Traumatic brain injury (TBI) affects 10 million people annually, attributes to major psychiatric disorders, and is among the leading causes of death and disability. Blast-induced TBI (bTBI) accounts for approximately 80% of all TBIs. These numbers are rapidly rising due, in part, to the increasing frequency of terrorist bombing attacks. The least studied form of bTBI, perhaps because of delayed symptom onset, is mild bTBI (mbTBI). Nonetheless, mbTBI increases the prevalence of psychiatric disorders, including memory impairment, anxiety, and mood disorders. Virtually every mbTBI in the battlefield is preceded and followed by a constant period of stress. However, how stress can prime the brain to deal with an insult, such as mbTBI, remains unknown. This work aims to identify the brain targets affected by mbTBI and elucidate how chronic stress could prime the brain for worse outcomes after mbTBI. In the first experiment, we examined the effect of mbTBI on resting and restraint-induced limbic-HPA axis reactivity in male and female mice 7-10 days post-injury. Mild bTBI increased anxiety-like behaviors (p<0.05) and dysregulated the stress response in a sex-specific manner. In the paraventricular nucleus of the hypothalamus, mbTBI decreased (p<0.05) activation of non-neuroendocrine corticotropin releasing factor neurons in females, but not males, suggesting a potential link to autonomic dysregulation. To further examine the impact of mbTBI on HPA axis-relevant limbic structures, we assessed neuronal activation via c-Fos-ir or EGR-1-ir markers in the medial prefrontal cortex (mPFC). Mild bTBI blunted the restraint induced neuronal activation observed in male and female infralimbic and prelimbic regions of the mPFC. These data suggest that the mPFC is a potential target of mbTBI in both sexes. In a second experiment, we used the Thy1-eGFP transgenic mouse model to elucidate the effects of mbTBI during a chronic variable stress (CVS) paradigm. This paradigm consisted of two weeks of CVS prior to our single mbTBI model and followed by another week of CVS after the single blast. The adverse effects of mbTBI on anxiety-like behaviors observed following a single mbTBI were further worsened in the animals exposed to CVS when compared to no-CVS animals. These data suggest that CVS makes the system more vulnerable to the effects of mbTBI. Thus, future experiments should consider implementing a stress component when assessing the impact of mbTBI. Our ongoing experiments aim to elucidate the effects of CVS and mbTBI on the dendritic spine architecture of the mPFC. These data will help us understand the mbTBI effects observed in the mPFC and whether the psychiatric disorders seen following mbTBI result from changes in the dendritic connectivity and architecture on the mPFC.