STUDY PURPOSE: Traumatic spinal cord injury (SCI) triggers a neuro-inflammatory response dominated by tissue-resident microglia and monocyte derived macrophages (MDMs). To better understand the specific role of microglia in SCI, we pharmacologically depleted microglia using the CSF1R antagonist PLX5622 (1200 ppm). We used behavioral, anatomical, histopathological, tract tracing, bulk RNA sequencing and single cell RNA sequencing techniques to reveal the cellular and molecular responses to SCI that are controlled by microglia. We also reconstituted mice with or without microglia, with recombinant CCL2 (rCCL2, 50 ng intraspinally at 2 dpi) and/or a TLR2 agonist (500 ng intraspinally at 2 dpi and/or 50 ug/kg i.p. at 3 dpi). We also collected baseline behavior and challenged mice with lipopolysaccharide (LPS, 1 mg/kg daily for four consecutive days) to determine whether PLX5622 has any off-target effects. DATA COLLECTED: The dataset includes n=230 female mice aged 10-12-weeks on a C57BL/6J background. Mice received a 75 kdyne T9 IH contusion SCI, sham surgery, or a L1 or T9 complete forceps crush SCI. Mice were fed PLX5622 (1200 ppm) or Vehicle chow from 2 weeks before surgery/ intervention until the experimental end point of 3d, 4d, 7d, 14d, 21d, 28d or 35d after surgery/intervention. The Basso Mouse Scale (BMS) main score and sub-score were used to assess motor function at baseline and 1, 3, 7, 10, 14, 21, 28, and 35 days post-injury. The horizontal ladder task was performed at baseline and day 20, 27 and 34 post-injury. Lesion volume, lesion length, spared myelin, spared axons, astrogliosis, NG2 cell presence, microglia and macrophage presence were analyzed in histological sections using standard immunohistochemical techniques. Dividing cells were identified based on Bromodeoxyuridine (BrdU) labeling (50 mg/kg i.p BrdU administered daily in a subset of mice from 1-7 dpi). Biotinylated dextran amine (BDA, 1 ul, 10% solution) was injected into the motor cortex at 14 dpi to assess the distance of corticospinal tract retraction from a T9 crush SCI at 28 dpi. Injury parameters for all mice, including those used for bulk RNA sequencing or single cell RNA sequencing experiments, are provided. Gene expression datasets are available on Gene Expression Omnibus (GSE196928) and code is available on GitHub at https://github.com/OSU-BMBL/Spinal-cord-scRNAseq. Additional uninjured mice were used to establish baseline behavior and immune responses to LPS challenge in mi...