Spinal cord injury as a window into hippocampal dysfunction: Linking inflammation, neurogenesis, and network...

The hippocampus, essential for learning, memory, and affective regulation, is increasingly recognized as vulnerable to systemic and remote insults. Spinal cord injury (SCI), traditionally viewed as a motor-sensory disorder, can trigger widespread neurobiological changes that extend beyond the lesion site and affect distant brain regions, particularly the hippocampus. SCI-induced systemic inflammation, oxidative stress, HPA axis dysregulation, autonomic dysfunction, chronic pain, and disrupted neuroimmune signaling collectively contribute to hippocampal pathology. Preclinical studies reveal a biphasic glial response characterized by early astrocytic and microglial activation followed by chronic pro-inflammatory polarization, sustained cytokine release, and loss of inhibitory checkpoints. Convergent mechanisms, including ER stress, chemokine signaling, cell-cycle re-entry, and α-synuclein accumulation, exacerbate neuronal loss and impair adult neurogenesis. Structural and functional consequences include persistent silent glutamatergic synapses enriched in NR2B-containing NMDA receptors, dendritic atrophy, mitochondrial dysfunction, and reductions in theta and gamma oscillations, all of which are associated with impaired synaptic plasticity and apoptosis. Behaviorally, experimental models consistently demonstrate spatial and recognition memory deficits, together with depression- and anxiety-like phenotypes. Translation to humans remains variable. While structural MRI studies often fail to demonstrate overt hippocampal atrophy, proton MR spectroscopy has revealed reduced hippocampal Glx levels associated with impaired memory performance. Together, these findings position SCI-induced hippocampal dysfunction as a multidimensional process involving neuroinflammation, oxidative stress, impaired neurogenesis, synaptic remodeling, and network disruption. These alterations may substantially contribute to the cognitive, emotional, and memory-related sequelae observed after SCI and identify the hippocampus as an important but often overlooked therapeutic target.