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.

Lifestyle induces long lasting effects on brain and cognition, with some interventions like stress including transgenerational inheritance mediated by epigenetic mechanisms. Physical exercise is one lifestyle intervention driving robust improvements of cognition, including intergenerational transmission to the litter. However, little is known about whether exercise effects are transgenerationally transmitted. Here we analyzed adult hippocampal neurogenesis (AHN) and behavioral phenotype of sedentary adult male mice of F2 generation of exercised grandfathers (F0). Both F1 and F2 were sedentary, while F0 performed moderate exercise. We found F2 mice from exercised F0 acquired and recalled both spatial and non-spatial information better than F2 from sedentary F0. Contextual fear conditioning was not affected, together with no differences in AHN markers. Hippocampal smallRNAseq analysis revealed 35 significant differentially expressed (sDE) microRNAs (miRNAs) associated to relevant brain function families. Moreover, 11 of the 35 miRNAs target gene sets were found also enriched in F0 and F1, as well as target genes of 6 of them were differentially expressed also in F0 or F1. One of these 6 is miRNA-144, that together with miRNA-298 were found inversely correlated to cognitive index in F2. These results demonstrate that transgenerational transmission of the effects of exercise on specific cognitive tasks persists after two generations, even though some cellular changes induced in F1 vanish in F2. Thus, they suggest moderate exercise training has longer-lasting effects than previously thought, probably mediated by a small group of miRNAs acting across generations, and this is worth taking into account in public health programs.

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.

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.