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enrichment alleviates cognitive and psychomotor alterations and increases adult hippocampal neurogenesis in cocaine withdrawn mice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

A Multiple-Choice Maze-like Spatial Navigation Task for Humans Implemented in a Real-Space, Multipurpose Circular Arena

Spatial navigation is a key aspect of human behavior and it is still not completely understood. A number of experimental approaches exist, although most of the published data in the last decades have relied on virtual maze on-screen simulation or not-completely freely moving 3D devices. Some interesting recent developments, such as circular mazes, have contributed to analyze critical aspects of freely moving human spatial navigation in real space, although dedicated protocols only allow for simple approaches. Here, we have developed both specifically designed and home-assembled hardware equipment, and a customized protocol for spatial navigation evaluation in freely moving humans in a real space circular arena. The spatial navigation protocol poses an imitation of a real-space multiple-choice path maze with cul-de-sac and instances of non-linear movement. We have compared the results of this system to those of a number of validated, both virtual and real, spatial navigation tests in a group of participants. The system composed by hardware, the test protocol, and dedicated measure analysis designed in our laboratory allows us to evaluate human spatial navigation in a complex maze with a small and portable structure, yielding a highly flexible, adaptable, and versatile access to information about the subjects’ spatial navigation abilities

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.info:eu-repo/semantics/publishedVersio

Deciphering the role of miR-148a in the brain development

miRNAs are endogenous non-coding RNAs that play a crucial role in post-transcriptional repression of gene expression. Among them, miR-148a has been involved in important biological and pathological processes such as immunity, metabolism, or cancer. Recent studies revealed that miR-148a is also expressed in the central nervous system of rodents, where it has been associated with febrile seizures, cognitive decline, or Alzheimer’s Disease. Despite these advances, the physiological function of miR-148a in the brain is still unknown. In this study we, therefore, aimed to determine the expression pattern and the role of miR-148a in the mouse brain. Taqman assay results showed miR-148a expression increases progressively from E14, reaches a peak in the adult stage, and decreases again in old mice. During adulthood, miR-148a was detected through in situ hybridization in the cortex, the CA2 and CA3 region of the hippocampus, the mitral layer of the olfactory bulb and the Purkinje layer in the cerebellum, among other areas. miR-148a expression in adult cortex was restricted to neurons from layers 2, 5 and 6, and displayed a decreasing gradient along the anteroposterior axis. MRI analysis revealed the deletion of this miRNA in miR-148a-KO adult mice leads to an anteriorization of the lateral ventricles, possibly as compensation for changes in the cortex where the miRNA would be expressed. Altering miR-148a levels in cortical neurons in vitro led to significant morphological changes. Overexpression of miR-148a induced a decrease in the number and complexity of neurites, with an increase in the axon number and length, while its downregulation caused a reduction in neurite length, suggesting miR-148a might be involved in axonal growth. Taken together, these results point to a potential role of miR-148a in neurite growth, highlighting its importance in the brain

Analysis of social interactions in a genetic model of Lamb-Shaffer syndrome autism spectrum disorders.

Many neurodevelopmental disorders associated with deficiencies in social interaction, language difficulties and repetitive behaviours are grouped under the name of autism spectrum disorders (ASD). Although the genetic causes of ASD are complex, one of the genes that have been associated with ASD is Sox5. In humans, heterozygous genetic alterations comprising Sox5 cause Lamb-Shaffer syndrome (OMIM #616803). Sox5 encodes a transcription factor with important functions in the control of neurogenesis (Li et al., 2022) and in the specification of projection neurons of the cerebral cortex (Lai et al., 2008). Moreover, it has been described that the CA2 region of the hippocampus is fundamental in social behaviour in mice, a region where we have previously shown that Sox5 is expressed (Fernandez-Lamo et al., 2019; Hitti & Siegelbaum, 2014). Using conditional Sox5 mutant mice specific for the CA2 region (Amigo2-cre/Sox5fl/fl;Sox5Amigo2) we have determined that robust lack of Sox5 expression causes PCP4 level decrease in more than half of the pyramidal neurons in CA2. Furthermore, using an extensive battery of behavioural assays we have determined that Sox5Amigo2 mutant mice: i) exhibit normal basic reflexes, weight, locomotion abilities, and anxiety levels; ii) exhibit a good performance in Morris water maze test; iii) present normal social preference and iv) both males and female lose social recognition memory. Preliminary data also suggest possible alterations in the expression of neuronal activity marker cFos in the CA2 region of Sox5Amigo2 mice after performing social interaction tasks. Thus, we propose that Sox5Amigo2 mice could provide a new model of ASD, based on cellular and functional alterations of the CA2 region of the hippocampus, that serves to understand the hippocampal component in the pathophysiology of ASD in Lamb-Shaffer syndrome and for the testing of new therapeutic strategies

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