Abscisic Acid Supplementation Rescues High Fat Diet-Induced Alterations in Hippocampal Inflammation and IRSs Expression

Accumulated evidence indicates that neuroinflammation induces insulin resistance in the brain. Moreover, both processes are intimately linked to neurodegenerative disorders, including Alzheimer’s disease. Potential mechanisms underlying insulin resistance include serine phosphorylation of the insulin receptor substrate (IRS) or insulin receptor (IR) misallocation. However, only a few studies have focused on IRS expression in the brain and its modulation in neuroinflammatory processes. This study used the high-fat diet (HFD) model of neuroinflammation to study the alterations of IR, an insulin-like growth factor receptor (IGF1R) and IRS expressions in the hippocampus. We observed that HFD effectively reduced mRNA and protein IRS2 expression. In contrast, a HFD induced the upregulation of the IRS1 mRNA levels, but did not alter an IR and IGF1R expression. As expected, we observed that a HFD increased hippocampal tumor necrosis factor alpha (TNFα) and amyloid precursor protein (APP) levels while reducing brain-derived neurotrophic factor (BDNF) expression and neurogenesis. Interestingly, we found that TNFα correlated positively with IRS1 and negatively with IRS2, whereas APP levels correlated positively only with IRS1 but not IRS2. These results indicate that IRS1 and IRS2 hippocampal expression can be affected differently by HFD-induced neuroinflammation. In addition, we aimed to establish whether abscisic acid (ABA) can rescue hippocampal IRS1 and IRS2 expression, as we had previously shown that ABA supplementation prevents memory impairments and improves neuroinflammation induced by a HFD. In this study, ABA restored HFD-induced hippocampal alterations, including IRS1 and IRS2 expression, TNFα, APP, and BDNF levels and neurogenesis. In conclusion, this study highlights different regulations of hippocampal IRS1 and IRS2 expression using a HFD, indicating the important differences of these scaffolding proteins, and strongly supports ABA therapeutic effects

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

Extinción de memorias condicionadas asociadas a la administración de drogas de abuso

Treball Final de Grau en Psicologia. Codi: PS1048. Curs 2013-2014Las señales contextuales previamente asociadas al consumo de una droga juegan un papel fundamental en el “craving” o deseo de volver a consumir y, por tanto, en las recaídas. Se han desarrollado estrategias, como la facilitación de la extinción o la disrupción de la reconsolidación de la memoria, para prevenir las recaídas en sujetos abstinentes. Su objetivo es reducir o bloquear la capacidad de las memorias patológicas relacionadas con los estímulos ambientales asociados a la droga de promover la búsqueda y consumo de la droga. A nivel farmacológico, uno de los sistemas objeto de estudio es el sistema noradrenérgico y, concretamente, los receptores β-adrenérgicos. En este estudio, hemos examinado si un estímulo contextual (tipo de suelo -barras o agujeros- de las cajas de actividad) es capaz de adquirir, tras su asociación con cocaína durante un procedimiento de sensibilización locomotora, las propiedades motivadoras y reforzantes de la droga convirtiéndose así en estímulo condicionado (EC).Exposure to contextual cues previously associated with drugs of abuse often induces craving and relapse in abstinent subjects. Different treatments and strategies, such as facilitation of extinction or disruption of memory reconsolidation, have been developed to interfere with drug-associated pathological memories related to environmental stimuli. Pharmacological manipulations targeting the noradrenergic system have been use to increase the efficacy of the behavioral strategies. The current study examined whether the floor type (grid or hole) of the activity chambers could acquire conditioned stimulus properties by its association with cocaine during a locomotor sensitization procedure

Neuroinflammation and insulin resistance underly cognitive impairment. Sex differences and potential treatments

