Circulating insulin-like growth factor I modulates mood and is a biomarker of vulnerability to stress:from mouse to man

Individual susceptibility to anxiety disorders after maladaptive responses to stress is not well understood. We now report that while exploring stress responses in mice after traumatic brain injury (TBI), a condition associated to stress susceptibility, we observed that the anxiogenic effects of either TBI or exposure to life-threatening experiences (predator) were blocked when both stressors were combined. Because TBI increases the entrance into the brain of serum insulin-like growth factor I (IGF-I), a known modulator of anxiety with a wide range of concentrations in the human population, we then determined whether circulating IGF-I is related to anxiety measures. In mice, anxiety-like responses to predator were inversely related to circulating IGF-I levels. Other indicators of mood regulation such as sensitivity to dexamethasone suppression and expression levels of blood and brain FK506 binding protein 5 (FKBP5), a co-chaperone of the glucocorticoid receptor that regulates its activity, were also associated to circulating IGF-I. Indeed, brain FKBP5 expression in mice was stimulated by IGF-I. In addition, we observed in a large human cohort (n = 2686) a significant relationship between plasma IGF-I and exposure to recent stressful life events, while FKBP5 expression in blood cells was significantly associated to plasma IGF-I levels. Collectively, these data indicate that circulating IGF-I appears to be involved in mood homeostasis across different species. Furthermore, the data in mice allow us to indicate that IGF-I may be acting at least in part by modulating FKBP5 expression

Exploring the distribution of waterborne pathogens Giardia and Cryptosporidium along a land-use gradient in Oregon in the context of One Health

Giardia and Cryptosporidium protozoans are resilient, zoonotic waterborne pathogens that can bypass water treatment and kill millions of people and animals annually. Giardia and Cryptosporidium cysts and oocysts, respectively, can spread through feces; poor sanitation and poverty can increase the risk for giardiasis and cryptosporidiosis diarrheal diseases. We are currently facing many global challenges from the increase of globalization, anthropogenic environmental change, emerging diseases, and the destruction of natural habitats and biodiversity. The One Health concept considers all these attributes by holistically prioritizing human, animal, and environmental health to improve the planet's overall health. Our aim is a multidisciplinary collaboration between healthcare professionals, veterinarians, and students to achieve the One Health principles in the community. We are exploring the distribution of waterborne pathogens Giardia and Crypto to see whether their presence and species abundance changes over a land-use gradient. Forty-three total sites were sampled in Oregon: 24 sites in Mary’s River in the Willamette Valley (western Oregon) and 19 sites along the White River in Tygh Valley (eastern Oregon). These locations and river systems start at undisturbed locations and travel through increasingly disturbed areas where agriculture and urbanization are prominent. One liter of water was collected at each sampling site and filtered through 0.45 µm cellulose nitrate filters later dissolved in acetone. Samples were aliquoted for a Merifluor immunoassay where the presence or absence of Giardia and Crypto were established. Using multilocus genotyping the 18S rRNA gene, β-giardin (bg)gene, triosephosphate isomerase (Tpi) gene, and glutamate dehydrogenase (Gdh) gene will be sequenced using MiSeq sequencing for Giardia. BLAST and Giardia database will be utilized to determine the species of Giardia and the relative abundance of each strain. A generalized linear model will be used to demonstrate the change in relative abundance of Giardia and Crypto species across the land-use gradient. Tygh Valley samples were positive for both Giardia and Cryptosporidium except for one site after Merifluor immunoassay. Mary’s River samples were not determined using Merifluor due to a procedure error, thus, the 18S rRNA gene will be used to PCR screen for the presence of Giardia at these sites. An ANOVA test was performed, results (Giardia and Crypto p-values = 0.684 & 0.507) demonstrated no significance over a land-use gradient for the presence of Giardia and Crypto. The next step is to determine species strain diversity for Giardia. We expect to see higher strain diversity at low disturbance sites because the high disturbance sites may allow strains that predominantly infect humans to outcompete the other strains. Currently, Giardia abundance is our focal point, but Cryptosporidium abundance research is pending. Further analyses are ongoing; however, our future results will demonstrate how human disturbance affects Giardia and Crypto diversity. This will help us determine what populations of animals and people are at risk in Oregon by knowing which strains are in higher abundance where human activity is prominent. It is important to understand the abundance of different assemblages of Giardia across these different land-use distributions by doing routine testing to predict and prevent the risk of outbreaks and disease in the community

Editorial: Insulin and The Brain

International audienceThe role of insulin in the brain has been suggested in the late 1950's based on experiments showing that insulin was able to increase glucose uptake in spinal cord tissue, in several brain regions such as the choroid plexus the pineal gland, and in the pituitary (1). Since then, increasing evidence attributed to insulin action in the brain numerous critical roles in the control of vital physiological functions: energy homeostasis, neuronal plasticity, and growth, lipid, and glucose metabolism through the control of peripheral organs. Furthermore, the alteration of insulin action observed in insulin-resistant state or obesity is considered a risk factor for several pathologies including neurodegenerative diseases and metabolic disorders. Nowadays, many studies aim to decipher the mechanisms of insulin action in different brain regions and the related physio-pathological outputs

Insulin regulates neurovascular coupling through astrocytes.

