Popovic Popovic, Miroljub

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Popovic Popovic, Miroljub

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Anatomía Humana y Psicobiología

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Open Access
Effects of long-term individual housing of middle-aged female Octodon degus on spatial learning and memory in the Barnes maze task
(Frontiers Media, 2023-08-03) Baño-Otalora, Beatriz; Rol, María Ángeles; Venero, César; Madrid, Juan Antonio; Popovic, Natalija; Popovic Popovic, Miroljub; Anatomía Humana y Psicobiología
Prolonged social isolation is a form of passive chronic stress that has consequences on human and animal behavior. The present study was undertaken to elucidate whether the long-term isolation would precipitate age-related changes in anxiety and spatial learning and memory in degus. Methods: We investigated the effects of long-term social isolation on anxiety levels in the light-dark test, and spatial orientation abilities in the Barnes maze. Middle-aged female Octodon degus were allocated to either group-housed (3 animals per cage) or individually-housed for 5 months. Results: Under this experimental condition, there were no significant group differences in the anxiety level tested in the light-dark test and in the motivation to escape from the Barnes maze. There were no significant differences in cortisol levels between individually- and group-housed animals. On the last acquisition training day of spatial learning, individually- housed animals had a significantly higher number of correct responses and a smaller number of reference and working memory errors than the group-housed animals. In addition, isolated animals showed a tendency for reference and working memory impairment on the retention trial, while group-housed degus showed improvement in these parameters. Discussion and conclusion: The present study indicates that prolonged social isolation during adulthood in female degus has a dual effect on spatial orientation. Specifically, it results in a significant improvement in acquisition skills but a slight impairment in memory retention. The obtained cognitive changes were not accompanied by modification in anxiety and cortisol levels. Keywords: Barnes maze; Octodon degus; anxiety; learning and memory; light-dark test; social isolation.
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The flavonoid apigenin delays forgetting of passive avoidance conditioning in rats
(SAGE Publications, 2013-11-27) Caballero Bleda, María; Benavente-García, Obdulio; Castillo, Julián; Popovic Popovic, Miroljub; Research Institute of Aging, University of Murcia,; Research & Development Department of Nutrafur S.A., Alcantarilla (Murcia),
The present experiments were performed to study the effect of the flavonoid apigenin (20 mg/kg intraperitoneally (i.p.), 1 h before acquisition), on 24 h retention performance and forgetting of a step-through passive avoidance task, in young male Wistar rats. There were no differences between saline- and apigenin-treated groups in the 24 h retention trial. Furthermore, apigenin did not prevent the amnesia induced by scopolamine (1mg/kg, i.p., 30 min before the acquisition). The saline- and apigenin-treated rats that did not step through into the dark compartment during the cut-off time (540 s) were retested weekly for up to eight weeks. In the saline treated group, the first significant decline in passive avoidance response was observed at four weeks, and complete memory loss was found five weeks after the acquisition of the passive avoidance task. At the end of the experimental period, 60% of the animals treated with apigenin still did not step through. These data suggest that 1) apigenin delays the long-term forgetting but did not modulate the 24 h retention of fear memory and 2) the obtained beneficial effect of apigenin on the passive avoidance conditioning is mediated by mechanisms that do not implicate its action on the muscarinic cholinergic system.
Open Access
Post-training scopolamine treatment induced maladaptive behavior in open field habituation task in rats
(Public Library of Science (PLoS), 2014-06-17) Caballero Bleda, María; Popovic, Natalija; Popovic Popovic, Miroljub; Anatomía Humana y Psicobiología; Research Institute of Aging, University of Murcia
The effects of scopolamine on memory consolidation are controversial and depend on several factors (i.e. site of administration, time of administration and testing, dose, cognitive task, experimental protocol, specie, strain, etc.). Generally, the range dose of systemic administered scopolamine, used in memory consolidation studies, has varied from 0.05 to 50 mg/kg. However, according to the literature, the most frequently used doses of scopolamine efficient on memory consolidation, are 1 and 30 mg/kg, low and high doses, respectively. In open field habituation studies only lower doses of scopolamine were used to test memory consolidation. Therefore, in the present study we compared the effects of low (1 mg/kg) and high (30 mg/kg) scopolamine dose, on the open field habituation task, in male Wistar rats. Scopolamine was administered immediately after the acquisition task and animals were retested 48 h later on. On the retested day, the ambulation and rearing in the open field decreased in the same manner in all tested groups. In saline- and 1 mg/kg scopolamine-treated animals, the time spent in grooming significantly decreased in the habituation task, while the same parameter significantly increased in animals treated with 30 mg/kg of scopolamine. The defecation rate significantly decreased (control group), maintained (1 mg/kg of scopolamine treated animals) or significantly increased (30 mg/kg of scopolamine treated group) on retention test. In conclusion, the present data suggest that post-training scopolamine administration does not affect locomotion neither exploration in the habituation to a novel environment, but increases defecation and grooming, two behaviours associated with fearful and stressful situations.
