Erin S. Barry

Neurobehavioral, cellular, and molecular consequences of single and multiple mild blast exposure

Mild traumatic brain injury, caused by the exposure to single or repeated blast overpressure, is a principal concern due to its pathological complexity and neurobehavioral similarities with posttraumatic stress disorder. In this study, we exposed rats to a single or multiple (five total; administered on consecutive days) mild blasts, assessed their behavior at 1 and 16 days postinjury) and performed histological and protein analyses of brains and plasma at an early (2 h) and a late (22 days) termination time point. One day postinjury, multiple‐injured (MI) rats showed the least general locomotion and the most depression‐ and anxiety‐related behaviors among the experimental groups; there were no such differences at 16 days. However, at the later time point, both injured groups displayed elevated levels of select protein biomarkers. Histology showed significantly increased numbers of TUNEL+ (terminal‐deoxy‐transferase‐mediated dUTP nick‐end labeling)‐positive cells in the dorsal and ventral hippocampus (DHC and VHC) of both injured groups as early as 2 h after injury. At 22 days, the increase was limited to the VHC of MI animals. Our findings suggest that the exposure to mild blast overpressure triggers early hippocampal cell death as well as neuronal, glial, and vascular damage that likely contribute to significant, albeit transient increases in depression‐ and anxiety‐related behaviors. However, the severity of the observed pathological changes in MI rats failed to support the hypothesized cumulative effect of repeated injury. We infer that at this blast frequency, a potential conditioning phenomenon counteracts with and reduces the extent of subsequent damage in MI rats.

Identification of Serum MicroRNA Signatures for Diagnosis of Mild Traumatic Brain Injury in a Closed Head Injury Model

Wars in Iraq and Afghanistan have highlighted the problems of diagnosis and treatment of mild traumatic brain injury (mTBI). MTBI is a heterogeneous injury that may lead to the development of neurological and behavioral disorders. In the absence of specific diagnostic markers, mTBI is often unnoticed or misdiagnosed. In this study, mice were induced with increasing levels of mTBI and microRNA (miRNA) changes in the serum were determined. MTBI was induced by varying weight and fall height of the impactor rod resulting in four different severity grades of the mTBI. Injuries were characterized as mild by assessing with the neurobehavioral severity scale-revised (NSS-R) at day 1 post injury. Open field locomotion and acoustic startle response showed behavioral and sensory motor deficits in 3 of the 4 injury groups at day 1 post injury. All of the animals recovered after day 1 with no significant neurobehavioral alteration by day 30 post injury. Serum microRNA (miRNA) profiles clearly differentiated injured from uninjured animals. Overall, the number of miRNAs that were significantly modulated in injured animals over the sham controls increased with the severity of the injury. Thirteen miRNAs were found to identify mTBI regardless of its severity within the mild spectrum of injury. Bioinformatics analyses revealed that the more severe brain injuries were associated with a greater number of miRNAs involved in brain related functions. The evaluation of serum miRNA may help to identify the severity of brain injury and the risk of developing adverse effects after TBI.

Impact of repeated stress on traumatic brain injury-induced mitochondrial electron transport chain expression and behavioral responses in rats.

A significant proportion of the military personnel returning from Iraq and Afghanistan conflicts have suffered from both mild traumatic brain injury (mTBI) and post-traumatic stress disorder. The mechanisms are unknown. We used a rat model of repeated stress and mTBI to examine brain activity and behavioral function. Adult male Sprague-Dawley rats were divided into four groups: Naïve; 3 days repeated tail-shock stress; lateral fluid percussion mTBI; and repeated stress followed by mTBI (S-mTBI). Open field activity, sensorimotor responses, and acoustic startle responses (ASRs) were measured at various time points after mTBI. The protein expression of mitochondrial electron transport chain (ETC) complex subunits (CI-V) and pyruvate dehydrogenase (PDHE1α1) were determined in four brain regions at day 7-post mTBI. Compared to Naïves, repeated stress decreased horizontal activity; repeated stress and mTBI both decreased vertical activity; and the mTBI and S-mTBI groups were impaired in sensorimotor and ASRs. Repeated stress significantly increased CI, CII, and CIII protein levels in the prefrontal cortex (PFC), but decreased PDHE1α1 protein in the PFC and cerebellum, and decreased CIV protein in the hippocampus. The mTBI treatment decreased CV protein levels in the ipsilateral hippocampus. The S-mTBI treatment resulted in increased CII, CIII, CIV, and CV protein levels in the PFC, increased CI level in the cerebellum, and increased CIII and CV levels in the cerebral cortex, but decreased CI, CII, CIV, and PDHE1α1 protein levels in the hippocampus. Thus, repeated stress or mTBI alone differentially altered ETC expression in heterogeneous brain regions. Repeated stress followed by mTBI had synergistic effects on brain ETC expression, and resulted in more severe behavioral deficits. These results suggest that repeated stress could have contributed to the high incidence of long-term neurologic and neuropsychiatric morbidity in military personnel with or without mTBI.

