ER-transiting bacterial toxins amplify STING innate immune responses and elicit ER stress.

The cGAS/STING sensor system drives innate immune responses to intracellular microbial double-stranded DNA (dsDNA) and bacterial cyclic nucleotide second messengers (e.g., c-di-AMP).

Early Postnatal Exposure to Midazolam Causes Lasting Histological and Neurobehavioral Deficits via Activation of the mTOR Pathway.

Exposure to general anesthetics can adversely affect brain development, but there is little study of sedative agents used in intensive care that act via similar pharmacologic mechanisms. Using quantitative immunohistochemistry and neurobehavioral testing and an established protocol for murine sedation, we tested the hypothesis that lengthy, repetitive exposure to midazolam, a commonly used sedative in pediatric intensive care, interferes with neuronal development and subsequent cognitive function via actions on the mechanistic target of rapamycin (mTOR) pathway. We found that mice in the midazolam sedation group exhibited a chronic, significant increase in the expression of mTOR activity pathway markers in comparison to controls.

Effects of Early Exposure to Isoflurane on Susceptibility to Chronic Pain Are Mediated by Increased Neural Activity Due to Actions of the Mammalian Target of the Rapamycin Pathway.

Patients who have undergone surgery in early life may be at elevated risk for suffering neuropathic pain in later life. The risk factors for this susceptibility are not fully understood. Here, we used a mouse chronic pain model to test the hypothesis that early exposure to the general anesthetic (GA) Isoflurane causes cellular and molecular alterations in dorsal spinal cord (DSC) and dorsal root ganglion (DRG) that produces a predisposition to neuropathic pain via an upregulation of the mammalian target of the rapamycin (mTOR) signaling pathway.

Early Isoflurane Exposure Impairs Synaptic Development in Fmr1 KO Mice via the mTOR Pathway.

General anesthetics (GAs) may cause disruptions in brain development, and the effect of GA exposure in the setting of pre-existing neurodevelopmental disease is unknown. We tested the hypothesis that synaptic development is more vulnerable to GA-induced deficits in a mouse model of fragile X syndrome than in WT mice and asked whether they were related to the mTOR pathway, a signaling system implicated in both anesthesia toxicity and fragile X syndrome. Early postnatal WT and Fmr1-KO mice were exposed to isoflurane and brain slices were collected in adulthood.

Effects of Early Exposure of Isoflurane on Chronic Pain via the Mammalian Target of Rapamycin Signal Pathway.

Persistent post-surgical pain (PPSP) is a chronic pain condition, often with neuropathic features, that occurs in approximately 20% of children who undergo surgery. The biological basis of PPSP has not been elucidated. Anesthetic drugs can have lasting effects on the developing nervous system, although the clinical impact of this phenomenon is unknown.

Early Postnatal Exposure to Isoflurane Disrupts Oligodendrocyte Development and Myelin Formation in the Mouse Hippocampus.

Background: Early postnatal exposure to general anesthetics may interfere with brain development. We tested the hypothesis that isoflurane causes a lasting disruption in myelin development via actions on the mammalian target of rapamycin pathway.

Methods: Mice were exposed to 1.

Anesthetics disrupt growth cone guidance cue sensing through actions on the GABA α2 receptor mediated by the immature chloride gradient.

Background: General anesthetics (GAs) may exert harmful effects on the developing brain by disrupting neuronal circuit formation. Anesthetics that act on γ-aminobutyric acid (GABA) receptors can interfere with axonal growth cone guidance, a critical process in the assembly of neuronal circuitry. Here we investigate the mechanism by which isoflurane prevents sensing of the repulsive guidance cue, Semaphorin 3A (Sema3A).

General Anesthesia Alters the Diversity and Composition of the Intestinal Microbiota in Mice.

Dysbiosis of the intestinal microbiota has been shown to result in altered immune responses and increased susceptibility to infection; as such, the state of the intestinal microbiome may have profound implications in the perioperative setting. In this first-in-class study, we used 16s ribosomal RNA sequencing and analysis in a mouse model of general anesthesia to investigate the effects of volatile anesthetics on the diversity and composition of the intestinal microbiome. After 4-hour exposure to isoflurane, we observed a decrease in bacterial diversity.

Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway.

Human epidemiologic studies and laboratory investigations in animal models suggest that exposure to general anesthetic agents (GAs) have harmful effects on brain development. The mechanism underlying this putative iatrogenic condition is not clear and there are currently no accepted strategies for prophylaxis or treatment. Recent evidence suggests that anesthetics might cause persistent deficits in synaptogenesis by disrupting key events in neurodevelopment.

Sevoflurane Impairs Growth Cone Motility in Dissociated Murine Neurons.

Background: Early postnatal exposure to general anesthetic agents causes a lasting impairment in learning and memory in animal models. One hypothesis to explain this finding is that exposure to anesthetic agents during critical points in neural development disrupts the formation of brain circuitry. Here, we explore the effects of sevoflurane on the neuronal growth cone, a specialization at the growing end of axons and dendrites that is responsible for the targeted growth that underlies connectivity between neurons.