Browsing by MeSH term "Maze Learning"
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Publication Cognitive impairment in metabolically-obese, normal-weight rats: identification of early biomarkers in peripheral blood mononuclear cells(BioMed Central (BMC), 2018-03-22) Cifre, Margalida; Palou, Andreu; Oliver, PaulaBackground: Metabolically-obese, normal-weight (MONW) individuals are not obese in terms of weight and height but have a number of obesity-related features (e.g. greater visceral adiposity, insulin resistance, and increased risk of cardiovascular disease). The MONW phenotype is related to the intake of unbalanced diets, such as those rich in fat. Increasing evidence shows a relationship between high-fat diet consumption and mild cognitive impairment and dementia. Thus, MONW individuals could be at a greater risk of cognitive dysfunction. We aimed to evaluate whether MONW-like animals present gene expression alterations in the hippocampus associated with an increased risk of cognitive impairment, and to identify early biomarkers of cognitive dysfunction in peripheral blood mononuclear cells (PBMC). Methods: Wistar rats were chronically fed with a 60% (HF60) or a 45% (HF45) high-fat diet administered isocalorically to control animals to mimic MONW features. Expression analysis of cognitive decline-related genes was performed using RT-qPCR, and working memory was assessed using a T-maze. Results: High-fat diet consumption altered the pattern of gene expression in the hippocampus, clearly pointing to cognitive decline, which was accompanied by a worse performance in the T-maze in HF60 animals. Remarkably, Syn1 and Sorl1 mRNA showed the same expression pattern in both the hippocampus and the PBMC obtained at different time-points in the HF60 group, even before other pathological signs were observed. Conclusions: Our results demonstrate that long-term intake of high-fat diets, even in the absence of obesity, leads to cognitive disruption that is reflected in PBMC transcriptome. Therefore, PBMC are revealed as a plausible, minimally-invasive source of early biomarkers of cognitive impairment associated with increased fat intake.Publication Comparing the Behavioural Effects of Exogenous Growth Hormone and Melatonin in Young and Old Wistar Rats(Hindawi, 2016) Barceló, Pere; Nicolau Llobera, Maria Cristina; Gamundí, Antoni; Fiol-deRoque, Maria Antonia; Tresguerres, Jesus A. F; Akaârir, Mourad; Rial, Rubén VGrowth hormone (GH) and melatonin are two hormones with quite different physiological effects. Curiously, their secretion shows parallel and severe age-related reductions. This has promoted many reports for studying the therapeutic supplementation of both hormones in an attempt to avoid or delay the physical, physiological, and psychological decay observed in aged humans and in experimental animals. Interestingly, the effects of the external administration of low doses of GH and of melatonin were surprisingly similar, as both hormones caused significant improvements in the functional capabilities of aged subjects. The present report aims at discerning the eventual difference between cognitive and motor effects of the two hormones when administered to young and aged Wistar rats. The effects were tested in the radial maze, a test highly sensitive to the age-related impairments in working memory and also in the rotarod test, for evaluating the motor coordination. The results showed that both hormones caused clear improvements in both tasks. However, while GH improved the cognitive capacity and, most importantly, the physical stamina, the effects of melatonin should be attributed to its antioxidant, anxiolytic, and neuroprotective properties.Publication Endocannabinoid regulation of acute and protracted nicotine withdrawal: effect of FAAH inhibition(Public Library of Science (PLOS), 2011-11-30) Cippitelli, Andrea; Astarita, Giuseppe; Duranti, Andrea; Caprioli, Giovanni; Ubaldi, Massimo; Stopponi, Serena; Kallupi, Marsida; Sagratini, Gianni; Rodríguez de Fonseca, Fernando; Piomelli, Daniele; Ciccocioppo, Roberto; [Cippitelli,A; Ubaldi,M; Stopponi,S; Kallupi,M; Ciccocioppo,R] School of Pharmacy,Pharmacology Unit,University of Camerino,Camerino,Italy. [Astarita,G; Piomelli,D] Department of Pharmacology, University of California Irvine, Irvine, California, United States of America. [Duranti,A] Department of Biomolecular Sciences, Medicinal Chemistry and Technology Unit, University of Urbino Carlo Bo, Urbino, Italy. [Caprioli,G; Sagratini,G] School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Camerino,Italy. [Rodríguez de Fonseca,F] Fundación IMABIS, Hospital Carlos Haya de Málaga, Málaga, Spain. [Piomelli,D] Drug Discovery and Development, Italian Institute of Technology, Genova, Italy.Evidence shows that the endocannabinoid system modulates the addictive properties of nicotine. In the present study, we hypothesized that spontaneous withdrawal resulting from removal of chronically implanted transdermal nicotine patches is regulated by the endocannabinoid system. A 7-day nicotine dependence procedure (5.2 mg/rat/day) elicited occurrence of reliable nicotine abstinence symptoms in Wistar rats. Somatic and affective withdrawal signs were observed at 16 and 34 hours following removal of nicotine patches, respectively. Further behavioral manifestations including decrease in locomotor activity and increased weight gain also occurred during withdrawal. Expression of spontaneous nicotine withdrawal was accompanied by fluctuation in levels of the endocannabinoid anandamide (AEA) in several brain structures including the amygdala, the hippocampus, the hypothalamus and the prefrontal cortex. Conversely, levels of 2-arachidonoyl-sn-glycerol were not significantly altered. Pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for the intracellular degradation of AEA, by URB597 (0.1 and 0.3 mg/kg, i.p.), reduced withdrawal-induced anxiety as assessed by the elevated plus maze test and the shock-probe defensive burying paradigm, but did not prevent the occurrence of somatic signs. Together, the results indicate that pharmacological strategies aimed at enhancing endocannabinoid signaling may offer therapeutic advantages to treat the negative affective state produced by nicotine withdrawal, which is critical for the maintenance of tobacco use.Publication Endocannabinoid regulation of acute and protracted nicotine withdrawal: effect of FAAH inhibition.