Neuroscience
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Movement dysfunction in Parkinson's disease (PD) is caused by the degeneration of dopaminergic (DA) neurons in the substantia nigra (SN). Here, we established a method for voxel-based morphometry (VBM) and automatic tissue segmentation of the marmoset monkey brain using a 7-T animal scanner and applied the method to assess DA degeneration in a PD model, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated animals, with tyrosine-hydroxylase staining. The most significant decreases of local tissue volume were detected in the bilateral SN of MPTP-treated marmoset brains (-53.0% in right and -46.5% in left) and corresponded with the location of DA neurodegeneration found in histology (-65.4% in right). ⋯ VBM using 7-T MRI was effective in detecting volume loss in the SN of the PD-model marmoset. This study provides a potential basis for the application of VBM with ultra-high field MRI in the clinical diagnosis of PD. The developed method may also offer value in automatic whole-brain evaluation of structural changes for the marmoset monkey.
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Insights into the stimulatory mechanism of 2-aminoethoxydiphenyl borate on TREK-2 potassium channel.
2-Aminoethoxydiphenyl borate (2-APB) has been recently identified as a common agonist of TWIK-related K(+) channel (TREK)/TRAAK channels, a subfamily of two-pore domain K(+) (K2P) channels. TREK-2 displays much higher sensitivity to 2-APB compared with TREK-1, despite that these two channels share the highest homology among K2P members. However, the structural basis for their difference in response to 2-APB still remains unknown. ⋯ Finally, we demonstrated that key residues or domains required for 2-APB activation are not involved in the gating mechanism of the selectivity filter. In summary, we reveal a unique modulatory model of TREK-2-Ct that distinguishes it from TREK-1 in high sensitivity to 2-APB. The cooperation of the non-conserved residues within the proximal Ct of TREK-2 plays a dominant role in the 2-APB-induced channel opening, whereas the distal Ct negatively regulates the process.
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Survivin, a unique member of the inhibitor of the apoptosis protein (IAP) family, has been suggested to play a crucial role in promoting the cell cycle and mediates mitosis during embryonic development. However, the role of survivin following traumatic brain injury (TBI) in adult neurogenesis and apoptosis in the mouse dentate gyrus (DG) remains only partially understood. We adopted adenovirus-mediated RNA interference (RNAi) as a means of suppressing the expression of survivin and observed its effects on adult regeneration and neurological function in mice after brain injury. ⋯ Furthermore, downregulation of survivin results in a significant increase in programmed cell death in the DG, as assessed using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and 4',6-diamidino-2-phenylindole (DAPI) double staining. The Morris water maze (MWM) test was adopted to evaluate neurological function, which confirmed that knockdown of survivin worsened the memory capacity that was already compromised following TBI. Survivin in adult mice brains after TBI can be successfully down-regulated by RNAi, which inhibited adult hippocampal neurogenesis, promoted apoptotic cell death, and resulted in a negative role in the recovery of dysfunction following injury.
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High-voltage-activated (HVA) calcium channels play an important role in synaptic transmission. Activation of Mas-related G-protein-coupled receptor subtype C (MrgC; mouse MrgC11, rat homolog rMrgC) inhibits HVA calcium current (ICa) in small-diameter dorsal root ganglion (DRG) neurons, but the intracellular signaling cascade underlying MrgC agonist-induced inhibition of HVA ICa in native DRG neurons remains unclear. To address this question, we conducted patch-clamp recordings in MrgA3-eGFP-wild-type mice, in which most MrgA3-eGFP(+) DRG neurons co-express MrgC11 and can be identified for recording. ⋯ The inhibition of HVA ICa in MrgA3-eGFP(+) neurons by JHU58 (100nM) was partially reduced by pretreatment with a Gβγ blocker (gallein, 100μM). However, applying a depolarizing prepulse and blocking the Gαi and Gαs pathways with pertussis toxin (PTX) (0.5μg/mL) and cholera toxin (CTX) (0.5μg/mL), respectively, had no effect. These findings suggest that activation of MrgC11 may inhibit HVA ICa in mouse DRG neurons through a voltage-independent mechanism that involves activation of the PLC, but not Gαi or Gαs, pathway.
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Ghrelin is a potent orexigenic hormone that acts in the central nervous system to stimulate food intake via the growth hormone secretagogue receptor (GHSR) that is abundantly expressed in the ventral tegmental area (VTA). Not only does ghrelin modulate feeding behavior via a homeostatic mechanism, but numerous studies have identified ghrelin as a key regulator of reward-based hedonic feeding behaviors. Nutritional states influence ghrelin and GHSR expression as well as the behavioral sensitivity to reward-inducing stimuli. ⋯ Moreover, our data showed that the injection of 1, 2, and 4μg of ghrelin in the VTA, enhanced fasting-induced hyperphagia on HFD in a dose-related manner following a 21-h food restriction as well as a 24-h body weight gain. Conversely, hyperphagia on HFD that is potentiated by ghrelin could be blocked by pretreatment with a 10-μg D-Lys3-GHRP-6 intra-VTA microinjection. Collectively, these data demonstrate that ghrelin signaling at the VTA level mediates both reward-based eating and fasting-induced hyperphagia and provides a primary target for the control of the intake of rewarding food.