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Summary: Microglia-mediated synaptic plasticity after CNS injury varies depending on injury severity, but the mechanisms that adjust synaptic plasticity according to injury differences are largely unknown. This study investigates differential actions of microglia on essential spinal motor synaptic circuits following different kinds of nerve injuries. Following nerve transection, microglia and C-C chemokine receptor type 2 signaling permanently remove Ia axons and synapses from the ventral horn, degrading proprioceptive feedback during motor actions and abolishing stretch reflexes. However, Ia synapses and reflexes recover after milder injuries (nerve crush). These different outcomes are related to the length of microglia activation, being longer after nerve cuts, with slower motor-axon regeneration and extended expression of colony-stimulating factor type 1 in injured motoneurons. Prolonged microglia activation induces CCL2 expression, and Ia synapses recover after ccl2 is deleted from microglia. Thus, microglia Ia synapse removal requires the induction of specific microglia phenotypes modulated by nerve regeneration efficiencies. However, synapse preservation was not sufficient to restore the stretch-reflex function.

Gait dysfunction and fall risk have been well documented in people with Alzheimer's Disease (AD) and individuals with mild cognitive impairment (MCI). Normal locomotor adaptation may be an important prerequisite for normal and safe community walking function, especially in older adults with age-related neural, musculoskeletal, or cardiovascular changes and cognitive impairments. The split-belt walking task is a well-studied and robust method to evaluate locomotor adaptation (e.g., the ability to adjust stepping movements to changing environmental demands). Here, we capitalized on the split-belt adaptation task to test our hypothesis that a decreased capacity for locomotor adaptation may be an important contributing factor and indicator of increased fall risk and cognitive decline in older individuals with MCI and AD. The objectives of this study were to (1) compare locomotor adaptation capacity in MCI and AD compared to healthy older adults (HOA) during split-belt treadmill walking, and (2) evaluate associations between locomotor adaptation and cognitive impairments. Our results demonstrated a significant decrease in split-belt locomotor adaptation magnitude in older individuals with MCI and AD compared to HOA. In addition, we found significant correlations between the magnitude of early adaptation and de-adaptation vs. cognitive test scores, demonstrating that individuals with greater cognitive impairment also display a reduced capacity to adapt their walking in response to the split-belt perturbation. Our study takes an important step toward understanding mechanisms underlying locomotor dysfunction in older individuals with cognitive impairment.

Peripheral nerve injuries induce a pronounced immune reaction within the spinal cord, largely governed by microglia activation in both the dorsal and ventral horns. The mechanisms of activation and response of microglia are diverse depending on the location within the spinal cord, type, severity, and proximity of injury, as well as the age and species of the organism. Thanks to recent advancements in neuro-immune research techniques, such as single-cell transcriptomics, novel genetic mouse models, and live imaging, a vast amount of literature has come to light regarding the mechanisms of microglial activation and alluding to the function of microgliosis around injured motoneurons and sensory afferents. Herein, we provide a comparative analysis of the dorsal and ventral horns in relation to mechanisms of microglia activation (CSF1, DAP12, CCR2, Fractalkine signaling, Toll-like receptors, and purinergic signaling), and functionality in neuroprotection, degeneration, regeneration, synaptic plasticity, and spinal circuit reorganization following peripheral nerve injury. This review aims to shed new light on unsettled controversies regarding the diversity of spinal microglial-neuronal interactions following injury.