ABSTRACT
Alcohol abuse induces changes in microglia morphology and immune function, but whether microglia initiate or simply amplify the harmful effects of alcohol exposure is still a matter of debate. Here, we determine microglia function in acute and voluntary drinking behaviors using a colony-stimulating factor 1 receptor inhibitor (PLX5622). We show that microglia depletion does not alter the sedative or hypnotic effects of acute intoxication. Microglia depletion also does not change the escalation or maintenance of chronic voluntary alcohol consumption. Transcriptomic analysis revealed that although many immune genes have been implicated in alcohol abuse, downregulation of microglia genes does not necessitate changes in alcohol intake. Instead, microglia depletion and chronic alcohol result in compensatory upregulation of alcohol-responsive, reactive astrocyte genes, indicating astrocytes may play a role in regulation of these alcohol behaviors. Taken together, our behavioral and transcriptional data indicate that microglia are not the primary effector cell responsible for regulation of acute and voluntary alcohol behaviors. Because microglia depletion did not regulate acute or voluntary alcohol behaviors, we hypothesized that these doses were insufficient to activate microglia and recruit them to an effector phenotype. Therefore, we used a model of repeated immune activation using polyinosinic:polycytidylic acid (poly(I:C)) to activate microglia. Microglia depletion blocked poly(I:C)-induced escalations in alcohol intake, indicating microglia regulate drinking behaviors with sufficient immune activation. By testing the functional role of microglia in alcohol behaviors, we provide insight into when microglia are causal and when they are consequential for the transition from alcohol use to dependence.
Subject(s)
Alcoholism/pathology , Microglia/drug effects , Organic Chemicals/pharmacology , Alcohol Drinking/pathology , Alcoholic Intoxication/pathology , Animals , Astrocytes/drug effects , Chronic Disease , Dose-Response Relationship, Drug , Inflammation Mediators/metabolism , Mice , Mice, Inbred C57BL , Motor Skills/drug effects , Receptors, Colony-Stimulating Factor/antagonists & inhibitors , Signal Transduction/drug effects , Sleep/drug effectsABSTRACT
Distal junctional kyphosis (DJK) is defined as the development of a kyphotic angulation over 10 degrees below a fusion construct and has been described as a complication of the treatment of adolescent idiopathic scoliosis, Scheuermann kyphosis, adult spinal deformity, and cervical deformity. There are some inherent risk factors to DJK: multilevel fusions, damage to the midline soft tissues including interspinous/supraspinous ligaments, T5-T12 thoracic kyphosis, T11-L2 thoracolumbar kyphosis, and increased mismatch between cervical lordosis and T1 slope. A 53-year-old male presented with cervicalgia, inability to sustain horizontal gaze, and kyphosis-enabled forward head posture. He underwent C3-T1 posterior decompression and fusion as treatment for cervical myelopathy 18 months prior. Neurologic examination was normal, with appreciable protrusion of the T1 vertebral spinous process. Surgery was initiated through subperiosteal exposure of C2-T6, followed by removal of previously set instrumentation, placement of new screws, and posterior column osteotomies of selected segments. Final steps involved compression across excised portions, locking pedicle screws, and a multirod insertion after closure of the posterior column osteotomies by compression maneuvers. Correction for DJK encompasses sagittal alignment restoration, a stable construct, and a good biological environment for healing. Failure of DJK realignment can occur if the patient's ligaments deteriorate distal to the construct or fractures develop in vertebral bodies at the lowest instrumented vertebra or lowest instrumented vertebra +1. One year after surgery, the patient's condition improved, evidenced from both patient self-report and a standing posture radiograph.