Abstract Major depressive disorder in individuals with spinal cord injury has a profound impact on quality of life, correlating with limited functional improvement during rehabilitation and increased mortality rates. The incidence of depression in these individuals is three times higher than the general population, while response rates to classical antidepressants are much lower. The underlying physiological mechanisms responsible for SCI-induced depression are not known; however, levels of pro-inflammatory cytokines, such as Interleukin (IL)-6 and TNFα, are often elevated in the serum of patients with major depression. In the case of SCI, there is evidence of remote, chronic inflammation in supraspinal brain regions that are associated with emotional regulation, such as the dorsal raphe nucleus. As the primary source of serotonergic input to the brain, perturbations of the dorsal raphe could result in an imbalance in serotonin- the neurotransmitter classically associated with depression. Activity of serotonin neurons is normally modulated through both local binding of serotonin autoreceptors on the soma and dendrites, as well as glutamatergic projections from the prefrontal cortex to local GABAergic interneurons in the dorsal raphe. The neural circuitry of the dorsal raphe could provide a potential source of vulnerability to inflammation through a disruption in glutamate homeostasis. Preliminary data from our lab indicate a significant correlation of increased levels of TNFα in the dorsal raphe with depressive behaviors after moderate thoracic spinal cord contusion. This cytokine has been shown to decrease expression of the glutamate transporter GLT1, significantly impairing glutamate reuptake. Increased extracellular glutamate could result in hyperactivity of the GABAergic interneurons, decreasing serotonin activity. We hypothesize that SCI-induced depression is mediated by hypoactivity of serotonin neurons in the dorsal raphe, resulting from TNFα-mediated glutamate imbalance. We will use a moderate, midline thoracic contusion model in adult female rats to test our hypothesis. Depressive phenotype will be assessed using a battery of behavioral tests that mimic classic symptoms of depression in patients. We believe this depressive phenotype can be ameliorated through the inhibition of TNFα after injury and will test for efficacy after acute or delayed treatment with XPro 1595.This study will provide us with greater insight into the mechanism of SCI-induced depression, as well as a potential for novel therapeutic treatment.