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Supplementary Table from An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination

Supplementary Data from An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination

Exercise prevents cancer incidence and recurrence, yet the underlying mechanism behind this relationship remains mostly unknown. Here we report that exercise induces the metabolic reprogramming of internal organs that increases nutrient demand and protects against metastatic colonization by limiting nutrient availability to the tumor, generating an exercise-induced metabolic shield. Proteomic and ex vivo metabolic capacity analyses of murine internal organs revealed that exercise induces catabolic processes, glucose uptake, mitochondrial activity, and GLUT expression. Proteomic analysis of routinely active human subject plasma demonstrated increased carbohydrate utilization following exercise. Epidemiologic data from a 20-year prospective study of a large human cohort of initially cancer-free participants revealed that exercise prior to cancer initiation had a modest impact on cancer incidence in low metastatic stages but significantly reduced the likelihood of highly metastatic cancer. In three models of melanoma in mice, exercise prior to cancer injection significantly protected against metastases in distant organs. The protective effects of exercise were dependent on mTOR activity, and inhibition of the mTOR pathway with rapamycin treatment ex vivo reversed the exercise-induced metabolic shield. Under limited glucose conditions, active stroma consumed significantly more glucose at the expense of the tumor. Collectively, these data suggest a clash between the metabolic plasticity of cancer and exercise-induced metabolic reprogramming of the stroma, raising an opportunity to block metastasis by challenging the metabolic needs of the tumor.Significance:Exercise protects against cancer progression and metastasis by inducing a high nutrient demand in internal organs, indicating that reducing nutrient availability to tumor cells represents a potential strategy to prevent metastasis.See related commentary by Zerhouni and Piskounova, p. 4124

C57BL/6 is the most commonly used mouse strain in neurobehavioral research, serving as a background for multiple transgenic lines. However, C57BL/6 exhibit behavioral and sensorimotor disadvantages that worsen with age. We bred FVB/NJ females and C57BL/6J males to generate first-generation hybrid offspring (FVB/NJ x C57BL/6J)F1. The hybrid mice exhibit reduced anxiety-like behavior, improved learning, and enhanced long-term spatial memory. In contrast to both progenitors, hybrids maintain sensorimotor performance upon aging and exhibit improved long-term memory. The hybrids are larger than C57BL/6J, exhibiting enhanced running behavior on a linear track during freely-moving electrophysiological recordings. Hybrids exhibit typical rate and phase coding of space by CA1 pyramidal cells. Hybrids generated by crossing FVB/NJ females with transgenic males of a C57BL/6 background support optogenetic neuronal control in neocortex and hippocampus. The hybrid mice provide an improved model for neurobehavioral studies combining complex behavior, electrophysiology, and genetic tools readily available in C57BL/6 mice.

Exercise prevents cancer incidence and recurrence, yet the underlying mechanism behind this relationship remains mostly unknown. Here we report that exercise induces the metabolic reprogramming of internal organs that increases nutrient demand and protects against metastatic colonization by limiting nutrient availability to the tumor, generating an exercise-induced metabolic shield. Proteomic and ex vivo metabolic capacity analyses of murine internal organs revealed that exercise induces catabolic processes, glucose uptake, mitochondrial activity, and GLUT expression. Proteomic analysis of routinely active human subject plasma demonstrated increased carbohydrate utilization following exercise. Epidemiologic data from a 20-year prospective study of a large human cohort of initially cancer-free participants revealed that exercise prior to cancer initiation had a modest impact on cancer incidence in low metastatic stages but significantly reduced the likelihood of highly metastatic cancer. In three models of melanoma in mice, exercise prior to cancer injection significantly protected against metastases in distant organs. The protective effects of exercise were dependent on mTOR activity, and inhibition of the mTOR pathway with rapamycin treatment ex vivo reversed the exercise-induced metabolic shield. Under limited glucose conditions, active stroma consumed significantly more glucose at the expense of the tumor. Collectively, these data suggest a clash between the metabolic plasticity of cancer and exercise-induced metabolic reprogramming of the stroma, raising an opportunity to block metastasis by challenging the metabolic needs of the tumor. Significance: Exercise protects against cancer progression and metastasis by inducing a high nutrient demand in internal organs, indicating that reducing nutrient availability to tumor cells represents a potential strategy to prevent metastasis. See related commentary by Zerhouni and Piskounova, p. 4124

