Closest horizons of Hsp70 engagement to manage neurodegeneration.

This is the final version. Available on open access from Frontiers Media via the DOI in this record. Our review seeks to elucidate the current state-of-the-art in studies of 70-kilodalton-weighed heat shock proteins (Hsp70) in neurodegenerative diseases (NDs). The family has already been shown to play a crucial role in pathological aggregation for a wide spectrum of brain pathologies. However, a slender boundary between a big body of fundamental data and its implementation has only recently been crossed. Currently, we are witnessing an anticipated advancement in the domain with dozens of studies published every month. In this review, we briefly summarize scattered results regarding the role of Hsp70 in the most common NDs including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We also bridge translational studies and clinical trials to portray the output for medical practice. Available options to regulate Hsp70 activity in NDs are outlined, too.Russian Science Foundatio

CRF1-R Activation of the Dynorphin/Kappa Opioid System in the Mouse Basolateral Amygdala Mediates Anxiety-Like Behavior

Stress is a complex human experience and having both rewarding and aversive motivational properties. The adverse effects of stress are well documented, yet many of underlying mechanisms remain unclear and controversial. Here we report that the anxiogenic properties of stress are encoded by the endogenous opioid peptide dynorphin acting in the basolateral amygdala. Using pharmacological and genetic approaches, we found that the anxiogenic-like effects of Corticotropin Releasing Factor (CRF) were triggered by CRF1-R activation of the dynorphin/kappa opioid receptor (KOR) system. Central CRF administration significantly reduced the percent open-arm time in the elevated plus maze (EPM). The reduction in open-arm time was blocked by pretreatment with the KOR antagonist norbinaltorphimine (norBNI), and was not evident in mice lacking the endogenous KOR ligand dynorphin. The CRF1-R agonist stressin 1 also significantly reduced open-arm time in the EPM, and this decrease was blocked by norBNI. In contrast, the selective CRF2-R agonist urocortin III did not affect open arm time, and mice lacking CRF2-R still showed an increase in anxiety-like behavior in response to CRF injection. However, CRF2-R knockout animals did not develop CRF conditioned place aversion, suggesting that CRF1-R activation may mediate anxiety and CRF2-R may encode aversion. Using a phosphoselective antibody (KORp) to identify sites of dynorphin action, we found that CRF increased KORp-immunoreactivity in the basolateral amygdala (BLA) of wildtype, but not in mice pretreated with the selective CRF1-R antagonist, antalarmin. Consistent with the concept that acute stress or CRF injection-induced anxiety was mediated by dynorphin release in the BLA, local injection of norBNI blocked the stress or CRF-induced increase in anxiety-like behavior; whereas norBNI injection in a nearby thalamic nucleus did not. The intersection of stress-induced CRF and the dynorphin/KOR system in the BLA was surprising, and these results suggest that CRF and dynorphin/KOR systems may coordinate stress-induced anxiety behaviors and aversive behaviors via different mechanisms

Absence of M-Ras modulates social behavior in mice

Background: The molecular mechanisms that determine social behavior are poorly understood. Pheromones play a critical role in social recognition in most animals, including mice, but how these are converted into behavioral responses is largely unknown. Here, we report that the absence of the small GTPase M-Ras affects social behavior in mice. Results: In their interactions with other males, Mras −/− males exhibited high levels of territorial aggression and social investigations, and increased fear-related behavior. They also showed increased mating behavior with females. Curiously, increased aggression and mating behaviors were only observed when Mras −/− males were paired with Mras −/− partners, but were significantly reduced when paired with wild-type (WT) mice. Since mice use pheromonal cues to identify other individuals, we explored the possibility that pheromone detection may be altered in Mras −/− mice. Unlike WT mice, Mras −/− did not show a preference for exploring unfamiliar urinary pheromones or unfamiliar isogenic mice. Although this could indicate that vomeronasal function and/or olfactory learning may be compromised in Mras −/− mice, these observations were not fully consistent with the differential behavioral responses to WT and Mras −/− interaction partners by Mras −/− males. In addition, induction of c-fos upon pheromone exposure or in response to mating was similar in WT and Mras −/− mice, as was the ex vivo expansion of neural progenitors with EGF. This indicated that acute pheromone detection and processing was likely intact. However, urinary metabolite profiles differed between Mras −/− and WT males. Conclusions: The changes in behaviors displayed by Mras −/− mice are likely due to a complex combination of factors that may include an inherent predisposition to increased aggression and sexual behavior, and the production of distinct pheromones that could override the preference for unfamiliar social odors. Olfactory and/or social learning processes may thus be compromised in Mras −/− mice.Other UBCReviewedFacult