Blast traumatic brain injury in the rat using a blast overpressure model.

Traumatic brain injury (TBI) is a serious health concern for civilians and military populations, and blast‐induced TBI (bTBI) has become an increasing problem for military personnel over the past 10 years. To understand the biological and psychological effects of blast‐induced injuries and to examine potential interventions that may help to prevent, attenuate, and treat effects of bTBI, it is valuable to conduct controlled animal experiments. This unit discusses available paradigms to model traumatic brain injury in animals, with an emphasis on the relevance of these various models to study blast‐induced traumatic brain injury (bTBI). This paper describes the detailed methods of a blast overpressure (BOP) paradigm that has been used to conduct experiments with rats to model blast exposure. This particular paradigm models the pressure wave created by explosions, including improvised explosive devices (IEDs). Curr. Protoc. Neurosci. 62:9.41.1‐9.41.14.

Do Reductions in Brain N-Acetylaspartate Levels Contribute to the Etiology of Some Neuropsychiatric Disorders?

N‐acetylaspartate (NAA) is recognized as a noninvasive diagnostic neuronal marker for a host of neuropsychiatric disorders using magnetic resonance spectroscopy (MRS). Numerous correlative clinical studies have found significant decreases in NAA levels in specific neuronal systems in an array of neuropsychiatric and substance‐abuse disorders. We have recently identified the methamphetamine‐induced neuronal protein known as “shati” as the NAA biosynthetic enzyme (aspartate N‐acetyltransferase [Asp‐NAT]; gene Nat8l). We have generated an Nat8l transgenic knockout mouse line to study the functions of NAA in the nervous system. We were unable to breed homozygous Nat8l knockout mice successfully for study and so used the heterozygous mice (Nat8l+/−) for initial characterization. MRS analysis of the Nat8l+/− mice indicated significant reductions in NAA in cortex (−38%) and hypothalamus (−29%) compared with wild‐type controls, which was confirmed using HPLC (−29% in forebrain). The level of the neuromodulator N‐acetylaspartylglutamate (NAAG), which is synthesized from NAA, was decreased by 12% in forebrain as shown by HPLC. Behavioral analyses of the heterozygous animals indicated normal behavior in most respects but reduced vertical activity in open‐field tests compared with age‐ and sex‐matched wild‐type mice of the same strain. Nat8l+/− mice also showed atypical locomotor responses to methamphetamine administration, suggesting that NAA is involved in modulating the hyperactivity effect of methamphetamine. These observations add to accumulating evidence suggesting that NAA has specific regulatory functional roles in mesolimbic and prefrontal neuronal pathways either directly or indirectly through impact on NAAG synthesis.© 2013 Wiley Periodicals, Inc.

Mitochondrial targeted neuron focused genes in hippocampus of rats with traumatic brain injury

Context: Mild traumatic brain injury (mTBI) represents a major health problem in civilian populations as well as among the military service members due to (1) lack of effective treatments, and (2) our incomplete understanding about the progression of secondary cell injury cascades resulting in neuronal cell death due to deficient cellular energy metabolism and damaged mitochondria. Aims: The aim of this study was to identify and delineate the mitochondrial targeted genes responsible for altered brain energy metabolism in the injured brain. Settings and Design: Rats were either grouped into naïve controls or received lateral fluid percussion brain injury (2–2.5 atm) and followed up for 7 days. Materials and Methods: Rats were either grouped into naïve controls or received lateral fluid percussion brain injury (2–2.5 atm) and followed for 7 days. The severity of brain injury was evaluated by the neurological severity scale—revised (NSS-R) at 3 and 5 days post TBI and immunohistochemical analyses at 7 days post TBI. The expression profiles of mitochondrial-targeted genes across the hippocampus from TBI and naïe rats were also examined by oligo-DNA microarrays. Results: NSS-R scores of TBI rats (5.4 ± 0.5) in comparison to naïe rats (3.9 ± 0.5) and H and E staining of brain sections suggested a mild brain injury. Bioinformatics and systems biology analyses showed 31 dysregulated genes, 10 affected canonical molecular pathways including a number of genes involved in mitochondrial enzymes for oxidative phosphorylation, mitogen-activated protein Kinase (MAP), peroxisome proliferator-activated protein (PPAP), apoptosis signaling, and genes responsible for long-term potentiation of Alzheimers and Parkinsons diseases. Conclusions: Our results suggest that dysregulated mitochondrial-focused genes in injured brains may have a clinical utility for the development of future therapeutic strategies aimed at the treatment of TBI.

