Project description:Ocular injuries and visual deterioration occur in a large percentage of Warfighters sustaining physical and psychological trauma. From 2000 through the end of 2017, more than 275,000 Service-members have suffered from eye injuries, as shown by Surveillance data from the Department of Defense (DOD). Exposure to blast overpressure (BOP) also directly affects the brain visual signal processing centers (e.g., optic tracts). Likewise, traumatic brain injury (TBI)-induced impairments of vision are commonly seen among Military Veterans even when there is no direct injury to the eye, e.g., retina. Hence, these traumatic insults can influence the regulation of the visual and nonvisual retinal signaling pathways. The ocular system could be directly injured or could degenerate secondary to injury induced by psychological stress. Despite the lifelong disservice that vision losses exhibit, there are only few studies demonstrating the effect of these insults on retinal transcriptomics and the signaling mechanisms underlying the eye damage. Studies have shown that docosahexaenoic acid (DHA) is the most abundant ω-3 PUFA (polyunsaturated fatty acid) in the central nervous system and especially the retina and plays an important role in neuronal membrane structure integrity and neural dendritic connectivity. Hence, inclusion of ω-3s as dietary supplements could possibly be a vital therapeutic approach in alleviating stress-related ocular impairments. The objective of this study is to study the role of essential nutrients i.e., dietary ω-3 fatty acids on the ocular vulnerability to TBI and psychological stress. The retina was collected at 14 days post-insult, and gene expression changes were assessed by analyzing extracted total RNA on whole rat genome microarrays. Our findings in rats showed that TBI exposure significantly impaired the expression of retinal genes in all the diet groups, with highest change observed in the ω-3 rich house chow (HC) group. Psychological stress had a greater effect on retinal gene expression, particularly in rats fed with ω-3 deficient 1% LA diet (2249 genes downregulated and 1256 genes upregulated). The network clusters like neurovascular coupling and synaptic signaling were affected by TBI in ω-3 rich HC diet group while chemokine and actin cytoskeleton signaling were shown to be disrupted in ω-3 deficient 8% LA diet. Together, the results showed that these two diets (i.e., house chow and 8% LA) had opposing effects on some of the signaling pathways including endocannabinoid pathway and neuronal plasticity. For the UWT (underwater trauma) study, exposure to psychological stress significantly altered CREB (cAMP response element-binding protein) and opioid signaling in rodents fed with ω-3 deficient diets (i.e., 8% LA and 1% LA). Additionally, ephrin receptor and calcium signaling were differentially regulated by psychological stress in 1% LA versus 8% LA diet. Overall, the findings of our study suggest that poor dietary conditions can greatly influence the resilience to TBI and psychological stress. This work was intramurally funded by the USAMRDC/MOMRP.

Project description:Warfare has long been associated with traumatic brain injury (TBI) in militarized zones. Common forms of TBI can be caused by a physical insult to the head-brain or by the effects of a high velocity blast shock wave generated by the detonation of an explosive device. While both forms of trauma are distinctly different regarding the mechanism of trauma induction, there are striking similarities in the cognitive and emotional status of survivors. Presently, proven effective therapeutics for the treatment of either form of TBI are unavailable. To be able to develop efficacious therapies, studies involving animal models of physical- and blast-TBI are required to identify possible novel or existing medicines that may be of value in the management of clinical events. We examined indices of cognition and anxiety-like behavior and the hippocampal gene transcriptome of mice subjected to both forms of TBI. We identified common behavioral deficits and gene expression regulations, in addition to unique injury-specific forms of gene regulation. Molecular pathways presented a pattern similar to that seen in gene expression. Interestingly, pathways connected to Alzheimer’s disease displayed a markedly different form of regulation depending on the type of TBI. While these data highlight similarities in behavioral outcomes after trauma, the divergence in hippocampal transcriptome observed between models suggests that, at the molecular level, the TBIs are quite different. These models may provide tools to help define therapeutic approaches for the treatment of physical- and blast-TBIs. Based upon observations of increasing numbers of personnel displaying TBI related emotional and behavioral changes in militarized zones, the development of efficacious therapies will become a national if not a global priority. Keywords: Physical-traumatic brain injury; Blast-traumatic brain injury; Cognitive dysfunction; Gene expression; Molecular pathway(s); Neurodegeneration; Stem cells; Alzheimer’s disease