Traumatic brain injury (TBI) is considered to be the leading cause of disability and death among young people. Up to 30% of mTBI patients report motor impairments, such as altered coordination and impaired balance and gait. The objective of the present study was to characterize motor performance and motor learning changes, in order to achieve a more thorough understanding of the possible motor consequences of mTBI in humans. Mice were exposed to traumatic brain injury using the weight-drop model and subsequently subjected to a battery of behavioral motor tests. Immunohistochemistry was conducted in order to evaluate neuronal survival and synaptic connectivity. TBI mice showed a different walking pattern on the Erasmus ladder task, without any significant impairment in motor performance and motor learning. In the running wheels, mTBI mice showed reduced activity during the second dark phase and increased activity during the second light phase compared to the control mice. There was no difference in the sum of wheel revolutions throughout the experiment. On the Cat-Walk paradigm, the mice showed a wider frontal base of support post mTBI. The same mice spent a significantly greater percent of time standing on three paws post mTBI compared with controls. mTBI mice also showed a decrease in the number of neurons in the temporal cortex compared with the control group. In summary, mTBI mice suffered from mild motor impairments, minor changes in the circadian clock, and neuronal damage. A more in-depth examination of the mechanisms by which mTBI compensate for motor deficits is necessary.

International audience; Academic Core Facilities are optimally situated to improve the quality of preclinical research by implementing quality control measures and offering these to their users.

Contains fulltext : 239279.pdf (Publisher’s version ) (Open Access) The reproducibility crisis (or replication crisis) in biomedical research is a particularly existential and under-addressed issue in the field of behavioral neuroscience, where, in spite of efforts to standardize testing and assay protocols, several known and unknown sources of confounding environmental factors add to variance. Human interference is a major contributor to variability both within and across laboratories, as well as novelty-induced anxiety. Attempts to reduce human interference and to measure more "natural" behaviors in subjects has led to the development of automated home-cage monitoring systems. These systems enable prolonged and longitudinal recordings, and provide large continuous measures of spontaneous behavior that can be analyzed across multiple time scales. In this review, a diverse team of neuroscientists and product developers share their experiences using such an automated monitoring system that combines Noldus PhenoTyper® home-cages and the video-based tracking software, EthoVision® XT, to extract digital biomarkers of motor, emotional, social and cognitive behavior. After presenting our working definition of a "home-cage", we compare home-cage testing with more conventional out-of-cage tests (e.g., the open field) and outline the various advantages of the former, including opportunities for within-subject analyses and assessments of circadian and ultradian activity. Next, we address technical issues pertaining to the acquisition of behavioral data, such as the fine-tuning of the tracking software and the potential for integration with biotelemetry and optogenetics. Finally, we provide guidance on which behavioral measures to emphasize, how to filter, segment, and analyze behavior, and how to use analysis scripts. We summarize how the PhenoTyper has applications to study neuropharmacology as well as animal models of neurodegenerative and neuropsychiatric illness. Looking forward, we examine current challenges and the impact of new developments. Examples include the automated recognition of specific behaviors, unambiguous tracking of individuals in a social context, the development of more animal-centered measures of behavior and ways of dealing with large datasets. Together, we advocate that by embracing standardized home-cage monitoring platforms like the PhenoTyper, we are poised to directly assess issues pertaining to reproducibility, and more importantly, measure features of rodent behavior under more ethologically relevant scenarios. 26 p.

Summary Ultraviolet (UV) light affects endocrinological and behavioral aspects of sexuality via an unknown mechanism. Here we discover that ultraviolet B (UVB) exposure enhances the levels of sex-steroid hormones and sexual behavior, which are mediated by the skin. In female mice, UVB exposure increases hypothalamus-pituitary-gonadal axis hormone levels, resulting in larger ovaries; extends estrus days; and increases anti-Mullerian hormone (AMH) expression. UVB exposure also enhances the sexual responsiveness and attractiveness of females and male-female interactions. Conditional knockout of p53 specifically in skin keratinocytes abolishes the effects of UVB. Thus, UVB triggers a skin-brain-gonadal axis through skin p53 activation. In humans, solar exposure enhances romantic passion in both genders and aggressiveness in men, as seen in analysis of individual questionaries, and positively correlates with testosterone level. Our findings suggest opportunities for treatment of sex-steroid-related dysfunctions., Graphical abstract, Highlights • UVB exposure increases circulating sex-steroid levels in mice and humans • UVB exposure enhances female attractiveness and receptiveness toward males • UVB exposure increases females’ estrus phase, HPG axis hormones, and follicle growth • Skin p53 regulates UVB-induced sexual behavior and ovarian physiological changes, Parikh et al. find that UVB exposure triggers a skin-brain-gonadal axis through skin p53 activation. UVB exposure increases in female mice sexual responsiveness and attractiveness, hypothalamus-pituitary-gonadal axis hormone levels, ovary size, and estrus duration, as well as male-female interactions. Solar exposure in humans enhances romantic passion and positively correlates with male testosterone levels.