Open Access
Verapamil parameter- and dose-dependently impairs memory consolidation in open field habituation task in rats
(Frontiers Media, 2017-01-10) Giménez de Béjar, Verónica; Caballero Bleda, María; Popovic, Natalija; Popovic Popovic, Miroljub; Anatomía Humana y Psicobiología
The purpose of the present study was to examine the effects of the phenylalkylamine class of the L-type voltage-dependent calcium channel antagonist, verapamil (1.0, 2.5, 5.0, or 10 mg/kg i.p.), administered immediately after the acquisition task, on memory consolidation of the open field habituation task, in male Wistar rats. On the 48 h retested trial, all tested parameters (ambulation in the side wall and in the central areas, number of rearing, time spent grooming and defecation rate) significantly decreased in the saline treated animals. A significant decrease of rearing was observed in all verapamil treated groups. On the retention day, the ambulation in the side wall and central areas significantly decreased in the animals treated with 1 mg/kg and 10 mg/kg of verapamil, while the time spent grooming and the defecation rate significantly decreased only in the group treated with 1 mg/kg of verapamil. According to the change ratio scores that correct the individual behavioral baseline differences during initial and final sessions, habituation deficit was found in animals treated with verapamil as follows: ambulation along the side wall area (1, 2.5, and 5 mg/kg), number of rearing (all used dose) and time spent grooming (2.5, 5, and 10 mg/kg). In conclusion, the present data suggest that the post-training administration of verapamil, parameter- and dose-dependently, impairs the habituation to a novel environment.
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Circadian system functionality, hippocampal oxidative stress, and spatial memory in the APPswe/PS1dE9 transgenic model of Alzheimer disease: effects of melatonin or ramelteon
(Taylor and Francis Group, Taylor and Francis, 2012-07-23) Baño-Otalora, Beatriz; Gambini, Juan; Viña, José; Bonet-Costa, Vicent; Reiter, Russel J.; Camello, Pedro Javier; Rol, María Ángeles; Madrid, Juan Antonio; Popovic, Natalija; Popovic Popovic, Miroljub; Anatomía Humana y Psicobiología
Alzheimer disease (AD) is a neurodegenerative disorder that primarily causes β-amyloid accumulation in the brain, resulting in cognitive and behavioral deficits. AD patients, however, also suffer from severe circadian rhythm disruptions, and the underlying causes are still not fully known. Patients with AD show reduced systemic melatonin levels. This may contribute to their symptoms, since melatonin is an effective chronobiotic and antioxidant with neuroprotective properties. Here, the authors critically assessed the effects of long-term melatonin treatment on circadian system function, hippocampal oxidative stress, and spatial memory performance in the APPswe/PS1 double transgenic (Tg) mouse model of AD. To test if melatonin MT1/MT2 receptor activation, alone, was involved, the authors chronically treated some mice with the selective MT1/MT2 receptor agonist ramelteon. The results indicate that many of the circadian and behavioral parameters measured, including oxidative stress markers, were not significantly affected in these AD mice. During the day, though, Tg controls (Tg-CON) showed significantly higher mean activity and body temperature (BT) than wild-type (WT) mice. Overall, BT rhythm amplitude was significantly lower in Tg than in WT mice. Although melatonin treatment had no effect, ramelteon significantly reduced the amplitude of the BT rhythm in Tg mice. Towards the end of the experiment, Tg mice treated with ramelteon (Tg-RAM) showed significantly higher circadian rhythm fragmentation than Tg-CON and reduced circadian BT rhythm strength. The free-running period (τ) for the BT and locomotor activity (LA) rhythms of Tg-CON was <24 h. Whereas melatonin maintained τ at 24 h for BT and LA in both genotypes, ramelteon treatment had no effect. In the behavioral tests, the number of approaches and time spent exploring novel objects were significantly higher in Tg-CON than WT controls. Brain tissue analysis revealed significant reduction in hippocampal protein oxidation in Tg-MEL and Tg-RAM compared with Tg-CON animals. These results suggest that not all aspects of the circadian system are affected in the APPswe/PS1 mice. Therefore, care should be taken when extending the results obtained in Tg mice to develop new therapies in humans. This study also revealed the complexity in the therapeutic actions of melatonin and ramelteon in this mouse model of AD.
