Early-life stress has long-lasting effects on the stress response, emotions, and behavior throughout an individual's life. Clinical reports have demonstrated that child abuse victims exhibit impairments in reward-associated behavior; yet, the mechanism for this effect remains unclear. Maternal separation (MS) or MS coupled with social isolation (SI) (MS+SI) is widely used as a model for early-life stress in rodent studies. We employed mice subjected to MS+SI to clarify the long-term effect of early-life stress on reward-seeking involving palatable foods by a conditioned place-preference (CPP) paradigm. Prior MS+SI experience decreased exploration time in a chocolate-paired compartment in adult female mice, but not in male mice. We then focused on the mesolimbic dopamine pathway associated with reward-seeking behavior and measured both mRNA and protein levels of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and dopamine D1 and D2 receptors in the nucleus accumbens (NAc). MS+SI female mice had significantly lower D1 receptor mRNA and protein levels than controls, whereas the expression of TH and the D2 receptor was similar in the 2 groups. All mRNA and protein levels were unchanged in MS+SI male mice. When attempting to elucidate the mechanism underlying downregulation of the D1 receptor in the NAc of MS+SI females, we found hypermethylation of the Drd1a promoter region. These results suggest that early-life stress affects reward-seeking behavior in female mice, which may be associated with the downregulation of D1 receptor in the NAc via epigenetic modification of its promoter region.

OBJECTIVE Transplantation of bone marrow stromal cells (BMSCs) is a theoretical potential as a therapeutic strategy in the treatment of spinal cord injury (SCI). Although a scaffold is sometimes used for retaining transplanted cells in damaged tissue, it is also known to induce redundant immunoreactions during the degradation processes. In this study, the authors prepared cell sheets made of BMSCs, which are transplantable without a scaffold, and investigated their effects on axonal regeneration, glial scar formation, and functional recovery in a completely transected SCI model in rats. METHODS BMSC sheets were prepared from the bone marrow of female Fischer 344 rats using ascorbic acid and were cryopreserved until the day of transplantation. A gelatin sponge (GS), as a control, or BMSC sheet was transplanted into a 2-mm-sized defect of the spinal cord at the T-8 level. Axonal regeneration and glial scar formation were assessed 2 and 8 weeks after transplantation by immunohistochemical analyses using anti-Tuj1 and glial fibrillary acidic protein (GFAP) antibodies, respectively. Locomotor function was evaluated using the Basso, Beattie, and Bresnahan scale. RESULTS The BMSC sheets promoted axonal regeneration at 2 weeks after transplantation, but there was no significant difference in the number of Tuj1-positive axons between the sheet- and GS-transplanted groups. At 8 weeks after transplantation, Tuj1-positive axons elongated across the sheet, and their numbers were significantly greater in the sheet group than in the GS group. The areas of GFAP-positive glial scars in the sheet group were significantly reduced compared with those of the GS group at both time points. Finally, hindlimb locomotor function was ameliorated in the sheet group at 4 and 8 weeks after transplantation. CONCLUSIONS The results of the present study indicate that an ascorbic acid–induced BMSC sheet is effective in the treatment of SCI and enables autologous transplantation without requiring a scaffold.

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IMPORTANCEThe optimal management for acute traumatic cervical spinal cord injury (SCI) is unknown. OBJECTIVE To determine whether early surgical decompression results in better motor recovery than delayed surgical treatment in patients with acute traumatic incomplete cervical SCI associated with preexisting canal stenosis but without bone injury. DESIGN, SETTING, AND PARTICIPANTSThis multicenter randomized clinical trial was conducted in 43 tertiary referral centers in Japan from December 2011 through November 2019. Patients aged 20 to 79 years with motor-incomplete cervical SCI with preexisting canal stenosis (American Spinal Injury Association [ASIA] Impairment Scale C; without fracture or dislocation) were included. Data were analyzed from September to November 2020. INTERVENTIONS Patients were randomized to undergo surgical treatment within 24 hours after admission or delayed surgical treatment after at least 2 weeks of conservative treatment. MAIN OUTCOMES AND MEASURES The primary end points were improvement in the mean ASIA motor score, total score of the spinal cord independence measure, and the proportion of patients able to walk independently at 1 year after injury. RESULTS Among 72 randomized patients, 70 patients (mean [SD] age, 65.1 [9.4] years; age range, 41-79 years; 5 [7%] women and 65 [93%] men) were included in the full analysis population (37 patients assigned to early surgical treatment and 33 patients assigned to delayed surgical treatment).Of these, 56 patients (80%) had data available for at least 1 primary outcome at 1 year. There was no significant difference among primary end points for the early surgical treatment group compared with the delayed surgical treatment group (mean [SD] change in ASIA motor score, 53.7 [14.7] vs 48.5 [19.1]; difference, 5.2; 95% CI, −4.2 to 14.5; P = .27; mean [SD] SCIM total score, 77.9 [22.7] vs 71.3 [27.3]; P = .34; able to walk independently, 21 of 30 patients [70.0%] vs 16 of 26 patients [61.5%]; P = .51). A mixed-design analysis of variance revealed a significant difference in the mean change in ASIA motor scores between the groups (F 1,49 = 4.80; P = .03). The early surgical treatment group, compared with the delayed surgical treatment group, had greater motor scores than the delayed surgical treatment group at 2 weeks (mean [SD] score, 34.2 [18.8] vs 18.9 [20.9]), 3 months (mean [SD] score, 49.1 [15.1] vs 37.2 [20.9]), and 6 months (mean [SD] score, 51.5 [13.9] vs 41.3 [23.4]) after injury. Adverse events were common in both groups (eg, worsening of paralysis, 6 patients vs 6 patients; death, 3 patients vs 3 patients).

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