PT  - JOURNAL ARTICLE
AU  - Yu-Qiu Jiang
AU  - Adrish Sarkar
AU  - Alzahraa Amer
AU  - John H. Martin
TI  - Transneuronal down-regulation of the premotor cholinergic system after corticospinal tract loss
AID  - 10.1523/JNEUROSCI.3410-17.2018
DP  - 2018 Jul 26
TA  - The Journal of Neuroscience
PG  - 3410-17
4099  - http://www.jneurosci.org/content/early/2018/07/26/JNEUROSCI.3410-17.2018.short
4100  - http://www.jneurosci.org/content/early/2018/07/26/JNEUROSCI.3410-17.2018.full
AB  - Injury to the supraspinal motor systems, especially the corticospinal tract, leads to movement impairments. In addition to direct disruption of descending motor pathways, spinal motor circuits that are distant to and not directly damaged by the lesion undergo remodeling that contributes significantly to the impairments. Knowing which spinal circuits are remodeled and the underlying mechanisms are critical for understanding the functional changes in the motor pathway and for developing repair strategies. Here we target spinal premotor cholinergic interneuron that directly modulate motoneuron excitability via their cholinergic C-bouton terminals. Using model of unilateral medullary corticospinal tract lesion in male rats, we found progressive transneuronal down-regulation of the premotor cholinergic pathway. Phagocytic microglial cells were up-regulated in parallel with cholinergic pathway down-regulation, and both were blocked by minocycline, a microglia activation inhibitor. Additionally, we found a transient increase in interneuronal complement protein C1q expression that preceded cell loss. Three-dimensional reconstructions showed ongoing phagocytosis of C1q-expressing cholinergic interneurons by microglia 3 days post-injury, which was complete by 10 days post-injury. Unilateral motor cortex inactivation using the GABAA receptor agonist muscimol replicated the changes detected at 3 days after lesion indicating an activity-dependence. The neuronal loss after the lesion was rescued by increasing spinal activity using cathodal trans-spinal direct current stimulation. Our finding of activity-dependent modulation of cholinergic premotor interneurons after CST injury provides the mechanistic insight that maintaining activity, possibly during a critical period, helps protect distant motor circuits from further damage, and as a result, may improve motor functional recovery and rehabilitation.SIGNIFICANCE STATEMENTSupraspinal injury to the motor system disrupts descending motor pathways, leading to movement impairments. Whether and how intrinsic spinal circuits are remodeled after a brain injury is unclear. Using a rat model of unilateral corticospinal tract lesion in the medulla, we show activity-dependent, transneuronal down-regulation of the spinal premotor cholinergic system, which is mediated by microglia phagocytosis and possibly involves a rapid and transient increase in neuronal C1q before neuronal loss. Spinal cord neuromodulation after injury, to augment spinal activity, rescued the premotor cholinergic system. Our findings provide the mechanistic insight that maintaining activity, possibly during an early critical period, could protect distant motor circuits from further damage mediated by microglia and interneuronal complement protein, and improve motor functional outcomes.