Molecular brain
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The neurotransmitter serotonin, involved in the regulation of pain and emotion, is critically regulated by the 5-HT1A autoreceptor and the serotonin transporter (5-HTT). Polymorphisms of these genes affect mood and endogenous pain modulation, both demonstrated to be altered in fibromyalgia subjects (FMS). Here, we tested the effects of genetic variants of the 5-HT1A receptor (CC/G-carriers) and 5-HTT (high/intermediate/low expression) on mood, pain sensitivity, cerebral processing of evoked pain (functional MRI) and concentrations of GABA and glutamate (MR spectroscopy) in rostral anterior cingulate cortex (rACC) and thalamus in FMS and healthy controls (HC). ⋯ No significant effects were seen for glutamate or in rACC. To our knowledge, this is the first report of this serotonergic gene-to-gene interaction associated with mood, both among FMS (depression) and across groups (anxiety). Additionally, our findings provide evidence of an association between the serotonergic system and thalamic GABA concentrations, with individuals possessing genetically inferred high serotonergic signalling exhibiting the highest GABA concentrations, possibly enhancing GABAergic inhibitory effects via 5-HT.
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The anterior cingulate cortex (ACC) serves as a critical hub for the anxiety and pain perception. The large-conductance Ca2+-activated potassium channels, or BKCa channels, are ubiquitously expressed throughout the central nervous system including the cingulate cortex. However, what changes of cortical BKCa channels undergo in the ACC remains unknown in pain-related anxiety. ⋯ Meanwhile, NS1619 reversed the enhanced AMPA receptor-mediated spontaneous excitatory postsynaptic current (sEPSC) frequency and the attenuated PPR of ACC neurons in mCCD rats. Local activation of BKCa channels in the ACC reversed mechanical allodynia and anxiety-like behaviors. These results suggest that the upregulation of postsynaptic and presynaptic BKCa β4 subunit may contribute to neuronal hyperexcitability and the enhanced synaptic transmission in the ACC in neuropathic pain state, and then may result in anxiety-like behavior induced by neuropathic pain.
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FKBP5 encodes the FK506 binding protein 5, a glucocorticoid receptor (GR) binding protein known to play an important role in the physiological stress response. However, results from previous studies examining the association between common variants of FKBP5 and stress have been inconsistent. To investigate whether the loss of FKBP5 affects the stress response, we examined the behavior of mice following the induction of chronic restraint stress between homozygous wild-type and Fkbp5 knock-out mice. ⋯ Weighted gene co-expression network analysis identified 60 characteristic modules that correlated with stress or the FKBP5 genotype. Among them, M55 showed a gene expression pattern consistent with behavioral changes after stress exposure, and the gene ontology analysis revealed that this was involved in nervous system development, gland morphogenesis, and inflammatory response. These results suggest that FKBP5 may be a crucial factor for the stress response, and that transcriptomic data can provide insight into stress-related pathophysiology.
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The alpha1 (α1) subunit of the sodium/potassium ATPase (i.e., Na+/K+-ATPase α1), the prototypical sodium pump, is expressed in each eukaryotic cell. They pump out three sodium ions in exchange for two extracellular potassium ions to establish a cellular electrochemical gradient important for firing of neuronal and cardiac action potentials. We hypothesized that myosin (myo or myh) motor proteins might interact with Na+/K+-ATPase α1 subunits in order for them to play an important role in the transport and trafficking of sodium pump. ⋯ However, recombinant myh9, myh10 and myh14 mutants having reduced or no actin binding ability, as a result of loss of their actin binding sites, displayed greatly reduced or null interaction with Na+/K+-ATPase α1 subunits. These results suggested the involvement of the actin binding site, but not tail regions, of NMHC-IIs in their interaction with Na+/K+-ATPase α1 subunits. Overall these results suggest a role for these diverse myosins in the trafficking and transport of sodium pump in neuronal and non-neuronal tissues.
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Memory consolidation, reconsolidation, and extinction have been shown to share similar molecular signatures, including new gene expression. Calpain is a Ca2+-dependent protease that exerts its effects through the proteolytic cleavage of target proteins. Neuron-specific conditional deletions of calpain 1 and 2 impair long-term potentiation in the hippocampus and spatial learning. ⋯ Importantly, the systemic administration of ALLN inhibited the induction of c-fos in the hippocampus, which is observed when memory is consolidated. Our observations showed that hippocampal calpain is required for the consolidation and reconsolidation of contextual fear memory. Further, the results suggested that calpain contributes to the regulation of new gene expression that is necessary for these memory processes as a regulator of Ca2+-signal transduction pathway.