Abstract
In adult pre-clinical models, traumatic brain injury (TBI) has been shown to prime microglia, exaggerating the central inflammatory response to an acute immune challenge, worsening depressive-like behavior, and enhancing cognitive deficits. Whether this phenomenon exists following mTBI during adolescence has yet to be explored, with age at injury potentially altering the inflammatory response. Furthermore, to date, studies have predominantly examined hippocampal-dependent learning domains, although pre-frontal cortex-driven functions, including attention, motivation, and impulsivity, are significantly affected by both adolescent TBI and acute inflammatory stimuli. As such, the current study examined the effects of a single acute peripheral dose of LPS (0.33 mg/kg) given in adulthood following mTBI in mid-adolescence in male Sprague–Dawley rats on performance in the 5-choice serial reaction time task (5-CSRTT). Only previously injured animals given LPS showed an increase in omissions and reward collection latency on the 5-CSRTT, with no effect noted in sham animals given LPS. This is suggestive of impaired motivation and a prolonged central inflammatory response to LPS administration in these animals. Indeed, morphological analysis of myeloid cells within the pre-frontal cortex, via IBA1 immunohistochemistry, found that injured animals administered LPS had an increase in complexity in IBA1+ve cells, an effect that was seen to a lesser extent in sham animals. These findings suggest that there may be ongoing alterations in the effects of acute inflammatory stimuli that are driven, in part by increased reactivity of microglial cells.
Highlights
The most common form of traumatic brain injury (TBI) is classified as mild (Bazarian et al, 2006; Langlois et al, 2006), resulting from biomechanical forces causing movement of the brain within the skull, without gross structural pathology (McKee et al, 2015)
This appeared to reflect a decrease in motivation, rather than attentional deficits, with a significantly higher rate of omissions and an increase in reward collection latency observed in response to LPS administration
The injury did not affect the peripheral response to LPS administration with both sham and TBI animals showing a similar increase in serum cytokine levels at 4 h post-administration
Summary
The most common form of traumatic brain injury (TBI) is classified as mild (Bazarian et al, 2006; Langlois et al, 2006), resulting from biomechanical forces causing movement of the brain within the skull, without gross structural pathology (McKee et al, 2015). Levels of these pro-inflammatory cytokines and chemokines increase both within the brain, as well as systemically, returning to baseline typically within 7 days (Shultz et al, 2011), levels of certain mediators, like CCL2, may remain mildly elevated in some individuals (Sun et al, 2019). In adult animals, a peripheral immune insult at 5 days post-injury led to chronic impairments in cognitive flexibility in the Barnes Maze at 3 months post-injury, an effect not seen with injury alone (Collins-Praino et al, 2018). Even remote inflammatory stimuli can drive this response, with a peripheral immune challenge at 1-month post-injury acutely worsening memory consolidation on the Barnes Maze (Muccigrosso et al, 2016) and enhancing depressive-like behavior on the tail suspension test (Fenn et al, 2014). Cognitive flexibility is strongly associated with medial prefrontal cortical (mPFC) function (Jett et al, 2017), with depressive symptoms linked to decreased mPFC volume related to inflammation (Belleau et al, 2019)
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