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Time course of scopolamine effect on memory consolidation and forgetting in rats
(Elsevier, 2014-11-18) Giménez de Béjar, Verónica; Caballero Bleda, María; Popovic, Natalija; Popovic Popovic, Miroljub; Anatomía Humana y Psicobiología
The effect of scopolamine on the consolidation and forgetting of emotional memory has not been completely elucidated yet. The aim of the present study was to investigate the time course of scopolamine effect on consolidation and forgetting of passive avoidance response. In a first experiment of the present study, we tested the effect of scopolamine (1mg/kg, i.p., immediately after acquisition), on 24h and 48h retention performance of the step-through passive avoidance task, in adult male Wistar rats. On the 24h retested trial, the latency of the passive avoidance response was significantly lower, while on the 48h retested trial it was significantly higher in scopolamine than in the saline-treated group. In a second experiment, we assessed the 24h time course of scopolamine (1mg/kg) effect on memory consolidation in passive avoidance task. We found that scopolamine administration only within the first six and half hours after acquisition improved memory consolidation in 48h retention performance. Finally, a third experiment was performed on the saline- and scopolamine-treated rats (given immediately after acquisition) that on the 48h retention test did not step through into the dark compartment during the cut-off time. These animals were retested weekly for up to first three months, and after that, every three months until the end of experiment (i.e., 15 months after acquisition). The passive avoidance response in the saline treated group lasted up to 6 weeks after acquisition, while in the scopolamine treated group 50% of animals conserved the initial level of passive avoidance response until the experiment end point. In conclusion, the present data suggest that (1) improving or impairment effect of scopolamine given in post-training periods depends on delay of retention trial, (2) memory consolidation process could be modify by scopolamine within first six and half hours after training and (3) scopolamine could delay forgetting of emotional memory.
Open Access
Effects of long-term individual housing of middle-aged female Octodon degus on spatial learning and memory in the Barnes maze task
(Frontiers Media, 2023-08-03) Baño Otalora, Beatriz; Rol de Lama, María de los Ángeles; Venero, César; Madrid, Juan Antonio; Popovic, Natalija; Popovic Popovic, Miroljub; Fisiología
Introduction: Prolonged social isolation is a form of passive chronic stress that has consequences on human and animal behavior. The present study was undertaken to elucidate whether the long-term isolation would precipitate age-related changes in anxiety and spatial learning and memory in degus. Methods: We investigated the effects of long-term social isolation on anxiety levels in the light-dark test, and spatial orientation abilities in the Barnes maze. Middle-aged female Octodon degus were allocated to either group-housed (3 animals per cage) or individually-housed for 5 months. Results: Under this experimental condition, there were no significant group differences in the anxiety level tested in the light-dark test and in the motivation to escape from the Barnes maze. There were no significant differences in cortisol levels between individually- and group-housed animals. On the last acquisition training day of spatial learning, individually- housed animals had a significantly higher number of correct responses and a smaller number of reference and working memory errors than the group-housed animals. In addition, isolated animals showed a tendency for reference and working memory impairment on the retention trial, while group-housed degus showed improvement in these parameters. Discussion and conclusion: The present study indicates that prolonged social isolation during adulthood in female degus has a dual effect on spatial orientation. Specifically, it results in a significant improvement in acquisition skills but a slight impairment in memory retention. The obtained cognitive changes were not accompanied by modification in anxiety and cortisol levels
Embargo
Verapamil and alzheimer’s disease: past, present, and future
(Frontiers Media, 2020-05-05) Morales-Delgado, Nicanor; Vidal Mena, David; Pascual Martínez, María; Caballero Bleda, María; Alonso Fuentes, Antonia; Popovic, Natalija; Popovic Popovic, Miroljub; Anatomía Humana y Psicobiología
Verapamil is a phenylalkylamine class calcium channel blocker that for half a century has been used for the treatment of cardiovascular diseases. Nowadays, verapamil is also considered as a drug option for the treatment of several neurological and psychiatric disorders, such as cluster headache, bipolar disorders, epilepsy, and neurodegenerative diseases. Here, we review insights into the potential preventive and therapeutic role of verapamil on Alzheimer’s disease (AD) based on limited experimental and clinical data. Pharmacological studies have shown that verapamil has a wide therapeutic spectrum, including antihypertensive, anti-inflammatory, and antioxidative effects, regulation of the blood-brain barrier function, due to its effect on P-glycoprotein, as well as adjustment of cellular calcium homeostasis, which may result in the delay of AD onset or ameliorate the symptoms of patients. However, the majority of the AD individuals are on polypharmacotherapy, and the interactions between verapamil and other drugs need to be considered. Therefore, for an appropriate and successful AD treatment, a personalized approach is more than necessary. A well-known narrow pharmacological window of verapamil efficacy may hinder this approach. It is therefore important to note that the verapamil efficacy may be conditioned by different factors. The onset, grade, and brain distribution of AD pathological hallmarks, the time-sequential appearances of AD-related cognitive and behavioral dysfunction, the chronobiologic and gender impact on calcium homeostasis and AD pathogenesis may somehow be influencing that success. In the future, such insights will be crucial for testing the validity of verapamil treatment on animal models of AD and clinical approaches.
