Secondary hypoxic ischemia alters neurobehavioral outcomes, neuroinflammation, and oxidative stress in mice exposed to controlled cortical impact

Abstract

Objective Hypoxic ischemia (HI) is a secondary insult that can cause fatal neurologic outcomes after traumatic brain injury (TBI), ranging from mild cognitive deficits to persistent vegetative states. We here aimed to unravel the underlying pathological mechanisms of HI injury in a TBI mouse model.Methods Neurobehavior, neuroinflammation, and oxidative stress were assessed in a mouse model of controlled cortical impact (CCI) injury followed by HI. Mice underwent CCI alone, CCI followed by HI, HI alone, or sham operation. HI was induced by one-vessel carotid ligation with 1 hour of 8% oxygen in nitrogen. Learning and memory were assessed using the novel object recognition test, contextual and cued fear conditioning, and Barnes maze test. Brain cytokine production and oxidative stress-related components were measured.Results Compared to TBI-only animals, TBI followed by HI mice exhibited significantly poorer survival and health scores, spatial learning and memory in the Barnes maze test, discrimination memory in the novel object recognition test, and fear memory following contextual and cued fear conditioning. Malondialdehyde levels were significantly lower, whereas glutathione peroxidase activity was significantly higher in TBI followed by HI mice compared to TBI-only and sham counterparts, respectively. Interleukin-6 levels were significantly higher in TBI followed by HI mice compared to both TBI-only and sham animals.Conclusion Post-traumatic HI aggravated deficits in spatial, fear, and discrimination memory in an experimental TBI mouse model. Our results suggest that increased neuroinflammation and oxidative stress contribute to HI-induced neurobehavioral impairments after TBI.

Chronic juvenile stress exacerbates neurobehavioral dysfunction and neuroinflammation following traumatic brain injury in adult mice

“…23 We previously reported that a 2-mm CCI injury resulted in significant spatial learning and memory deficits compared with that in sham adults. 11,12 In previous studies, the Barnes circular maze was shown to be an efficient cognitive task to assess spatial/non-spatial learning following CCI injury in adult mice. 11,12 In addition to cognitive changes, TBI has been frequently linked to affective disorders such as anxiety and depression.…”

“…11,12 In previous studies, the Barnes circular maze was shown to be an efficient cognitive task to assess spatial/non-spatial learning following CCI injury in adult mice. 11,12 In addition to cognitive changes, TBI has been frequently linked to affective disorders such as anxiety and depression. However, much remains to be understood about the underlying molecular and signaling mechanisms that mediate affective dysfunctions following injury.…”

“…CCI was performed as described previously [ 11 , 12 ]. Briefly, mice were anesthetized with an intramuscular injection of 15 mg/kg tiletamine/zolazepam (Zoletil, Virbac).…”

“…CCI was performed as described previously. 11,12 Briefly, mice were anesthetized with an intramuscular injection of 15 mg/kg tiletamine/zolazepam (Zoletil; Virbac, Carros, France). After cleaning the shaved head area between the ears with betadine, a midline scalp incision was made, and the right parietal bone was exposed.…”

“…The Barnes maze test was conducted as previously described with minor modifications. [11][12][13] The maze consisted of a white acrylic circular platform (diameter, 91 cm) with 20 equally spaced holes and a black acrylic escape box (20×5×6 cm) along the perimeter. The maze was surrounded by four spatial cues at its height.…”