Project description:Warfare has long been associated with traumatic brain injury (TBI) in militarized zones. Common forms of TBI can be caused by a physical insult to the head-brain or by the effects of a high velocity blast shock wave generated by the detonation of an explosive device. While both forms of trauma are distinctly different regarding the mechanism of trauma induction, there are striking similarities in the cognitive and emotional status of survivors. Presently, proven effective therapeutics for the treatment of either form of TBI are unavailable. To be able to develop efficacious therapies, studies involving animal models of physical- and blast-TBI are required to identify possible novel or existing medicines that may be of value in the management of clinical events. We examined indices of cognition and anxiety-like behavior and the hippocampal gene transcriptome of mice subjected to both forms of TBI. We identified common behavioral deficits and gene expression regulations, in addition to unique injury-specific forms of gene regulation. Molecular pathways presented a pattern similar to that seen in gene expression. Interestingly, pathways connected to AlzheimerM-bM-^@M-^Ys disease displayed a markedly different form of regulation depending on the type of TBI. While these data highlight similarities in behavioral outcomes after trauma, the divergence in hippocampal transcriptome observed between models suggests that, at the molecular level, the TBIs are quite different. These models may provide tools to help define therapeutic approaches for the treatment of physical- and blast-TBIs. Based upon observations of increasing numbers of personnel displaying TBI related emotional and behavioral changes in militarized zones, the development of efficacious therapies will become a national if not a global priority. Keywords: Physical-traumatic brain injury; Blast-traumatic brain injury; Cognitive dysfunction; Gene expression; Molecular pathway(s); Neurodegeneration; Stem cells; AlzheimerM-bM-^@M-^Ys disease A mild physical-TBI was induced using a concussive head trauma device described previously (Milman et al., 2005; Zohar et al., 2003). Briefly, mice were lightly anesthetized (Isoflurane) and placed under the weight-drop concussive head trauma instrument. The device consisted of a metal tube (inner diameter 13 mm), placed vertically over the mouse head. A metal weight (30 g) was dropped from the top of the tube (80 cm) and struck the skull at the right side temporal area between the corner of the eye and the ear. A sponge supported the head, allowing some antero-posterior motion without any rotational head movement at the moment of the impact. Experimental conditions used to create a mild low-level blast-TBI and the subsequent model characterization, have been described in detail elsewhere (Rubovitch et al., 2011). In brief, mice were anaesthetized with a combination of ketamine (100 mg/kg) and xylazine (10 mg/kg). Once the animals were fully anaesthetized they were placed at a defined distance from a detonation source, in this case 7 meters. Pressure sensors were used to measure the explosion shock wave pressure (PSI) generated by the detonation (Free-Field ICPM-BM-. Blast Pressure Sensor; PCB Piezoelectronics, Depew, NY, USA, Model 137). At 7 meters from the source of the detonation, the animals were exposed to a maximum of a 2.5 PSI (17.2 kPa) pressure shock wave. Immediately after the induction of the injury, mice were placed back in their cages. Once the animals had recovered from the anesthesia, basic neurological assessments were undertaken to identify any acute neurological dysfunction. Only animals exhibiting no evidence of acute neurological damage post injury were subsequently used in further experiments. Sham treated mouse groups were treated identically; however, they were not exposed to physical- or blast-TBI. Mouse hippocampus tissues were randomly selected from the larger library of samples generated from the behavioral experiments and the numbers utilized in the gene expression study were as follows: sham, n = 5: physical-TBI, n = 4; blast-TBI, n = 7.

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Boldine treatment prevents chronic cognitive impairment and exaggerated fear learning in rats exposed to repetitive low-level blast injury

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