Neuroscience
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The behavioral and motivational changes that result from use of abused substances depend upon activation of neuronal populations in the reward centers of the brain, located primarily in the corpus striatum in primates. To gain insight into the cellular mechanisms through which abused drugs reinforce behavior in the primate brain, changes in firing of neurons in the ventral (VStr, nucleus accumbens) and dorsal (DStr, caudate-putamen) striatum to "natural" (juice) vs. drug (i.v. cocaine) rewards were examined in four rhesus monkeys performing a visual Go-Nogo decision task. ⋯ Results show that neurons in the primate striatum encoded cocaine-rewarded trials similar to juice-rewarded trials, except for (1) increased firing on cocaine-rewarded trials, (2) prolonged activation during delivery of i.v. cocaine infusion, and (3) differential firing in ventral (VStr cells) vs. dorsal (DStr cells) striatum cocaine-rewarded trials. Reciprocal activations of antithetic subpopulations of cells during different temporal intervals within the same trial suggest a functional interaction between processes that encode drug and natural rewards in the primate brain.
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The hypothalamic paraventricular nucleus (PVN) and angiotensin II (AngII) play critical roles in cardiovascular and neurohumoral regulation ascribed in part to vasopressin (VP) release. The AngII actions in the PVN are mediated largely through angiotensin II type 1 (AT1) receptors. However, there is indirect evidence that the functionally elusive central angiotensin II type 2 (AT2) receptors are also mediators of AngII signaling in the PVN. ⋯ AT2 receptor immunoreactivity in dendrites was commonly localized to cytoplasmic endomembranes, but was occasionally observed on extra- or peri-synaptic portions of the plasma membrane apposed by astrocytic processes or by unlabeled axon terminals. The labeled dendritic plasmalemmal segments containing AT2 receptors received asymmetric excitatory-type or more rarely symmetric inhibitory-type contacts from unlabeled axon terminals containing dense core vesicles, many of which are known to store neuropeptides. These results provide the first ultrastructural evidence that AT2 receptors in PVN neurons expressing VP and other neuromodulators are strategically positioned for surface activation by AngII and/or intracellular trafficking.
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I.c.v. administration of the peptide insulin-like growth factor-1 (IGF-1) has been shown to be an effective neuroprotective strategy in the brain of different animal models, a major advantage being the achievement of high concentrations of IGF-1 in the brain without altering serum levels of the peptide. In order to exploit this therapeutic approach further, we used high performance recombinant adenoviral (RAd) vectors expressing their transgene under the control of the potent mouse cytomegalovirus immediate early (mCMV) promoter, to transduce brain ependymal cells with high efficiency and to achieve effective release of transgenic IGF-1 into the cerebrospinal fluid (CSF). We constructed RAd vectors expressing either a chimeric green fluorescent protein fused to HSV-1 thymidine kinase (TK/GFP)(fus), or the cDNA encoding rat IGF-1, both driven by the mCMV promoter. ⋯ For tanycytes (TK/GFP)(fus) expression was evident in their cytoplasmic processes as they penetrated deep into the hypothalamic parenchyma. I.c.v. injection of RAd-IGF-1 induced high levels of IGF-1 in the CSF but not in serum. We conclude that the ependymal route constitutes an effective approach for implementing experimental IGF-1 gene therapy in the brain.
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Cerebral ischemia/reperfusion injury is characterized by the development of inflammatory response, in which vascular macrophages and endogenous microglia are involved. Recent studies showed marked induction of hematopoietic prostaglandin D synthase (HPGDS) after ischemic/reperfusion injury and its localization in microglia, but the molecular mechanism(s) of HPGDS actions in cerebral ischemia is not clear. To clarify the role of HPGDS in cerebral ischemia, C57BL/6 mice and bone marrow chimera mice with cerebral ischemia/reperfusion injury were treated with (4-benzhydryloxy-(1) {3-(1H-tetrazol-5-yl)-propyl}piperidine (HQL-79), a specific inhibitor of HPGDS. ⋯ HQL-79 reduced NeuN expression in the transition area and Iba1 expression (P<0.0001) in the ischemic peri- and penumbra area, but increased COX-2 (P<0.05) and NF-kB expression (P<0.05) in ischemic penumbra and increased formation of nitrotyrosine (P<0.0001) and iNOS (P<0.0001) in the ischemic core area at 72 h and 7 days after reperfusion. In EGFP chimera mice, HQL-79 increased the migration of Iba1/EGFP-positive bone marrow-derived monocytes/macrophages, and simultaneously upregulated iNOS expression in the ischemic core area (P<0.0001), but increased intrinsic microglia/macrophages in ischemic peri-area and penumbra (P<0.0001) at 72 h and 7 days after reperfusion, suggesting involvement of monocytes/macrophages in HQL-79-induced expansion of ischemic injury. Our results demonstrated that the neuroprotective effects of HPGDS in our model are mediated by suppression of activation and infiltration of inflammatory cells.
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The present study investigated the time course of segment and tone encoding in Chinese spoken production with an event-related brain potentials (ERPs) experiment. Native Chinese speakers viewed a series of pictures and made Go/noGo decisions along dimensions of segmental onset or tone information of picture names. ⋯ Moreover, the results of scalp distributions and onset latency patterns of the N200 effect on segmental and tonal decisions suggest that segmental and metrical encoding is relatively disassociated in Chinese spoken production. Our findings provide additional evidence from Chinese as a kind of non-alphabetic language concerning theories of phonological encoding based on alphabetic languages.