Temozolomide treatment inhibits spontaneous motivation for exploring a complex object in mice: a potential role of adult hippocampal neurogenesis in ‘curiosity’.

Intrinsic exploratory biases are an innate motivation for exploring certain types of stimuli or environments over others, and they may be associated with cognitive, emotional, and even personality-like traits. However, their neurobiological basis has been scarcely investigated. Considering the involvement of the hippocampus in novelty recognition and in spatial and pattern separation tasks, this work researched the role of adult hippocampal neurogenesis (AHN) in intrinsic exploratory bias for a perceptually complex object in mice. Spontaneous object preference tasks revealed that both male and female C57BL/6J mice showed a consistent unconditioned preference for exploring “complex”—irregular—objects over simpler ones. Furthermore, increasing objects’ complexity resulted in an augmented time of object exploration. In a different experiment, male mice received either vehicle or the DNA alkylating agent temozolomide (TMZ) for 4 weeks, a pharmacological treatment that reduced AHN as evidenced by immunohistochemistry. After assessment in a behavioral test battery, the TMZ-treated mice did not show any alterations in general exploratory and anxiety-like responses. However, when tested in the spontaneous object preference task, the TMZ-treated mice did not display enhanced exploration of the complex object, as evidenced both by a reduced exploration time—specifically for the complex object—and a lack of preference for the complex object over the simple one. This study supports a novel role of AHN in intrinsic exploratory bias for perceptual complexity. Moreover, the spontaneous complex object preference task as a rodent model of “curiosity” is discussed.This study was funded by Grant PID2020-114374RB-I00 funded by MCIN/AEI/10.13039/501100011033 (to C.R.-P. and E.C.-O.). Author P.R. holds a “Miguel Servet I” research contract from the National System of Health, EU-ERDF-ISCIII (CP19/00068). Authors M.C.M.-P. and S.G.-R. hold predoctoral grants from the Spanish Ministry of Science, Innovation and Universities (FPU17/00276 to M.C.M.-P. and FPU18/00941 to S.G.-R.). The authors acknowledge the IBIMA's common research support structure—ECAI—of animal experimentation and behavior (“Centro de Experimentación y Conducta Animal”; University of Malaga) for maintenance of the mice and the ECAI of Image for the use of the microscope. We are especially thankful to María Visitación Jacinto Hernández and Vanesa Jiménez Gálvez for their valuable contribution to the behavioral experiments and to Lourdes Sánchez Salido and Ana Mar Gálvez Callejón for their technical support. Open access funding provided by University of Málaga CBUA

Where to place the rewards? Exploration bias in mice influences performance in the classic hole-board spatial memory test

Author manuscriptThe classic hole-board paradigm (a square arena with 16 holes arranged equidistantly in a 4x4 pattern) assesses both exploration and spatial memory in rodents. For spatial memory training, food rewards are hidden in a fixed set of holes. The animal must not visit (i.e. nose-poke) the holes that are never baited (reference memory; RM) nor re-visit a baited hole within a session (working memory; WM). However, previous exploratory bias may affect performance during reward searching. During habituation sessions with either all holes rewarded or all holes empty, mice intrinsically preferred poking peripheral holes (especially those located in the maze’s corners) over centre holes. During spatial memory training, mice progressively shifted their hole pokes and staying time to the central area that contained hidden rewards, while mice exposed to the empty apparatus still preferred the periphery. A group of pseudotrained mice, for whom rewards were located randomly throughout the maze, also increased their central preference. Furthermore, reward location influenced memory measures. Most repeated pokes (WM-errors) were scored in the locations that were most intrinsically appealing to mice (i.e. the corner and wall baited holes), supporting a strong influence of previous exploratory bias. Regarding RM, finding rewards located in the centre holes, which were initially less preferred, entailed more difficulty and required more trials to learn. This outcome was confirmed by a second experiment that varied the pattern of rewarded holes, as well as the starting positions. Therefore, reward location is a relevant aspect to consider when designing a hole-board memory task.This study was funded by grants from the Spanish Ministry of Economy and Competitiveness (MINECO, Agencia Estatal de Investigación) cofounded by the European Research Development Fund -AEI/FEDER, UE- (PSI2015-73156-JIN to E.C.O.; PSI2017-82604R to L.J.S.) and from University of Malaga (Plan Propio 2017 – ‘Ayudas para proyectos dirigidos por jóvenes investigadores’, PPIT.UMA.B1.2017/38 to P.S.P). Author P.S.P. holds a ‘Juan de la Cierva-formación’ grant from the Spanish Ministry of Economy, Industry and Competitiveness (code: FJCI-2015-23925). Author M.M.P. holds Predoctoral contract from University of Malaga (Plan Propio 2017). Author F.A.G holds Young researchers contract from the University of Malaga co-funded by the Regional Government of Andalusia and the European Social Fund. Author E.C.O holds a ‘Jóvenes Investigadores’ grant (code: PSI2015-73156-JIN) from MINECO-AEI/FEDER, UE