Sexual dimorphisms are responsible for profound metabolic differences in health and behavior. Whether males and females react differently to environmental cues, such as solar ultraviolet (UV) exposure, is unknown. Here we show that solar exposure induces food-seeking behavior, food intake, and food-seeking behavior and food intake in men, but not in women, through epidemiological evidence of approximately 3,000 individuals throughout the year. In mice, UVB exposure leads to increased food-seeking behavior, food intake and weight gain, with a sexual dimorphism towards males. In both mice and human males, increased appetite is correlated with elevated levels of circulating ghrelin. Specifically, UVB irradiation leads to p53 transcriptional activation of ghrelin in skin adipocytes, while a conditional p53-knockout in mice abolishes UVB-induced ghrelin expression and food-seeking behavior. In females, estrogen interferes with the p53–chromatin interaction on the ghrelin promoter, thus blocking ghrelin and food-seeking behavior in response to UVB exposure. These results identify the skin as a major mediator of energy homeostasis and may lead to therapeutic opportunities for sex-based treatments of endocrine-related diseases.

While high risk of failure is an inherent part of developing innovative therapies, it can be reduced by adherence to evidence-based rigorous research practices. Numerous analyses conducted to date have clearly identified measures that need to be taken to improve research rigor. Supported through the European Union's Innovative Medicines Initiative, the EQIPD consortium has developed a novel preclinical research quality system that can be applied in both public and private sectors and is free for anyone to use. The EQIPD Quality System was designed to be suited to boost innovation by ensuring the generation of robust and reliable preclinical data while being lean, effective and not becoming a burden that could negatively impact the freedom to explore scientific questions. EQIPD defines research quality as the extent to which research data are fit for their intended use. Fitness, in this context, is defined by the stakeholders, who are the scientists directly involved in the research, but also their funders, sponsors, publishers, research tool manufacturers and collaboration partners such as peers in a multi-site research project. The essence of the EQIPD Quality System is the set of 18 core requirements that can be addressed flexibly, according to user-specific needs and following a user-defined trajectory. The EQIPD Quality System proposes guidance on expectations for quality-related measures, defines criteria for adequate processes (i.e., performance standards) and provides examples of how such measures can be developed and implemented. However, it does not prescribe any pre-determined solutions. EQIPD has also developed tools (for optional use) to support users in implementing the system and assessment services for those research units that successfully implement the quality system and seek formal accreditation. Building upon the feedback from users and continuous improvement, a sustainable EQIPD Quality System will ultimately serve the entire community of scientists conducting non-regulated preclinical research, by helping them generate reliable data that are fit for their intended use.

Activity-dependent neuroprotective protein (ADNP) mutations are linked with cognitive dysfunctions characterizing the autistic-like ADNP syndrome patients, who also suffer from delayed motor maturation. We thus hypothesized that ADNP is deregulated in versatile myopathies and that local ADNP muscle deficiency results in myopathy, treatable by the ADNP fragment NAP. Here, single-cell transcriptomics identified ADNP as a major constituent of the developing human muscle. ADNP transcript concentrations further predicted multiple human muscle diseases, with concentrations negatively correlated with the ADNP target interacting protein, microtubule end protein 1 (EB1). Reverting back to modeling at the single-cell level of the male mouse transcriptome, Adnp mRNA concentrations age-dependently correlated with motor disease as well as with sexual maturation gene transcripts, while Adnp expressing limb muscle cells significantly decreased with aging. Mouse Adnp heterozygous deficiency exhibited muscle microtubule reduction and myosin light chain (Myl2) deregulation coupled with motor dysfunction. CRISPR knockdown of adult gastrocnemius muscle Adnp in a Cas9 mouse resulted in treadmill (male) and gait (female) dysfunctions that were specifically ameliorated by treatment with the ADNP snippet, microtubule interacting, Myl2&mdash, regulating, NAP (CP201). Taken together, our studies provide new hope for personalized diagnosis/therapeutics in versatile myopathies.