Gender and Leadership

The topic of leadership has been addressed and applied for millennia. Yet, it is only within the past 80 years that leadership has been a topic of serious discussion. It is important to understand variables relevant to effective leadership. Gender is one such variable that must be examined with regard to optimizing leadership effectiveness. The topic of gender and leadership deserves serious and thoughtful consideration and discussion because of professional, political, cultural, and personal realities of the twenty‐ first century. Women and men have been, are, and should be leaders. Gender must be considered to determine how each leader can reach maximum potential and effectiveness. The FourCe‐PITO conceptual framework of leadership is designed to help guide leadership development and education. The present chapter uses this conceptual framework of leadership to discuss how consideration of gender may affect and optimize leadership development and effectiveness. It is the goal of this chapter to lay out the issues that educators of leaders, potential leaders, and “practicing” leaders should be aware of, to achieve success for the good of the groups and individuals they have the responsibility to lead.

The Revised Neurobehavioral Severity Scale (NSS‐R) for Rodents

Motor and sensory deficits are common following traumatic brain injury (TBI). Although rodent models provide valuable insight into the biological and functional outcomes of TBI, the success of translational research is critically dependent upon proper selection of sensitive, reliable, and reproducible assessments. Published literature includes various observational scales designed to evaluate post-injury functionality; however, the heterogeneity in TBI location, severity, and symptomology can complicate behavioral assessments. The importance of choosing behavioral outcomes that can be reliably and objectively quantified in an efficient manner is becoming increasingly important. The Revised Neurobehavioral Severity Scale (NSS-R) is a continuous series of specific, sensitive, and standardized observational tests that evaluate balance, motor coordination, and sensorimotor reflexes in rodents. The tasks follow a specific order designed to minimize interference: balance, landing, tail raise, dragging, righting reflex, ear reflex, eye reflex, sound reflex, tail pinch, and hindpaw pinch. The NSS-R has proven to be a reliable method differentiating brain-injured rodents from non-brain-injured rodents across many brain injury models.

A conceptual framework for leader and leadership education and development

ABSTRACT Conceptual frameworks for Leader and Leadership Education and Development guide the curriculum and assessment of students, faculty, and programs. This commentary defines leader and leadership and presents a leadership conceptual framework that includes four ‘C’ elements (FourCe) – Character, Competence, Context, and Communication – across four levels of psychosocial interaction – Personal, Interpersonal, Team, and Organizational (PITO). This FourCe-PITO framework delineates elements of leadership, considers interactions of these elements, guides curriculum content, and is the basis for assessments. The application of this framework is discussed for all levels of education.

Seven Steps to Establish a Leader and Leadership Education and Development (LEAD) Program

Despite long-standing debates about whether leaders are born or made, current thinking within the leadership field is that leaders can be developed. In the arena of health and healthcare, developing effective, value-driven and outcome-focused leaders is critical to address the many challenges facing systems that promote and maintain health as well as focus on healthcare delivery and practices. Effective health and healthcare leaders are needed to set thoughtful policies; educate the public about primary prevention strategies; identify best practices (administrative and clinical); allocate healthcare resources wisely; address healthcare needs and disparities; focus on optimal clinical outcomes and value in the delivery of care; and encourage individuals to engage in behaviors that enhance well-being. This chapter presents seven steps to establish a Leader and Leadership Education and Development (LEAD) program. These steps were based on the authors’ experience establishing a LEAD program at the Uniformed Services University of the Health Sciences (USU) where physicians, advanced practice nurses, dentists, psychologists, and scientists are trained for the Army, Navy, Air Force, and Public Health Service, and civilians are trained to become scientists, academicians, and clinicians with a focus on national service and health. These same steps also could be used as a guide to establish programs that educate and develop leaders for other professions and careers.