Neuroscience
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The molecular sensor of innocuous (painless) cold sensation is well-established to be transient receptor potential cation channel, subfamily M, member 8 (TRPM8). However, the role of transient receptor potential cation channel, subfamily A, member 1 (TRPA1) in noxious (painful) cold sensation has been controversial. We find that TRPA1 channels contribute to the noxious cold sensitivity of mouse somatosensory neurons, independent of TRPM8 channels, and that TRPA1-expressing neurons are largely non-overlapping with TRPM8-expressing neurons in mouse dorsal-root ganglia (DRG). ⋯ The combination of these two factors, combined with the relatively weak agonist-like activity of cold temperature on TRPA1 channels, partially explains why few TRPA1-expressing neurons respond to cold. Blocking KV channels also reveals another subclass of noxious cold-sensitive DRG neurons that do not express TRPM8 or TRPA1 channels. Altogether, the results of this study provide novel insights into the cold-sensitivity of different subclasses of somatosensory neurons.
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Comprehensive knowledge of the synaptic plasma membrane (SPM) proteome of a distinct brain region in a defined pathological state would greatly advance the understanding of the underlying biology of synaptic plasticity. The development of innovative approaches for studying the SPM proteome of small brain tissues is highly desired. This study presents a suitable protocol that integrates biotinylation-based affinity capture of cell surface-exposed proteins, isolation of synaptosomes, and biochemical extraction of SPM proteins from biotinylated hippocampal slices. ⋯ Analysis of the interaction network using STRING indicated that the two groups showed a relatively strong functional correlation. Using MCODE analysis, we observed that 65 nonclassical SPM proteins formed 12 highly interconnected clusters with 47 classical SPM proteins, suggesting that they were the more likely SPM candidates. Taken together, the results of this study provide an integrated tool for analyzing the SPM proteome of small brain tissues, as well as a dataset of putative novel SPM proteins to improve the understanding of hippocampal synaptic plasticity.
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Numerous clinical and experimental observations suggest that deficient neuronal signaling in the globus pallidus externa (GPe) is integral to both Parkinson's disease (PD) and dystonia. In our previous studies in jaundiced dystonic rats, widespread silencing of neurons in GP (rodent equivalent to GPe) preceded and persisted during dystonic motor activity. We therefore hypothesized that on a background of slow and highly irregular and bursty neuronal activity in GP, cortical motor drive produces profound inhibition of GP as the basis for action-induced dystonia in Gunn rats. ⋯ Next, we compared the deep brain stimulation contact sites in the GP internus used to treat patients with PD (n=21 implants in 12 successive patients) versus dystonia (n=16 implants in nine patients) and found the efficacious territory for ameliorating PD to be located chiefly dorsal to that for dystonia. The comparative distribution for treating PD versus dystonia was therefore anatomically consistent with that for inducing these features via GP lesions in rodents. Our collective findings thus suggest that dystonia and parkinsonism are differentially produced by pathological silencing of GPe neurons along distinct motor sub-circuits, resulting in disparate pathological basal ganglia output signaling.
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The group II metabotropic glutamate receptors mGluR2 and mGluR3 are key modulators of glutamatergic neurotransmission. In order to identify novel Group II metabotropic glutamate receptor (mGluR)-interacting partners, we screened the C-termini of mGluR2 and mGluR3 for interactions with an array of PDZ domains. These screens identified the Na+/H+ exchanger regulatory factors 1 and 2 (NHERF-1 & -2) as candidate interacting partners. ⋯ Electron microscopic analyses revealed that Group II mGluRs were primarily expressed in glia and unmyelinated axons in WT, NHERF-1 and NHERF-2 KO mice, but the relative proportion of labeled axons over glial processes was higher in NHERF-2 KO mice than in controls and NHERF-1 KO mice. Interestingly, our anatomical studies also revealed that loss of either NHERF protein results in ventriculomegaly, which may be related to the high incidence of hydrocephaly that has previously been observed in NHERF-1 KO mice. Together, these studies support a role for NHERF-1 and NHERF-2 in regulating the distribution of Group II mGluRs in the murine brain, while conversely the effects of the mGluR2/3 PDZ-binding motifs on receptor signaling are likely mediated by interactions with other PDZ scaffold proteins beyond the NHERF proteins.
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Even when performing invariant behavioral task repeatedly on invariant physical stimuli, our behavioral performance always changes as manifested in varying response times (RTs), which is associated with fluctuations in attentional control and thus the underlying self-organization states of the human brain. In a visuospatial task of the present fMRI study, physical stimuli differed across six levels of spatial scope, but were kept invariant within each level. The slower RTs with larger spatial area attended suggested higher demands on visuospatial attention. ⋯ These findings thus for the first time suggested that the within-level variance of attentional control corresponded to dynamic changes in the frontoparietal network and the DMN, in terms of not only the height but also the latency of neural activity. Moreover, although the two networks are anti-correlated in terms of the height of neural activity, they are tightly coupled in terms of the temporal dynamics. Based on the current results, we proposed a tentative hypothesis on the optimal working mode of the frontoparietal attentional control system in the human brain: even a lower height of neural activity in frontoparietal network can significantly improve behavioral performance as long as it starts relatively early.