Schizophrenia is a debilitating psychiatric disorder with a significant number of patients not adequately responding to treatment. Phencyclidine (PCP) is used as a validated model for schizophrenia, shown to reliably induce positive, negative and cognitive-like behaviors in rodents. It was previously shown in our lab that behavioral phenotypes of PCP-treated mice can be alleviated after intracranial transplantation of mesenchymal stem cells (MSC). Here, we assessed the feasibility of intranasal delivery of MSCs-derived-extracellular vesicles (EVs) to alleviate schizophrenia-like behaviors in a PCP model of schizophrenia. As MSCs-derived EVs were already shown to concentrate at the site of lesion in the brain, we determined that in PCP induced injury the EVs migrate to the prefrontal cortex (PFC) of treated mice, a most involved area of the brain in schizophrenia. We show that intranasal delivery of MSC-EVs improve social interaction and disruption in prepulse inhibition (PPI) seen in PCP-treated mice. In addition, immunohistochemical studies demonstrate that the EVs preserve the number of parvalbumin-positive GABAergic interneurons in the PFC of treated mice. Finally, MSCs-EVs reduced glutamate levels in the CSF of PCP-treated mice, which might explain the reduction of toxicity. In conclusion, we show that MSCs-EVs improve the core schizophrenia-like behavior and biochemical markers of schizophrenia and might be used as a novel treatment for this incurable disorder.

Ultraviolet (UV) light affects endocrinological and behavioral aspects of human sexuality via an unknown mechanism. Using a unique male-female comparative approach, we discovered that the sexual behavioral and hormonal features enhanced by UVB are mediated by the skin. In mice, UV exposure increases hypothalamus-pituitary-gonadal axis hormone levels, resulting in enhanced ovary size, extended estrus days, and anti-Mullerian hormone (AMH) expression. It likewise enhances sexual responsiveness and attractiveness of females and heterosexual interactions of both males and females. Conditional knockout of p53 specifically in skin keratinocytes abolished UV’s effects. In humans, UV exposure enhanced romantic passion in both genders, increased testosterone levels in men and correlated with heightened plasma AMH levels in women. Our data, revealing that UVB triggers a skin-brain-gonadal axis through skin p53 activation, offers therapeutic opportunities for sex-steroid-related dysfunctions. We speculate that during human furless skin evolution, the skin became the front-line regulator of the response to UVB.

The present study was designed to tackle two notorious features of mild traumatic brain injury (mTBI)-heterogeneity and invisibility-by characterizing the full scope of mTBI symptoms. Mice were exposed to brain injuries of different intensities utilizing a weight-drop model (10, 30, 50, and 70 g) and subsequently subjected to a comprehensive battery of behavioral tests at different time points and immunohistochemical examination of cortical slices. Whereas the physiological, neurological, emotional, and motor function of mTBI mice (i.e., their well-being) remained largely intact, cognitive deficits were identified by the y-maze and novel object recognition. Results from these two cognitive tests were combined and a dose-response relationship was established between injury intensity and cognitive impairment, ranging from an 85% decline after a 70-g impact (p 0.001) to a 20% decline after a 10-g impact (essentially no effect). In addition, higher intensities of injury were accompanied by decreased expression of axonal and synaptic markers. Thus, our mTBI mice showed a clear discrepancy between performance (poor cognitive function) and appearance (healthy demeanor). This is of major concern given that diagnosis of mTBI is established on the presence of clinical symptoms and emphasizes the need for an alternative diagnostic modality.

Scientific investigations, in general, and research in neuroscience, in particular, are becoming ever more complex and require the integration of different techniques. Behavioral assays, which are among the most frequently used methodologies in neuroscience, nowadays rely on advanced, sophisticated technologies that require proficient application. Therefore, behavioral core facilities are becoming essential support units, as they provide the specialized expert research services needed to conduct advanced neuroscience. We here review the lessons learned and insights gathered from managing behavioral core facilities in different academic research institutes. This review addresses several issues, including: the advantages of behavioral core facilities, considerations for establishing a behavioral core facility, and the methodological advances made through calibration and standardization of assay protocols and the development of new assays. Collectively, the review highlights the benefits of both working within and collaborating with behavioral core facility units and emphasizes the potential progress in neuro-phenotyping that such facilities provide.