Thy1-Neuron p38α knockdown protects against neurological consequences following repetitive mild traumatic brain injury

Mild traumatic brain injuries (mTBI) can substantially impact quality of life, and repetitive mTBIs (rmTBIs) can amplify injury effects compared to a single injury. However, effective clinical treatments remain elusive, largely due to an incomplete understanding of the underlying injury mechanisms. Neuroinflammation has emerged as a key contributor to worse functional outcomes after mTBI/rmTBI. While microglia are traditionally viewed as primary mediators of post-injury inflammation, accumulating evidence suggests neurons play an immunomodulatory role in initiating the rmTBI inflammatory cascade through activation of intracellular proinflammatory pathways like p38 MAPK and secretion of cytokines that, in turn, stimulate microglial activation. Here, we tested whether inducible neuronal p38α knockdown protects against functional, immune, and cerebrovascular consequences of a weight-drop closed head injury (CHI) model of rmTBI. A battery of functional assays were conducted 4 weeks post-injury, and tissues were collected at both 4 h and 4 weeks following final CHI. In males, neuronal p38α knockout protected against injury-induced depressive-like behavior, anxiety-related behavior, synaptic loss, microglial reactivity, cytokine upregulation, and reduction in cerebral blood flow. In females, neuronal p38α knockout protected against anxiety-related behavior and partially protected against cytokine upregulation but had limited effect on microglial reactivity and cerebral blood flow. Together, these findings identify neuronal p38α as a sex-dependent driver of rmTBI-associated neurological consequences, and they suggest neuronal p38α-immune signaling may be a relevant mechanistic pathway for therapeutic targeting in future studies.