(Public Library of Science (PLOS), 2011-11-30) Cippitelli, Andrea; Astarita, Giuseppe; Duranti, Andrea; Caprioli, Giovanni; Ubaldi, Massimo; Stopponi, Serena; Kallupi, Marsida; Sagratini, Gianni; Rodríguez de Fonseca, Fernando; Piomelli, Daniele; Ciccocioppo, Roberto; [Cippitelli,A; Ubaldi,M; Stopponi,S; Kallupi,M; Ciccocioppo,R] School of Pharmacy,Pharmacology Unit,University of Camerino,Camerino,Italy. [Astarita,G; Piomelli,D] Department of Pharmacology, University of California Irvine, Irvine, California, United States of America. [Duranti,A] Department of Biomolecular Sciences, Medicinal Chemistry and Technology Unit, University of Urbino ‘‘Carlo Bo’’, Urbino, Italy. [Caprioli,G; Sagratini,G] School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Camerino,Italy. [Rodríguez de Fonseca,F] Fundación IMABIS, Hospital Carlos Haya de Málaga, Málaga, Spain. [Piomelli,D] Drug Discovery and Development, Italian Institute of Technology, Genova, Italy.Evidence shows that the endocannabinoid system modulates the addictive properties of nicotine. In the present study, we hypothesized that spontaneous withdrawal resulting from removal of chronically implanted transdermal nicotine patches is regulated by the endocannabinoid system. A 7-day nicotine dependence procedure (5.2 mg/rat/day) elicited occurrence of reliable nicotine abstinence symptoms in Wistar rats. Somatic and affective withdrawal signs were observed at 16 and 34 hours following removal of nicotine patches, respectively. Further behavioral manifestations including decrease in locomotor activity and increased weight gain also occurred during withdrawal. Expression of spontaneous nicotine withdrawal was accompanied by fluctuation in levels of the endocannabinoid anandamide (AEA) in several brain structures including the amygdala, the hippocampus, the hypothalamus and the prefrontal cortex. Conversely, levels of 2-arachidonoyl-sn-glycerol were not significantly altered. Pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for the intracellular degradation of AEA, by URB597 (0.1 and 0.3 mg/kg, i.p.), reduced withdrawal-induced anxiety as assessed by the elevated plus maze test and the shock-probe defensive burying paradigm, but did not prevent the occurrence of somatic signs. Together, the results indicate that pharmacological strategies aimed at enhancing endocannabinoid signaling may offer therapeutic advantages to treat the negative affective state produced by nicotine withdrawal, which is critical for the maintenance of tobacco use.Publication Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer's disease.(2019-04-20) Boza-Serrano, Antonio; Ruiz, Rocío; Sanchez-Varo, Raquel; García-Revilla, Juan; Yang, Yiyi; Jimenez-Ferrer, Itzia; Paulus, Agnes; Wennström, Malin; Vilalta, Anna; Allendorf, David; Davila, Jose Carlos; Stegmayr, John; Jiménez, Sebastian; Roca-Ceballos, Maria A; Navarro-Garrido, Victoria; Swanberg, Maria; Hsieh, Christine L; Real, Luis M; Englund, Elisabet; Linse, Sara; Leffler, Hakon; Nilsson, Ulf J; Brown, Guy C; Gutierrez, Antonia; Vitorica, Javier; Venero, Jose Luis; Deierborg, TomasAlzheimer's disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer's disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2-DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.Publication Oleoyl lysophosphatidic acid: a new mediator of emotional behavior in rats.(Public Library of Science (PLOS), 2014-01-07) Castilla-Ortega, Estela; Escuredo, Leticia; Bilbao, Ainhoa; Pedraza, Carmen; Orio, Laura; Estivill-Torrús, Guillermo; Santín, Luis J; Rodríguez de Fonseca, Fernando; Pavón, Francisco Javier; [Castilla-Ortega,E; Bilbao,A; Orio,L; Rodríguez de Fonseca,F; Pavón,FJ] Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain. [Castilla-Ortega,E; Pedraza,C; Santín, LJ] Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Universidad de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain. [Escuredo,L; Orio,L; Rodríguez de Fonseca,F] Departamento de Psicobiología, Universidad Complutense de Madrid, Madrid, Spain. [Estivill-Torrús,G] Unidad de Gestión Clínica de Neurociencias, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain.The role of lysophosphatidic acid (LPA) in the control of emotional behavior remains to be determined. We analyzed the effects of the central administration of 1-oleoyl-LPA (LPA 18∶1) in rats tested for food consumption and anxiety-like and depression-like behaviors. For this purpose, the elevated plus-maze, open field, Y maze, forced swimming and food intake tests were performed. In addition, c-Fos expression in the dorsal periaqueductal gray matter (DPAG) was also determined. The results revealed that the administration of LPA 18∶1 reduced the time in the open arms of the elevated plus-maze and induced hypolocomotion in the open field, suggesting an anxiogenic-like phenotype. Interestingly, these effects were present following LPA 18∶1 infusion under conditions of novelty but not under habituation conditions. In the forced swimming test, the administration of LPA 18∶1 dose-dependently increased depression-like behavior, as evaluated according to immobility time. LPA treatment induced no effects on feeding. However, the immunohistochemical analysis revealed that LPA 18∶1 increased c-Fos expression in the DPAG. The abundant expression of the LPA1 receptor, one of the main targets for LPA 18∶1, was detected in this brain area, which participates in the control of emotional behavior, using immunocytochemistry. These findings indicate that LPA is a relevant transmitter potentially involved in normal and pathological emotional responses, including anxiety and depression.