Central relaxin-3 receptor (RXFP3) activation increases ERK phosphorylation in septal cholinergic neurons and impairs spatial working memory.

The medial septum/diagonal band (MS/DB) is a relay region connecting the hypothalamus and brainstem with the hippocampus, and both the MS/DB and dorsal/ventral hippocampus receive strong topographic GABA/peptidergic projections from the nucleus incertus of the pontine tegmentum. The neuropeptide relaxin-3, released by these neurons, is the cognate ligand for a Gi/o-protein-coupled receptor, RXFP3, which is highly expressed within the MS/DB, and both cholinergic and GABAergic neurons in this region of rat brain receive relaxin-3 positive terminals/boutons. Comprehensive in vitro studies have demonstrated that a range of cell signaling pathways can be altered by RXFP3 stimulation, including inhibition of forskolin-activated cAMP levels and activation of ERK phosphorylation. In this study we investigated whether intracerebroventricular (icv) injection of RXFP3-A2, a selective relaxin-3 receptor agonist, altered ERK phosphorylation levels in the MS/DB of adult male rats. In addition, we assessed the neurochemical phenotype of phosphorylated (p) ERK-positive neurons in MS/DB after RXFP3-A2 administration by dual-label immunostaining for pERK and key neuronal markers. RXFP3-A2 injection significantly increased pERK levels in MS/DB, compared to vehicle at 20 and 90 min post-injection. In addition, icv injection of RXFP3-A2 increased the number of cells expressing pERK in the MS/DB after 90 min, with increases detected in cholinergic, but not GABAergic neurons. Moreover, we found that septal cholinergic neurons express RXFP3 and that icv infusions of RXFP3-A2 impaired alternation in a spatial working memory behavioral paradigm. The presence of the receptor and the specific RXFP3-related activation of the MAPK/ERK pathway in MS/DB cholinergic neurons identifies them as a key target of ascending relaxin-3 projections with implications for the acute and chronic inhibition of cholinergic neuron activity/function by relaxin-3/RXFP3 signaling.This research was supported by a predoctoral fellowship (FPI-UJI: PREDOC/2014/35) to HAG; a traineeship fellowship (UJI P1·1A2014-06) to AGA; the FP7-PEOPLE-IRSES PIRSES-GA-2012-318997 NEUREN project to ALG and FEO-B; NHMRC (Australia) project grants (1027522, 1026939) and a Brain and Behavior Research Foundation (USA) NARSAD Independent Investigator Award to ALG; Generalitat Valenciana (AICO/2015/042) project grant and Universitat Jaume I (P1·1A2014-06) project grant to AMS

The effect of abscisic acid chronic treatment on neuroinflammatory markers and memory in a rat model of high-fat diet induced neuroinflammation

Background Western diet and lifestyle are associated with overweight, obesity, and type 2 diabetes, which, in turn, are correlated with neuroinflammation processes. Exercise and a healthy diet are important in the prevention of these disorders. However, molecules inhibiting neuroinflammation might also be efficacious in the prevention and/or treatment of neurological disorders of inflammatory etiology. The abscisic acid (ABA) is a phytohormone involved in hydric-stress responses. This compound is not only found in plants but also in other organisms, including mammals. In rodents, ABA can play a beneficial role in the regulation of peripheral immune response and insulin action. Thus, we hypothesized that chronic ABA administration might exert a protective effect in a model of neuroinflammation induced by high-fat diet (HFD). Methods Male Wistar rats were fed with standard diet or HFD with or without ABA in the drinking water for 12 weeks. Glucose tolerance test and behavioral paradigms were performed to evaluate the peripheral and central effects of treatments. One-Way ANOVA was performed analyzed statistical differences between groups. Results The HFD induced insulin resistance peripherally and increased the levels of proinflammatory markers in in the brain. We observed that ABA restored glucose tolerance in HFD-fed rats, as expected. In addition, chronic ABA treatment rescued cognitive performance in these animals, while not affecting control diet fed animals. Moreover, it counteracted the changes induced by HFD in the hypothalamus; microglia activations and TNFα mRNA levels. Conclusion These results suggest that ABA might become a new therapeutic molecule improving the neuroinflammatory status and insulin resistance.This work was supported by Plan Propi Universitat Jaume I P1.1A2014-06 and GVA AICO/2015/042 to AMSP