Cognitive deficits develop 1 month after diffuse brain injury and are exaggerated by microglia-associated reactivity to peripheral immune challenge

Abstract

Traumatic brain injury (TBI) elicits immediate neuroinflammatory events that contribute to acute cognitive, motor, and affective disturbance. Despite resolution of these acute complications, significant neuropsychiatric and cognitive issues can develop and progress after TBI. We and others have provided novel evidence that these complications are potentiated by repeated injuries, immune challenges and stressors. A key component to this may be increased sensitization or priming of glia after TBI. Therefore, our objectives were to determine the degree to which cognitive deterioration occurred after diffuse TBI (moderate midline fluid percussion injury) and ascertain if glial reactivity induced by an acute immune challenge potentiated cognitive decline 30 days post injury (dpi). In post-recovery assessments, hippocampal-dependent learning and memory recall were normal 7 dpi, but anterograde learning was impaired by 30 dpi. Examination of mRNA and morphological profiles of glia 30 dpi indicated a low but persistent level of inflammation with elevated expression of GFAP and IL-1β in astrocytes and MHCII and IL-1β in microglia. Moreover, an acute immune challenge 30 dpi robustly interrupted memory consolidation specifically in TBI mice. These deficits were associated with exaggerated microglia-mediated inflammation with amplified (IL-1β, CCL2, TNFα) and prolonged (TNFα) cytokine/chemokine expression, and a marked reactive morphological profile of microglia in the CA3 of the hippocampus. Collectively, these data indicate that microglia remain sensitized 30 dpi after moderate TBI and a secondary inflammatory challenge elicits robust microglial reactivity that augments cognitive decline.

Mangosteen Extract Reduces the Expression of Matrix Metalloproteinase -2 and -9 in Traumatic Brain Injury

“…Using the weight drop models, we could only make focal injury 34 . Diffuse injury itself could also contribute to acute cognitive, motor, and affective disturbance 35 . We also only gave the ME in crude form, not the active xanthone.…”

Recovery from Diffuse Brain Injuries: Two Case Studies

“…Diffuse brain injury occurs in the absence of a cerebral contusion (i.e., bruising of the brain) and does not lead to gross neuronal damage. However, diffuse axonal injury in the cortex, hippocampus, and dorsolateral thalamus may occur in the absence of a contusion and yet lead to cognition, attention, language, and memory impairments [2]. Damage to the hippocampus is associated with memory difficulties [20].…”

“…Damage to the hippocampus is associated with memory difficulties [20]. In conclusion, cognitive communication disorders seen in diffuse brain injuries may affect such abilities as memory, word retrieval, attention, an organization of information, and problem-solving [2,18,21]. Therapy concerns regarding cognitive communication disorders will be addressed in the following section.…”

“…Brain injuries are a major cause of death and disability worldwide [1][2][3]. It is well documented that brain injuries exhibit immediate and long-term consequences on language abilities [4].…”

“…Diffuse brain damage is likely to affect white matter tracts resulting from diffuse axonal injury affecting memory and executive function [18]. In addition, secondary inflammation resulting from a brain trauma may induce microglial activity which leads to further cognitive decline [2].…”