ABSTRACT
Severe spinal cord contusions interrupt nearly all brain projections to lumbar circuits producing leg movement. Failure of these projections to reorganize leads to permanent paralysis. Here we modeled these injuries in rodents. A severe contusion abolished all motor cortex projections below injury. However, the motor cortex immediately regained adaptive control over the paralyzed legs during electrochemical neuromodulation of lumbar circuits. Glutamatergic reticulospinal neurons with residual projections below the injury relayed the cortical command downstream. Gravity-assisted rehabilitation enabled by the neuromodulation therapy reinforced these reticulospinal projections, rerouting cortical information through this pathway. This circuit reorganization mediated a motor cortex-dependent recovery of natural walking and swimming without requiring neuromodulation. Cortico-reticulo-spinal circuit reorganization may also improve recovery in humans.
Subject(s)
Motor Cortex/physiology , Recovery of Function/physiology , Spinal Cord Injuries/pathology , Spinal Cord Injuries/physiopathology , Spinal Cord/physiology , Vestibular Nucleus, Lateral/physiology , 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Animals , Brain/anatomy & histology , Brain/drug effects , Channelrhodopsins/genetics , Channelrhodopsins/metabolism , Disease Models, Animal , Female , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Motor Cortex/drug effects , Psychomotor Performance/drug effects , Quipazine/pharmacology , Rats , Rats, Inbred Lew , Recovery of Function/drug effects , Recovery of Function/genetics , Serotonin Receptor Agonists/pharmacology , Spinal Cord/drug effects , Spinal Cord Injuries/diagnostic imaging , Spinal Cord Injuries/drug therapy , Thy-1 Antigens/administration & dosage , Thy-1 Antigens/genetics , Thy-1 Antigens/metabolism , Vestibular Nucleus, Lateral/drug effectsABSTRACT
Glucocorticoids are widely prescribed for renal diseases. It is believed that glucocorticoids attenuate immune-mediated renal diseases by suppressing the cell-mediated immune system. However, there is evidence that glucocorticoids influence the expression of such growth factors as vascular endothelial growth factor (VEGF), transforming growth factor-beta1 (TGF-beta1), and connective tissue growth factor (CTGF), which are known to influence the development or progression of renal diseases. Therefore, we undertook this study to determine whether glucocorticoids regulate proteinuria or extracellular matrix (ECM) production by altering these growth factors. Mesangial proliferative glomerulonephritis was induced in rats by intravenous injection of monoclonal antibody (OX-7), and dexamethasone (20 mg/kg) was administered intraperitoneally from the third to seventh disease day. Glomerular expression of VEGF, TGF-beta1, and CTGF, the amount of urinary protein, and glomerular ECM were measured on the seventh disease day. The nephritic group showed proteinuria and greater VEGF, TGF-beta1, and ECM production. Dexamethasone aggravated proteinuria (protein, 0.4 +/- 0.1 mg/mg creatinine in the NC group, 6.3 +/- 2.0 mg/mg creatinine in the DC group, and 21.1 +/- 1.9 mg/mg creatinine in the D-Dex group; P < 0.05) and diminished VEGF release (22 +/- 3 pg/mg total protein in the NC group, 292 +/- 26 pg/mg total protein in the DC group, and 198 +/- 23 pg/mg total protein in the D-Dex group; P < 0.05). Expression of TGF-beta1, CTGF, and ECM was not altered significantly by dexamethasone treatment. We found that glucocorticoid diminishes VEGF release and at the same time exacerbates proteinuria in rats with this type of glomerulonephritis.