Reduction of adult neurogenesis by temozolomide inhibits intrinsic preference for exploring complex objects in mice

Póster de congresoIntrinsic exploratory bias is an innate tendency to prefer certain types of stimuli or environments over others. For example, mice would genuinely spent more time exploring perceptually complex objects (i.e. with edges and concavities) than simpler objects without irregularities. Intrinsic exploratory bias are relevant as they may be associated to cognitive, emotional and even personality-like traits. However, their neurobiological basis are scarcely investigated. Adult hippocampal neurogenesis (AHN) is a key neuroplastic phenomenon for the processing of spatial and contextual stimuli in rodents, being involved in novelty recognition, spatial navigation and spatial pattern separation tasks. Therefore, here we studied whether a pharmacological inhibition of AHN influences intrinsic motivation for exploring complex objects. Twenty male young adult C57BL/6J mice (∼3 months old) received vehicle or the DNA alkylating agent temozolomide (TMZ) for four weeks. Bromodeoxyuridine (BrdU) was administered weekly, confirming a reduction of AHN-related markers by TMZ. After the pharmacological treatment, mice were tested for behavior. TMZ did not impair mice’s health nor their general exploratory and anxiety-like responses. Unlike control mice, the TMZ-treated mice did not prefer exploring a complex (i.e. irregular) object over a simple (i.e. non-irregular) object of similar size presented at once. Nevertheless, they were able to discriminate a novel complex object from a familiar complex object. This suggest that the lack of intrinsic preference for complexity could be explained by motivational and not by cognitive variables. Future studies should investigate a new role of AHN in modulating exploratory bias.Universidad de Málaga; Project PID2020-114374RB-I00 funded by MCIN/AEI/10.13039/501100011033/ Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Enhancement of adult hippocampal neurogenesis by spatial memory training and its effect on the maintenance of cocaine-contextual memory

Aims:Modulation of hippocampal memories related with cocaine addiction such as cocaine-context associations could have important clinical implications. It has been asserted that learning-related experiences promote hippocampal plasticity enhancing adult hippocampal neurogenesis (AHN). Here we aimed to evaluate (1) the stimulation of AHN using a spatial learning task dependent on the hippocampus and (2) whether spatial learning reduces the long-term maintenance and reinstatement of previously acquired cocaine-associated contextual memories. Methods: Male C57BL/6J mice were first submitted to a cocaine induced conditioned place preference paradigm (CPP). Then, bromodeoxyuridine (BrdU) was administered in order to label newborn neurons. One week after the last BrdU injection, a group of mice were trained in a spatial learning task using the Morris water maze while control animals received a non-hippocampal training or stayed undisturbed in their home-cages. Twenty seven days after conditioning, mice were tested for CPP retention and extinction. Finally, a cocaine priming-induced reinstatement of drug seeking was performed. Results: Animals trained in the spatial learning task exhibited a lower long-term CPP retention memory. In addition, cocaine-induced CPP reinstatement was attenuated in trained animals. Immunohistochemistry showed an increment in the BrdU+ cells in the hippocampus of trained animals in contrast with control animals. Conclusions: Spatial memory training using the Morris water maze constitutes a tool to promote the survival of newborn neurons in the hippocampus. Furthermore, stimulation of AHN might be a neurobiological mechanism by which spatial learning reduces the long-term maintenance of previous cocaine-context associative memory. Supported by PSI2017-82604 (MICINN Spain); PSI2015-73156-JIN. Universidad de Málaga.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Environmental enrichment alleviates cognitive and psychomotor alterations and increases adult hippocampal neurogenesis in cocaine withdrawn mice

