Neuroscience
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Serotonin is a neurotransmitter that plays a role in regulating activities such as sleep, appetite, mood and substance abuse disorders; serotonin receptors 5-HT2AR and 5-HT2CR are active within pathways associated with substance abuse. It has been suggested that 5-HT2AR and 5-HT2CR may form a dimer that affects behavioral processes. Here we study the coevolution of residues in 5-HT2AR and 5-HT2CR to identify potential interactions between residues in both proteins. ⋯ We also discuss how co-expression of the receptors suggests the predicted interaction is functional. Finally, we analyze how several single nucleotide polymorphisms for the 5-HT2AR and 5-HT2CR genes affect their interaction. Our findings are the first to characterize the binding interface of 5-HT2AR/5-HT2CR and indicate a correlation between this interface and location of SNPs in both proteins.
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Calpain-mediated tau cleavage into the neurotoxic tau45-230 fragment plays an important role in Alzheimer's disease (AD). This tau fragment accumulates mainly in the cytoplasm of degenerating neurons. However, subcellular localization studies indicated that a pool of tau45-230 associates with the cytoskeleton in hippocampal neurons. ⋯ The data obtained also showed a significant reduction in actin filaments in tau45-230-expressing neurons. These changes in microtubules and actin filaments correlated with delayed neurite elongation and axonal differentiation in the presence of this tau fragment. Together, these results suggest that tau45-230 could exert its toxic effects, at least in part, by modifying the composition of the neuronal cytoskeleton and impairing neurite elongation in neurons undergoing degeneration.
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Ghrelin is an important orexigenic brain-gut hormone that regulates feeding, metabolism and glucose homeostasis in human and rodents at multiple levels. Ghrelin functions by binding to its receptor, the growth hormone secretagogue receptor 1a (GHS-R1a), which is widely expressed both inside and outside of the brain. Both acute and chronic calorie restrictions (CRs) were reported to increase endogenous ghrelin levels and lead to beneficial effects on brain functions, including anti-anxiety effects, anti-depressive effects, and memory improvement. ⋯ This effect was abolished by a GHS-R1a antagonist, suggesting a GHS-R1a dependent mechanism. Ad-libitum refeeding masked behavioral responses induced by acute CR in both Ghsr-/- and Ghsr+/+ mice. Altogether, our findings indicate that acute and chronic CRs mitigate anxiety- and despair-like behaviors with different physiological mechanisms, with the former being dependent on endogenous ghrelin release and GHS-R1a signaling, while the latter may not be.
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Reward-paired optogenetic manipulation of dopamine neurons can increase or decrease behavioral responding to antecedent cues when subjects have the opportunity for new learning, in accordance with a dopamine-mediated error learning signal. Here we examined the impact of reward-paired dopamine neuron inhibition on behavioral responding to reward-predictive cues after subjects had learned. We trained male TH-IRES-Cre mice to lever press for food reward in a progressive ratio procedure, a 2-cue choice procedure, or when continuously reinforced; in all procedures, completion of the response requirement was signaled by an auditory cue presented prior to food delivery. ⋯ Extinction-like behavioral responding was selective for learned associations: it was observed in the 2-cue choice procedure in which each subject was trained on two associations and inhibition was paired with reward for only one of the associations. Thus, inhibition during reward receipt can decrease responding to reward-predictive cues, sharing some features of behavioral extinction. These findings suggest changes in mesolimbic dopaminergic transmission at the time of experienced reward impacts subsequent responding to cues in well-trained subjects as predicted for a learning signal.
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A single session of aerobic exercise may offer one means to "prime" motor regions to be more receptive to the acquisition of a motor skill; however, the mechanisms whereby this priming may occur are not clear. One possible explanation may be related to the post-translational modification of plasticity-related receptors and their associated intracellular signaling molecules, given that these proteins are integral to the development of synaptic plasticity. In particular, phosphorylation governs the biophysical properties (e.g., Ca2+ conductance) and the migratory patterns (i.e., trafficking) of plasticity-related receptors by altering the relative density of specific receptor subunits at synapses. ⋯ We observed a robust (1.2-2.0× greater than sedentary) increase in tyrosine phosphorylation of AMPA (GluA1,2) and NMDA (GluN2A,B) receptor subunits, and a clear indication that exercise preferentially affects pPKA over pCaMKII. The changes were found, specifically, following moderate, but not maximal, acute aerobic exercise in both motor cortex and hippocampus. Given the requirement for these proteins during the early phases of plasticity induction, the possibility exists that exercise-induced priming may occur by altering the phosphorylation of plasticity-related proteins.