Neuropathic pain is a complex chronic condition characterized by a wide range of sensory, cognitive, and affective symptoms. A large percentage of neuropathic pain patients are also afflicted with depression and anxiety disorders – a pattern that is reliably replicated in animal models. Furthermore, clinical and preclinical studies indicate that chronic pain corresponds with adaptations in several brain networks involved in mood, motivation, and reward. Chronic stress is also a major risk factor for depression. We investigated whether chronic pain and stress affect similar mechanisms, and whether chronic pain can affect gene expression patterns known to be involved in depression. Using two mouse models for neuropathic pain and depression (spared nerve injury (SNI) and chronic unpredictable stress (CUS)) we performed next generation RNA-sequencing and pathway analysis to monitor changes in gene expression in the nucleus accumbens (NAc), the medial prefrontal cortex (mPFC), and the periaqueductal grey (PAG). These three brain regions are implicated in the pathophysiology of depression and in the modulation of pain. In addition to finding unique transcriptome profiles across the three brain regions,.we identified a substantial number of signaling pathway-associated genes with similar changes in expression in both SNI and CUS mice. Many of these genes have been implicated in depression, anxiety and chronic pain in patients. Our study provides a resource of the changes in gene expression induced by long-term neuropathic pain in three distinct brain regions and reveals molecular connections between pain and chronic stress.

Tissue repair after spinal cord injury (SCI) requires mobilization of immune and glial cells to form a protective barrier that seals the wound and facilitates debris clearing, inflammatory containment, and matrix compaction. This process involves corralling, wherein phagocytic immune cells become confined to the necrotic core surrounded by an astrocytic border. Here, we elucidate a temporally distinct gene signature in injury-activated microglia/macrophages (IAM), which engages axon guidance pathways. Plexin-B2 is upregulated in IAM, which is required for motosensory recovery after SCI. Plexin-B2 deletion in myeloid cells impairs corralling, leading to diffuse tissue damage, inflammatory spillover, and hampered axon regeneration. Corralling begins early and requires Plexin-B2 in both microglia and macrophages. Mechanistically, Plexin-B2 promotes microglia motility, steers IAM away from colliding cells, and facilitates matrix compaction. Our data thus establish Plexin-B2 as an important link that integrates biochemical cues and physical interactions of IAM with the injury microenvironment during wound healing.

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