Physical exercise has positive effects on cognition, but very little is known about the inheritance of these effects to sedentary offspring and the mechanisms involved. Here, we use a patrilineal design in mice to test the transmission of effects from the same father (before or after training) and from different fathers to compare sedentary- and runner-father progenies. Behavioral, stereological, and whole-genome sequence analyses reveal that paternal cognition improvement is inherited by the offspring, along with increased adult neurogenesis, greater mitochondrial citrate synthase activity, and modulation of the adult hippocampal gene expression profile. These results demonstrate the inheritance of exercise-induced cognition enhancement through the germline, pointing to paternal physical activity as a direct factor driving offspring’s brain physiology and cognitive behavior.

frank Zufall 9 , pablo chamero 10 & José Luis trejo 11* pheromone detection by the vomeronasal organ (Vno) mediates important social behaviors across different species, including aggression and sexual behavior. However, the relationship between vomeronasal function and social hierarchy has not been analyzed reliably. We evaluated the role of pheromone detection by receptors expressed in the apical layer of the VNO such as vomeronasal type 1 receptors (V1R) in dominance behavior by using a conditional knockout mouse for G protein subunit Gαi2, which is essential for V1R signaling. We used the tube test as a model to analyze the within-acage hierarchy in male mice, but also as a paradigm of novel territorial competition in animals from different cages. In absence of prior social experience, Gαi2 deletion promotes winning a novel social competition with an unfamiliar control mouse but had no effect on an established hierarchy in cages with mixed genotypes, both Gαi2 −/− and controls. to further dissect social behavior of Gαi2 −/− mice, we performed a 3-chamber sociability assay and found that mutants had a slightly altered social investigation. Finally, gene expression analysis in the medial prefrontal cortex (mPFC) for a subset of genes previously linked to social status revealed no differences between group-housed Gαi2 −/− and controls. Our results reveal a direct influence of pheromone detection on territorial dominance, indicating that olfactory communication involving apical VNO receptors like V1R is important for the outcome of an initial social competition between two unfamiliar male mice, whereas final social status acquired within a cage remains unaffected. These results support the idea that previous social context is relevant for the development of social hierarchy of a group. Overall, our data identify two context-dependent forms of dominance, acute and chronic, and that pheromone signaling through V1R receptors is involved in the first stages of a social competition but in the long term is not predictive for high social ranks on a hierarchy. Social dominance comprises a set of behaviors related to the control of resources between animals of the same species, including access to territory, reproduction, and food 1. Such imposition can be either chronic or acute when animals face either repetitive or sporadic encounters. In group-living animals, repetitive encounters of animals living in the same group can lead to social dominance, i.e. social hierarchy, conditioned by the group's social history 2. In non-group living animals, territorial control can occur as a result of acute dyadic interactions 3 between animals with no record of previous contact. Whether these two different types of dominance are regulated by the same neural mechanisms is currently unclear.

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.

Adult neural plasticity is an important and intriguing phenomenon in the brain, and adult hippocampal neurogenesis is directly involved in modulating neural plasticity by mechanisms that are only partially understood. We have performed gainof-function and loss-of-function experiments to study Smad2, a transcription factor selected from genes that are demethylated after exercise through the analysis of an array of physical activity-induced factors, and their corresponding gene expression, and an efficient inducer of plasticity. In these studies, changes in cell number and morphology were analyzed in the hippocampal dentate gyrus (cell proliferation and survival, including regional distribution, and structural maturation/differentiation, including arborization, dendritic spines, and neurotransmitter-specific vesicles) of sedentary male mice, after evaluation in a battery of behavioral tests. As a result, we reveal a role for Smad2 in the balance of proliferation versus maturation of differentiating immature cells (Smad2 silencing increases both the proliferation and survival of cycling cells in the dentate granule cell layer), and in the plasticity of both newborn and mature neurons in mice (by decreasing dendritic arborization and dendritic spine number). Moreover, Smad2 silencing specifically compromises spatial learning in mice (through impairments of spatial tasks acquisition both in long-term learning and working memory). These data suggest that Smad2 participates in adult neural plasticity by influencing the proliferation and maturation of dentate gyrus neurons.

Phytoestrogens are considered beneficial for health, but some studies have shown that they may cause adverse effects. This study investigated the effects of genistein administration during the second week of life on energy metabolism and on the circuits regulating food intake. Two different genistein doses, 10 or 50 µg/g, were administered to male and female rats from postnatal day (P) 6 to P13. Physiological parameters, such as body weight and caloric intake, were then analyzed at P90. Moreover, proopiomelanocortin (POMC) expression in the arcuate nucleus (Arc) and orexin expression in the dorsomedial hypothalamus (DMH), perifornical area (PF) and lateral hypothalamus (LH) were studied. Our results showed a delay in the emergence of sex differences in the body weight in the groups with higher genistein doses. Furthermore, a significant decrease in the number of POMC-immunoreactive (POMC-ir) cells in the Arc in the two groups of females treated with genistein was observed. In contrast, no alteration in orexin expression was detected in any of the structures analyzed in either males or females. In conclusion, genistein can modulate estradiol’s programming actions on the hypothalamic feeding circuits differentially in male and female rats during development.

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.

No abstract

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.