Neuroscience
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Chromatin regulation, in particular ATP-dependent chromatin remodelers, have previously been shown to be important in the regulation of reward-related behaviors in animal models of mental illnesses. Here we demonstrate that BAZ1A, an accessory subunit of the ISWI family of chromatin remodeling complexes, is downregulated in the nucleus accumbens (NAc) of mice exposed repeatedly to cocaine and of cocaine-addicted humans. ⋯ Furthermore, we investigate nucleosome repositioning genome-wide by conducting chromatin immunoprecipitation (ChIP)-sequencing for total H3 in NAc of control mice and after repeated cocaine administration, and find extensive nucleosome occupancy and shift changes across the genome in response to cocaine exposure. These findings implicate BAZ1A in molecular and behavioral plasticity to cocaine and offer new insight into the pathophysiology of cocaine addiction.
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To understand the behavioral consequences of intermittent anticipatory stress resulting from threats without accompanying physiological challenges, we developed a semi-naturalistic rodent housing and foraging environment that can include threats that are unpredictable in timing. Behavior is automatically recorded while rats forage for food or water. Over three weeks, the threats have been shown to elicit risk assessment behaviors, increase defensive burying and increase adrenal gland weight. ⋯ There was an increase in COX activity in the hypothalamic premammillary dorsal nucleus (PMD) and lateral septum (LS), whereas a decrease was observed in the periaqueductal gray (PAG) and CA3 region of the hippocampus. There were no significant differences in the anterior cingulate cortex, prefrontal cortex, striatum or motor cortex. The sites with changes in metabolic capacity are candidates for the sites of plasticity that may underlie the behavioral adaptations to intermittent threats.
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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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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.