Cocaine is a widely used psychostimulant drug whose repeated exposure induces persistent cognitive/emotional dysregulation, which could be a predictor of relapse in users. However, there is scarce evidence on effective treatments to alleviate these symptoms. Environmental enrichment (EE) has been shown to be associated with improved synaptic function and cellular plasticity changes related to adult hippocampal neurogenesis (AHN), resulting in cognitive enhancement. Therefore, EE could mitigate the negative impact of chronic administration of cocaine in mice and reduce the emotional and cognitive symptoms present during cocaine abstinence. In this study, mice were chronically administered with cocaine for 14 days, and control mice received saline. After the last cocaine or saline dose, mice were submitted to control or EE housing conditions, and they stayed undisturbed for 28 days. Subsequently, mice were evaluated with a battery of behavioural tests for exploratory activity, emotional behaviour, and cognitive performance. EE attenuated hyperlocomotion, induced anxiolytic-like behaviour and alleviated cognitive impairment in spatial memory in the cocaine-abstinent mice. The EE protocol notably upregulated AHN in both control and cocaine-treated mice, though cocaine slightly reduced the number of immature neurons. Altogether, these results demonstrate that EE could enhance hippocampal neuroplasticity ameliorating the behavioural and cognitive consequences of repeated administration of cocaine. Therefore, environmental stimulation may be a useful strategy in the treatment cocaine addiction.This study was funded by the following grants: PSI2015-73,156-JIN to E.C-O. and PSI2017-82604R to L.J.S. (MINECO-AEI cofounded by FEDER), PID2020-114374RB-I00 (funded by MCIN/AEI/10.13039/501100011033) to E.C-O., PID2020-113806RB-I00 to L.J.S. (MICINN) and University of Malaga (B4: ‘Ayudas para Proyectos Puente’ to E. C–O). Authors M. C. M-P., P. T. and S. G-R. hold predoctoral grants from the Spanish Ministry of Science, Innovation and Universities (FPU17/00276 to M. C. M-P.; FPU18/00069 to P. T and FPU18/00941 to S. G-R.). The authors acknowledge the IBIMA's common research support structure of animal experimentation and behaviour (“Centro de Experimentación y Conducta Animal”; University of Malaga) and their staff for their valuable assistance during the behavioural experiments and maintenance of the mice and to Belén García and Carmen Hernández for their help with the confocal microscopy at the Cajal Institute // Funding for open access charge: Universidad de Málaga/CBUA

Persistent changes in exploration and hyperactivity coexist with cognitive impairment in mice withdrawn from chronic cocaine

Repeated cocaine exposure induces lasting neurobehavioral adaptations such as cognitive decline in animal models. However, persistent changes in spontaneous –unconditioned- motor and exploratory responses are scarcely reported. In this study, mice were administered with cocaine (20 mg/kg/day) or vehicle for 12 consecutive days. After 24 days of drug abstinence, a behavioral assessment was carried out in drug-free conditions and in unfamiliar environments (i.e. no cocaine-associated cues were presented). The cocaine-withdrawn mice showed cognitive deficits in spontaneous alternation behavior and place recognition memory. Importantly, they also displayed hyperlocomotion, increased rearing activity and altered exploratory patterns in different tasks. In the forced swimming test, they were more active (struggled/climbed more) when trying to escape from the water albeit showing normal immobility behavior. In conclusion, in addition to cognitive deficits, chronic cocaine in rodents may induce long-lasting alterations in exploratory activity and psychomotor activation that are triggered even in absence of drug-related stimuli.This study was funded by grants from the Spanish Ministry of Economy and Competitiveness (MINECO, Agencia Estatal de Investigación –AEI-) cofounded by the European Regional Development Fund-FEDER, UE- (PSI2015–73,156-JIN to E.C–O.; PSI2017–82604R to L.J.S.), RETICS Red de Trastornos Adictivos (ERDF-EU; RD16/0017/0001 to F.R.F.) and University of Málaga (B4: ‘Ayudas para Proyectos Puente’to E.C–O). Funding for open access charge: Universidad de Málaga /CBUA. Authors M.C.M-P., F. A-G. and S. G-R. hold predoctoral grants from the Spanish Ministry of Science, Innovation and Universities (FPU17/00276 to M.C.M-P.; PRE2018–085673 to F.A-G.; and FPU18/00941 to S.G-R.). Author D.L.G.M. holds a postdoctoral grant from University of Málaga (A.3. Plan Propio de Investigación y Transferencia Universidad de Málaga)

