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Most low-mass stars form in stellar clusters that also contain massive stars, which are sources of far-ultraviolet (FUV) radiation. Theoretical models predict that this FUV radiation produces photodissociation regions (PDRs) on the surfaces of protoplanetary disks around low-mass stars, which affects planet formation within the disks. We report James Webb Space Telescope and Atacama Large Millimeter Array observations of a FUV-irradiated protoplanetary disk in the Orion Nebula. Emission lines are detected from the PDR; modeling their kinematics and excitation allowed us to constrain the physical conditions within the gas. We quantified the mass-loss rate induced by the FUV irradiation and found that it is sufficient to remove gas from the disk in less than a million years. This is rapid enough to affect giant planet formation in the disk.

Despite decades of intense research, disease-modifying therapeutic approaches for Alzheimer's disease (AD) are still very much needed. Apart from the extensively analyzed tau and amyloid pathological cascades, two promising avenues of research that may eventually identify new druggable targets for AD are based on a better understanding of the mechanisms of resilience and vulnerability to this condition. We argue that insulin-like growth factor I (IGF-I) activity in the brain provides a common substrate for the mechanisms of resilience and vulnerability to AD. We postulate that preserved brain IGF-I activity contributes to resilience to AD pathology as this growth factor intervenes in all the major pathological cascades considered to be involved in AD, including metabolic impairment, altered proteostasis, and inflammation, to name the three that are considered to be the most important ones. Conversely, disturbed IGF-I activity is found in many AD risk factors, such as old age, type 2 diabetes, imbalanced diet, sedentary life, sociality, stroke, stress, and low education, whereas the Apolipoprotein (Apo) E4 genotype and traumatic brain injury may also be influenced by brain IGF-I activity. Accordingly, IGF-I activity should be taken into consideration when analyzing these processes, while its preservation will predictably help prevent the progress of AD pathology. Thus, we need to define IGF-I activity in all these conditions and develop a means to preserve it. However, defining brain IGF-I activity cannot be solely based on humoral or tissue levels of this neurotrophic factor, and new functionally based assessments need to be developed.

Mice with insulin receptor (IR)-deficient astrocytes (GFAP-IR knockout [KO] mice) show blunted responses to insulin and reduced brain glucose uptake, whereas IR-deficient astrocytes show disturbed mitochondrial responses to glucose. While exploring the functional impact of disturbed mitochondrial function in astrocytes, we observed that GFAP-IR KO mice show uncoupling of brain blood flow with glucose uptake. Since IR-deficient astrocytes show higher levels of reactive oxidant species (ROS), this leads to stimulation of hypoxia-inducible factor-1α and, consequently, of the vascular endothelial growth factor angiogenic pathway. Indeed, GFAP-IR KO mice show disturbed brain vascularity and blood flow that is normalized by treatment with the antioxidant N -acetylcysteine (NAC). NAC ameliorated high ROS levels, normalized angiogenic signaling and mitochondrial function in IR-deficient astrocytes, and normalized neurovascular coupling in GFAP-IR KO mice. Our results indicate that by modulating glucose uptake and angiogenesis, insulin receptors in astrocytes participate in neurovascular coupling.

Background: Pleiotropic actions of insulin and insulin-like growth factor I (IGF-I) in the brain are context- and cell-dependent, but whether this holds for their receptors (insulin receptor (IR) and IGF-I receptor (IGF-IR), respectively), is less clear. Methods: We compared mice lacking IR or IGF-IR in glial fibrillary astrocytic protein (GFAP)-expressing astrocytes in a tamoxifen-regulated manner, to clarify their role in this type of glial cells, as the majority of data of their actions in brain have been obtained in neurons. Results: We observed that mice lacking IR in GFAP astrocytes (GFAP IR KO mice) develop mood disturbances and maintained intact cognition, while at the same time show greater pathology when cross-bred with APP/PS1 mice, a model of familial Alzheimer´s disease (AD). Conversely, mice lacking IGF-IR in GFAP astrocytes (GFAP-IGF-IR KO mice) show cognitive disturbances, maintained mood tone, and show control-dependent changes in AD-like pathology. Conclusions: These observations confirm that the role of IR and IGF-IR in the brain is cell-specific and context-dependent., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Zegarra-Valdivia J et al.)

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 μL) 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.

It is known that aging is frequently accompanied by a decline in cognition. Furthermore, aging is associated with lower serum IGF-I levels that may contribute to this deterioration. We studied the effect of IGF-I in neurons of the horizontal diagonal band of Broca (HDB) of young (≤6 months old) and old (≥20-month-old) mice to determine if changes in the response of these neurons to IGF-I occur along with aging. Local injection of IGF-I in the HDB nucleus increased their neuronal activity and induced fast oscillatory activity in the electrocorticogram (ECoG). Furthermore, IGF-I facilitated tactile responses in the primary somatosensory cortex elicited by air-puffs delivered in the whiskers. These excitatory effects decreased in old mice. Immunohistochemistry showed that cholinergic HDB neurons express IGF-I receptors and that IGF-I injection increased the expression of c-fos in young, but not in old animals. IGF-I increased the activity of optogenetically-identified cholinergic neurons in young animals, suggesting that most of the IGF-I-induced excitatory effects were mediated by activation of these neurons. Effects of aging were partially ameliorated by chronic IGF-I treatment in old mice. The present findings suggest that reduced IGF-I activity in old animals participates in age-associated changes in cortical activity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zegarra-Valdivia, Chaves-Coira, Fernandez de Sevilla, Martinez-Rachadell, Esparza, Torres-Aleman and Nuñez.)