Use of human mesenchymal stem cell treatment to prevent anhedonia in a rat model of traumatic brain injury.

Purpose: Major depression and related mood disorders are the most common long-term outcomes associated with traumatic brain injury (TBI). Given the potentially debilitating consequences of depression, and the fact that TBI patients are frequently refractory to antidepressant drugs, new therapies are clearly needed. We hypothesized that human bone marrow-derived mesenchymal stem cells (hMSC), delivered intravenously, can effectively treat TBI-induced depression and other behavioral deficits associated with TBI. Methods: Rats (n= 8 per group) were subjected to experimental TBI or control sham operation. Six hours post TBI, rats were treated with 1 x 10(6) hMSC or vehicle control Immediately after TBI and prior to hMSC or control treatment, rats were subjected to either targeted precision x-ray irradiation to eliminate subventricular zone (SVZ) proliferation or sham irradiation. One week after TBI, SVZ irradiation, and hMSC treatment, rats were evaluated for the depression -like behavior, anhedonia, using the two-bottle saccharin preference paradigm; and for working memory using the novel object recognition test. Results: TBI resulted in a 54% (p < 0.05) decrease in saccharin preference scores while treatment of TBI with hMSC fully prevented this anhedonic behavior. TBI was also found to produce a 73% (p < 0.05) decrease in novel object interaction time, indicating impaired working memory, and was similarly improved by treatment with hMSC. The ability of hMSC to prevent TBI-associated depression and working memory impairment was eliminated when SVZ proliferation was inhibited by irradiation. Conclusions: This work has identified a possible role for hMSC in the treatment of TBI-induced depression and other behaviors and suggests a mechanistic role for proliferative cells of the SVZ proliferation in hMSC efficacy.