Open Access
Intracranial pressure analysis software: a mapping study and proposal
(Elsevier, 2021-09) Pérez-Sánchez, Juanjo; Carrillo de Gea, Juan Manuel; Rodríguez Barceló, Sandra; Toval, Ángel; Fernández Alemán, José Luis; García-Berná, José A.; Toval, Ambrosio; Popovic Popovic, Miroljub; Anatomía Humana y Psicobiología
Introduction Intracranial pressure (ICP) monitoring and analysis are techniques that are, each year, applied to millions of patients with pathologies with million of patients annually. The detection of the so called A and B-waves, and the analysis of subtle changes in C-waves, which are present in ICP waveform, may indicate decreased intracranial compliance, and may improve the clinical outcome. Despite the advances in the field of computerized data analysis, the visual screening of ICP continues to be the means prin- cipally employed to detect these waves. To the best of our knowledge, no review study has addressed automated ICP analysis in sufficient detail and a need to research the state of the art of ICP analysis has, therefore, been identified. Methodology This paper presents a systematic mapping study to provide answers to 7 research questions: publication time, venue and source trends, medical tasks undertaken, research methods used, compu- tational systems developed, validation methodology, tools and systems employed for evaluation and re- search problems identified. An ICP software prototype is presented and evaluated as a consequence of the results. Results A total of 23 papers, published between 1990 and 2020, were selected from 6 online databases. After analyzing these papers, the following information was obtained: diagnosis and monitoring medical tasks were addressed to the same extent, and the main research method used was evaluation research. Several computational systems were identified in the papers, the main one being image classification, while the main analysis objective was single pulse analysis. Correlation with expert analysis was the most frequent validation method, and few of the papers stated the use of a published dataset. Few authors re- ferred to the tools used to build or evaluate the proposed solutions. The most frequent research problem was the need for new analysis methods. These results have inspired us to propose a software prototype with which provide an automated solution that integrates ICP analysis and monitoring techniques. Conclusions The papers in this study were selected and classified with regard to ICP automated analysis methods. Several research gaps were identified, which the authors of this study have employed as a based on which to recommend future work. Furthermore, this study has identified the need for an empirical comparison between methods, which will require the use and development of certain standard metrics. An in-depth analysis conducted by means of systematic literature review is also required. The software prototype evaluation provided positive results, showing that the prototype may be a reliable system for A-wave detection.
Embargo
Widespread doublecortin expression in the cerebral cortex of the octodon degus
(Frontiers Media, 2021-04-29) Van Groen, Thomas; Kadish, Inga; Caballero Bleda, María; Baño-Otalora, Beatriz; Rol, María Ángeles; Madrid, Juan Antonio; Popovic, Natalija; Popovic Popovic, Miroljub; Anatomía Humana y Psicobiología
It has been demonstrated that in adulthood rodents show newly born neurons in the subgranular layer (SGL) of the dentate gyrus (DG), and in the subventricular zone (SVZ). The neurons generated in the SVZ migrate through the rostral migratory stream (RMS) to the olfactory bulb. One of the markers of newly generated neurons is doublecortin (DCX). The degu similarly shows significant numbers of DCX-labeled neurons in the SGL, SVZ, and RMS. Further, most of the nuclei of these DCX-expressing neurons are also labeled by proliferating nuclear antigen (PCNA) and Ki67. Finally, whereas in rats and mice DCX-labeled neurons are predominantly present in the SGL and SVZ, with only a few DCX neurons present in piriform cortex, the degu also shows significant numbers of DCX expressing neurons in areas outside of SVZ, DG, and PC. Many areas of neocortex in degu demonstrate DCX-labeled neurons in layer II, and most of these neurons are found in the limbic cortices. The DCX-labeled cells do not stain with NeuN, indicating they are immature neurons.