Neuroscience
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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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Mesolimbic dopamine has been implicated in reward learning. Fischbach-Weiss and Janak (this issue) use optogenetics to attenuate dopamine signaling and study its role in cue-driven motivated behavior.
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Neuroinflammation is considered to be a critical component in the pathological process after intracerebral hemorrhage (ICH). Microglia are the foremost and earliest inflammatory cells participating in the pathological process of ICH. AdipoRon is the agonist of AdipoR1 (Adiponectin receptor 1), which enhances P-AMPK (phosphorylated AMP-activated protein kinase) activation. ⋯ The in vitro experiment showed that AdipoRon not only directly inhibited neuronal ROS overproduction, but also indirectly decreased the neuronal death in a transwell co-culture system. In summary, AdipoRon protects against ICH induced injury through promoting M2a microglia polarization and reducing neuronal death. These effects of AdipoRon rely on the activation of AdipoR1-AMPK signaling pathway.
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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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Explanations of memory-guided navigation in rodents typically suggest that cue- and place-based navigations are independent aspects of behavior and neurobiology. The results of many experiments show that hippocampal damage causes both anterograde and retrograde amnesia (AA; RA) for place memory, but only RA for cue memory. In the present experiments, we used a concurrent cue-place water task (CWT) to study the effects of hippocampal damage before or after training on cue- and place-guided navigation, and how cue and place memory interact in damaged and control rats. ⋯ By contrast to these anterograde effects, damage made after training causes RA for cue choice accuracy and latency to navigate to the correct cue. In addition, the extent of hippocampal damage predicted impairments in choice accuracy when lesions were made after training. These data extend previous work on the role of the hippocampus in cue and place memory-guided navigation, and show that the hippocampus plays an important role in both aspects of memory and navigation when present during the learning experience.