Circulating insulin enters the brain through mechanisms incompletely characterized. We now report that mice lacking insulin receptors (IR) in astrocytes (GFAP-IR KO mice) show blunted brain responses to insulin, uncoupling of brain blood flow with glucose uptake with concomitant changes in brain vasculature and glucose transporter 1 levels. IR-deficient astrocytes show increased expression of HIF-1α/VEGF, promote growth of co-cultured endothelial cells, display increased reactive oxidant species (ROS) and disturbed mitochondrial activity. Treatment with the antioxidant N-acetylcysteine (NAC), ameliorated high ROS levels, normalized angiogenic signaling, and mitochondrial function including mitochondrial glucose and oxygen sensors. In vivo treatment with NAC also normalized brain perfusion. Thus, insulin receptors in astrocytes regulate neuro-vascular coupling.pre-print4711 K

Combining 2D organic and 1D inorganic nanoblocks to develop free-standing hybrid nanomembranes for conformable biosensors

We report a simple approach to fabricate free-standing perforated 2D nanomembranes hosting well-ordered 1D metallic nanostructures to obtain hybrid materials with nanostructured surfaces for flexible electronics. Nanomembranes are formed by alternatively depositing perforated poly(lactic acid) (PLA) and poly(3,4-ethylenedioxythiophene) layers. Copper metallic nanowires (NWs) were incorporated into the nanoperforations of the top PLA layer by electrodeposition and further coated with silver via a transmetallation reaction. The combination of 2D polymeric nanomembranes and aligned 1D metallic NWs allows merging the flexibility and conformability of the ultrathin soft polymeric nanomembranes with the good electrical properties of metals for biointegrated electronic devices. Thus, we were able to tailor the nanomembrane surface chemistry as it was corroborated by SEM, EDX, XPS, CV, EIS and contact angle. The obtained hybrid nanomembranes were flexible and conformable showing sensing capacity towards H2O2 with good linear concentration range (0.35–10 mM), sensitivity (120 µA cm?2 mM?1) and limit of detection (7 ?m). Moreover, the membranes showed good stability, reproducibility and selectivity towards H2O2

Interaction of gonadal steroids and growth factors in brain sex differentiation

Sex hormones have developmental trophic actions on neurons and glial cells and activational effects in the adult brain. It has been proposed that sex steroids may interact with peptide trophic factors to induce part of their biological effects in the nervous system. The first evidence of such an interaction was provided by Toran-Allerand et al (Brain Research 1980; 184: 517-524), showing that in explant cultures of fetal rodent hypothalamus, estrogen and insulin have synergistic effects on neurite growth, an effect probably mediated by insulin-like growth factor-1 receptors. Recent data indicate that estrogen and insulin-like growth factor-1 signaling pathways interact on hypothalamic neurons to regulate survival and differentiation and that sex steroids interact with a variety of different trophic signals in vivo to regulate neuroendocrine events. These findings suggest that trophic factors may be involved in the genesis of sex differences in the developing brain and in the maintenance of a sexually differentiated brain function in the adult.Biomedical Reviews 1997; 7: 67-74

Response Facilitation Induced by Insulin-like Growth Factor-I in the Primary Somatosensory Cortex of MiceWas Reduced in Aging.

Aging is accompanied by a decline in cognition that can be due to a lower IGF-I level. We studied response facilitation induced in primary somatosensory (S1) cortical neurons by repetitive stimulation of whiskers in young and old mice. Layer 2/3 and 5/6 neurons were extracellularly recorded in young ( 6 months of age) and old ( 20 month of age) anesthetized mice. IGF-I injection in S1 cortex (10 nM; 0.2 L) increased whisker responses in young and old animals. A stimulation train at 8 Hz induced a long-lasting response facilitation in only layer 2/3 neurons of young animals. However, all cortical neurons from young and old animals showed long-lasting response facilitation when IGF-I was applied in the S1 cortex. The reduction in response facilitation in old animals can be due to a reduction in the IGF-I receptors as was indicated by the immunohistochemistry study. Furthermore, a reduction in the performance of a whisker discrimination task was observed in old animals. In conclusion, our findings indicate that there is a reduction in the synaptic plasticity of S1 neurons during aging that can be recovered by IGF-I. Therefore, it opens the possibility of use IGF-I as a therapeutic tool to ameliorate the effects of heathy aging.post-print2685 K

Astrocytes require insulin-like growth factor I to protect neurons against oxidative injury

Oxidative stress is a proposed mechanism in brain aging, making the study of its regulatory processes an important aspect of current neurobiological research. In this regard, the role of the aging regulator insulin-like growth factor I (IGF-I) in brain responses to oxidative stress remains elusive as both beneficial and detrimental actions have been ascribed to this growth factor. Because astrocytes protect neurons against oxidative injury, we explored whether IGF-I participates in astrocyte neuroprotection and found that blockade of the IGF-I receptor in astrocytes abrogated their rescuing effect on neurons. The protection mediated by IGF-I against oxidative stress (H2O2) in astrocytes is probably needed for these cells to provide adequate neuroprotection. Indeed, in astrocytes but not in neurons, IGF-I helps decrease the pro-oxidant protein thioredoxin-interacting protein 1 and normalizes the levels of reactive oxygen species. Furthermore, IGF-I cooperates with trophic signals produced by astrocytes in response to H2O2 such as stem cell factor (SCF) to protect neurons against oxidative insult. After stroke, a condition associated with brain aging where oxidative injury affects peri-infarcted regions, a simultaneous increase in SCF and IGF-I expression was found in the cortex, suggesting that a similar cooperative response takes place in vivo. Cell-specific modulation by IGF-I of brain responses to oxidative stress may contribute in clarifying the role of IGF-I in brain aging