Resuscitation using fresh-frozen plasma is associated with improved contextual fear memory in a non-TBI mouse model of trauma and hemorrhagic shock

BACKGROUND: Cognitive dysfunction is a consequence of traumatic injury with lasting impacts. Even without direct brain injury, trauma and hemorrhagic shock (T/HS) can cause malperfusion, inflammation, and neuronal injury. Disruption of the endothelial glycocalyx (eGC), a key regulator of vascular homeostasis, contributes to trauma-induced endotheliopathy and may influence secondary neurologic injury. Prior work demonstrated that fresh-frozen plasma (FFP) resuscitation preserves eGC expression and reduces maladaptive vascular repair in a murine T/HS model. This study evaluates post-injury cognition and FFP protection against cognitive impairment compared with lactated Ringer’s (LR). METHODS: Male C57BL/6 mice were randomized to sham procedure or T/HS followed by a volume-driven LR or pressure-directed FFP resuscitation approach. T/HS mice underwent laparotomy, femoral artery cannulation, hemorrhagic shock, pseudofractures via bone homogenate injection, and hindlimb muscle crush injuries. Sham mice received laparotomy and femoral artery cutdown. Four days postsurgery, open field testing assessed locomotion, followed by fear conditioning on days 7 to 8 to assess cognition. Brains were collected to analyze hippocampal glycosaminoglycans hyaluronan, heparan sulfate (HS), and chondroitin sulfate (CS). RESULTS: Open field testing showed intact locomotion at post-injury day 4 in all groups. On day 8, mice resuscitated with FFP had significantly greater contextual freezing compared with mice resuscitated with LR, consistent with improved hippocampal-dependent contextual memory. Cued fear conditioning did not differ between groups. LR and FFP resuscitation strategies resulted in distinct hippocampal hyaluronan and HS staining patterns, without synthesis gene expression differences. T/HS+LR brains showed increased 4- O -sulfated CS (CS-4S), a neurologically detrimental sulfation pattern, whereas FFP decreased CS-4S and increased CS-6S. CONCLUSIONS: Goal-directed plasma resuscitation is associated with improved spatial memory and distinct eGC structural remodeling compared with volume-driven crystalloid resuscitation following T/HS. These findings highlight the potential for resuscitation strategy after hemorrhagic shock to influence neurological recovery, even in the absence of direct brain injury.