Neuroinflammation and insulin resistance are two correlated processes. Abscisic acid(ABA) is a phytohormone also found in mammals. In a model of neuroinflammation induced by high fat diet(HFD), ABA administration rescued memory alterations and prevented pro-inflammatory markers’ increase. Furthermore, ABA restored the HFD-induced changes in insulin receptor substrates, IRS1 and IRS2. Inflammation has been proposed a contributing factor in attention-deficit-hyperactivity-disorder(ADHD). In a pilot study, female and male mice seem to display differences in ADHD symptomatology. ABA administration appeared to also affect differentially males and females. The role of IRS1 and IRS2 isolated from inflammation has not been fully established.We used AAV expressing shRNA targeting IRS1 into hippocampus of female and male rats. Female rats showed spatial and recognition memory deficits but males only showed spatial memory alterations. In medial septum, we observed reduced synaptophysin levels on shIRS1-AAV fibers, suggesting impaired synaptic plasticity. Thus, IRS1 is required for proper neuronal activity.Neuroinflamación y resistencia a insulina son dos procesos correlacionados. Ácido abscísico(ABA) es una fitohormona que también está en mamíferos. En un modelo de neuroinflamación inducida por dieta alta en grasa, ABA mejora alteraciones en memoria y previene el aumento de marcadores proinflamatorios. Además, ABA restaura los cambios en sustratos-del-receptor-de-insulina, IRS1 e IRS2. La inflamación se ha propuesto como factor que contribuye al trastorno-por-déficit-de-atención-e-hiperactividad. En un estudio piloto, ratones hembra y macho parecen presentar diferencias en sintomatología. ABA parece afectar también de forma distinta ambos sexos. El papel de IRS1/IRS2 en ausencia de inflamación se desconoce. Inyectamos un AAV expresando shARN anti-IRS1 en hipocampo de ratas macho y hembra. Las hembras mostraron déficits de memoria espacial y de reconocimiento;los machos únicamente de memoria espacial. En septum medial, observamos niveles reducidos de sinaptofisina en fibras shIRS1-AAV, indicando alteraciones en plasticidad sináptica. Por tanto, IRS1 se requiere para una correcta actividad neuronal.Programa de Doctorat en Ciències Biomèdiques i Salu

Nucleus incertus ablation disrupted conspecific recognition and modified immediate early gene expression patterns in ‘social brain’ circuits of rats

Social interaction involves neural activity in prefrontal cortex, septum, hippocampus, amygdala and hypothalamus. Notably, these areas all receive projections from the nucleus incertus (NI) in the pontine tegmentum. Therefore, we investigated the effect of excitotoxic lesions of NI neurons in adult male, Wistar rats on performance in a social discrimination test, and associated changes in immediate-early gene protein levels. NI was lesioned with quinolinic acid, and after recovery, rats underwent two trials in the 3-chamber test. In the first trial, NI-lesioned and sham-lesioned rats spent longer exploring a conspecific than an inanimate object. By contrast, in the second trial, NI-lesioned rats visited the familiar and novel conspecific chambers equally, whereas sham-lesioned rats spent longer engaging with the novel rat. Quantification of Fos- and Egr-1-immunoreactivity (IR) levels in brain areas implicated in social behaviour, revealed that social encounter and NI lesion produced complex, differential changes. For example, Egr-1-IR was broadly decreased in several amygdala nuclei in NI-lesioned rats relative to sham, but Fos-IR levels were unaltered. In hippocampus, NI-lesioned rats displayed decreased Fos-IR in CA2 and CA3, while Egr-1-IR was increased in the polymorphic dentate gyrus, CA1, CA2 and subiculum of NI-lesioned rats, relative to sham. Social encounter-related Egr-1-IR was also decreased in septum and anterior and lateral hypothalamus of NI-lesioned rats. Overall, these data suggest NI networks can modulate the activity of sensory, emotional and executive brain areas involved in social recognition, with a likely involvement of neuronal Egr-1 activation in amygdala, septum and hypothalamus, and Erg-1 inhibition in hippocampus