Characterization of deconditioning-update on fear memory attenuation.

Fear memory expression can be attenuated by updating the footshock perception during the plastic state induced by retrieval, from a strong unconditioned stimulus to a very weak one through deconditioning. In this process, the original fear association of the conditioned stimulus with the footshock is substituted by an innocuous stimulus and the animals no longer express a fear response. In the present study, we explore the boundaries of this deconditioning-update strategy by the characterization of this phenomenon. We found that there is an optimal mismatch between the footshock intensity delivered in the training and in the reactivation. Likewise, we characterized the temporal window that the protocol is efficient in hindering fear response. Our findings contribute to a better understanding of the limits in which deconditioning acts in attenuating fear memory, so that an optimized protocol using this strategy can be planned in order to deal with emotional disorders.

Effects of hippocampal IP3R inhibition on contextual fear memory consolidation, retrieval, reconsolidation and extinction.

Intracellular calcium stores (ICS) play a dynamic role in neuronal calcium (Ca2+) homeostasis both by buffering Ca2+ excess in the cytoplasm or providing an additional source of Ca2+ when concentration increase is needed. However, in spite of the large body of evidence showing Ca2+ as an essential second messenger in many signaling cascades underlying synaptic plasticity, the direct involvement of the intracellular Ca2+-release channels (ICRCs) in memory processing has been highly overlooked. Here we investigated the role of the ICRC inositol 1,4,5-trisphosphate receptor (IP3R) activity during different memory phases using pharmacological inhibition in the dorsal hippocampus during contextual fear conditioning. We first found that post-training administration of the IP3R antagonist 2-aminoethyl diphenylborinate (2-APB) impaired memory consolidation in a dose and time-dependent manner. Inhibiting IP3Rs also disrupted memory retrieval. Contextual fear memory reconsolidation or extinction, however, were not sensitive to IP3R blockade. Taken together, our results indicate that hippocampal IP3Rs play an important role in contextual fear memory consolidation and retrieval.

Anti-RAGE antibody selectively blocks acute systemic inflammatory responses to LPS in serum, liver, CSF and striatum.

Systemic inflammation induces transient or permanent dysfunction in the brain by exposing it to soluble inflammatory mediators. The receptor for advanced glycation endproducts (RAGE) binds to distinct ligands mediating and increasing inflammatory processes. In this study we used an LPS-induced systemic inflammation model in rats to investigate the effect of blocking RAGE in serum, liver, cerebrospinal fluid (CSF) and brain (striatum, prefrontal cortex, ventral tegmental area and substantia nigra). Intraperitoneal injection of RAGE antibody (50µg/kg) was followed after 1h by a single LPS (5mg/kg) intraperitoneal injection. Twenty-four hours later, tissues were isolated for analysis. RAGE antibody reduced LPS-induced inflammatory effects in both serum and liver; the levels of proinflammatory cytokines (TNF-α, IL-1ß) were decreased and the phosphorylation/activation of RAGE downstream targets (ERK1/2, IκB and p65) in liver were significantly attenuated. RAGE antibody prevented LPS-induced effects on TNF-α and IL-1ß in CSF. In striatum, RAGE antibody inhibited increases in IL-1ß, Iba-1, GFAP, phospho-ERK1/2 and phospho-tau (ser202), as well as the decrease in synaptophysin levels. These effects were caused by systemic RAGE inhibition, as RAGE antibody did not cross the blood-brain barrier. RAGE antibody also prevented striatal lipoperoxidation and activation of mitochondrial complex II. In conclusion, blockade of RAGE is able to inhibit inflammatory responses induced by LPS in serum, liver, CSF and brain.