development of CNP. The LC is the major noradrenergic nucleus of the brain and plays a significant role in central modulation of nociceptive neurotransmission. ⋯ Hyperalgesia was accompanied by significant increases in noradrenochrome (oxidized norepinephrine) and expression of 4-hydroxynonenal in CSF and spinal cord tissue respectively at day 21, indicative of oxidative stress. In addition, spinal levels of pro-inflammatory cytokines (interleukins 6 and 17A, tumor necrosis factor-α), as well as the anti-inflammatory cytokine interleukin10 were also significantly elevated at day 21, indicating that an inflammatory response occurred. The inflammatory effect of DSP-4 presented in this study that includes oxidative stress may be particularly useful in elucidating mechanisms of CNP in inflammatory disease states.
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During acute brain ischemia, α2-antiplasmin markedly enhances brain injury, blood-brain barrier breakdown and matrix metalloproteinase-9 (MMP-9) expression. Although α2-antiplasmin inhibits fibrin thrombus-degradation, and MMP-9 is a collagen-degrading enzyme altering blood-brain barrier, both have similar deleterious effects on the ischemic brain. We examined the hypothesis that MMP-9 is an essential downstream mediator of α2-antiplasmin's deleterious effects during brain ischemia. ⋯ MMP-9+/+ mice (p < 0.05), as measured by quantitative immunofluorescence. We conclude that MMP-9 deficiency ablates many of the deleterious effects of high α2-antiplasmin levels, significantly reducing blood-brain barrier breakdown, TUNEL-positive cell death, brain hemorrhage, swelling and infarction. This suggests that the two molecules may be in a shared pathway in which MMP-9 is essential downstream for the deleterious effects of α2-antiplasmin in ischemic stroke.
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Alzheimer's disease (AD) is the leading cause of dementia worldwide. This pathological condition is characterized not only by Aβ and tau accumulation in the central nervous system (CNS), but also by inflammation, processes that can lead to neurodegeneration. ⋯ Furthermore, cholesterol-associated genes are frequently associated with AD. Here, we extensively reviewed the literature and, based on the existing evidences, we suggest inflammation as an important link between dyslipidemias and AD.