Training memory without aversion: Appetitive hole-board spatial learning increases adult hippocampal neurogenesis.

Learning experiences are potent modulators of adult hippocampal neurogenesis (AHN). However, the vast majority of findings on the learning-induced regulation of AHN derive from aversively-motivated tasks, mainly the water maze paradigm, in which stress is a confounding factor that affects the AHN outcome. Currently, little is known regarding the effect of appetitively-motivated training on AHN. Hence we studied how spatial learning to find food rewards in a hole-board maze modulates AHN (cell proliferation and immature neurons) and AHN-related hippocampal neuroplasticity markers (BDNF, IGF-II and CREB phosphorylation) in mice. The 'Trained' mice were tested for both spatial reference and working memory and compared to 'Pseudotrained' mice (exposed to different baited holes in each session, thus avoiding the reference memory component of the task) and 'Control' mice (exposed to the maze without rewards). In contrast to Pseudotrained and Control mice, Trained mice reduced the number of proliferating hippocampal cells but they notably increased their population of immature neurons assessed by immunohistochemistry. This evidence shows that hole-board spatial reference learning diminishes cell proliferation in favor of enhancing young neurons' survival. Interestingly, the enhanced AHN in the Trained mice (specifically in the suprapyramidal blade) positively correlated with their reference memory performance, but not with their working memory. Furthermore, the Trained animals increased the hippocampal protein expression of all the neuroplasticity markers analyzed by western blot. Results show that the appetitively-motivated hole-board task is an useful paradigm to potentiate and/or investigate AHN and hippocampal plasticity minimizing aversive variables such as fear or stress.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. This study was funded by grants from the Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación) co-funded by the European Research Development Fund -AEI/FEDER, UE- (PSI2015-73156-JIN ‘Jóvenes Investigadores grant’ to E.C.O. and PSI2013-44901-P to L.J.S. and C.P.), from ‘Junta de Andalucía’ SEJ1863 to C.P. and from University of Málaga (Plan Propio 2017 – ‘Ayudas para proyectos puente’) to M.G.F. Author P.S.P. holds a ‘Juan de la Cierva-formación‘grant from the Spanish Ministry of Economy, Industry and Competitiveness (code: FJCI-2015-23925) and a ‘D.3. Estancia de investigadores de reconocido prestigio en la UMA‘ grant from the University of Málaga. Authors R.D.M.F. and D.L.G.M. hold ‘FPU’ grants from the Spanish Ministry of Education, Culture and Sports (code: FPU14-01610 and FPU13/04819, respectively). Author F.J.P. holds a ‘Miguel Servet’ grant (code: CP14/00212) from the National System of Health-Instituto de Salud Carlos-III co-funded by FEDER, UE

Experiencia de uso de un cómic (“Arrugas”) como material didáctico en el aula universitaria.

En la actualidad, existen pocas experiencias docentes que incorporen el cómic al entorno universitario. En este trabajo hemos explorado la utilidad de un cómic (“Arrugas”, de Paco Roca) para mejorar el proceso de enseñanza-aprendizaje de contenidos relacionados con la vejez y la demencia, en una asignatura del Grado en Psicología.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Autoantibodies against type I IFNs in patients with critical influenza pneumonia

In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-alpha and/or -omega, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine. Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-alpha 2 alone (five patients) or with IFN-omega (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-alpha 2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-omega. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-alpha 2 and IFN-omega (OR = 11.7, P = 1.3 x 10(-5)), especially those <70 yr old (OR = 139.9, P = 3.1 x 10(-10)). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for similar to 5% of cases of life-threatening influenza pneumonia in patients <70 yr old