ABSTRACT Approximately 2.8 million people sustain a traumatic brain injury (TBI) yearly in the United States, with over 500,000 emergency room visits being attributed to childhood-acquired brain trauma (<14 years of age). Survivors often endure long-term cognitive and emotional disabilities that reduce quality of life and the ability to return to school/workforce. Current and past research has largely overlooked complex attention impairments post-TBI, especially in conjunction with overlapping clinical comorbidities, which may exacerbate injury effects. We aim to remedy the paucity of studies examining comorbidities of TBI by exploring how hypertension/high blood pressure, a common underlying condition, can affect TBI-related neurological, physiological, and cognitive impairments. An estimated 50% of the adult population is diagnosed with hypertension, which can lead to heart attacks, blocked or damaged arteries, reduced blood flow to the muscles, strokes, and premature death. Thus, there is a critical need to investigate preclinical models of TBI that are also affected by hypertension (i.e., hypertensive rats) to better characterize neurological, physiological, and cognitive impairments, in an effort to enhance bench-to-bedside translatability by more closely reflecting the existing clinical landscape. This study explores the effects of TBI on Spontaneously Hypertensive Rats (SHR), a widely used animal model of hypertension, by administering a battery of behavioral assays across different modalities, such as motor coordination/balance, higher-order sustained and flexible attention, and anxiety-like symptoms. Moreover, it is important to determine whether being subjected to TBI during pediatric (i.e., prior to developing stable hypertension at 16 weeks of age) or adult age (i.e., after hypertension onset) alters physiological, emotional, and cognitive outcomes long term. The aims are designed to 1) determine interactions of moderate parietal TBI and age-at-impact (pediatric versus adulthood) on motor function (rotarod test), sustained attention and impulsivity (3-choice serial reaction time task), cognitive flexibility (attentional set- shifting test), and anxiety-like responses (elevated plus-maze test, shock-probe defensive burying) in SHR versus normotensive male and female adult rats, and 2) evaluate TBI-induced and sex-related differences in histological assessments of lesion volumes, neuronal survival, and neuroinflammation markers in SHR versus normotensive rats. Studies will be conducted in both male and normal cycling female rats, an approach that is clinically relevant. Women represent up to 45% of the TBI cases, thus evaluating normal cycling female rats parallels the real world, where injuries occur independent of menstrual cycles. The findings from this R21 Exploratory/Developmental Research Grant will serve as proof-of-concept for significant future funding support from the National Institutes of Health, the American Heart Association, or the US Department of Veterans Affairs, as dissecting the impact that underlying conditions such as hypertension may have on TBI preclinically is critical to further developing clinically-relevant therapies.

Project Narrative Traumatic brain injuries (TBIs) are heterogeneous and affect approximately 69 million persons annually worldwide, causing debilitating and enduring complex cognitive and psychosocial impairments regardless of injury location, yet the preclinical research to date has largely overlooked attention and emotional deficits post- TBI, which may be exacerbated by the presence of clinical comorbidities. The overarching aim of this R21 proposal is to remedy the paucity of studies examining comorbidities during the TBI recovery phase, by exploring how adult-onset hypertension (i.e., high blood pressure), a common underlying condition for approximately 50% of the adult United States population, may impact long-term motor, complex cognitive, and anxiety-like alterations subsequent to pediatric or adult injuries. The findings from the proposed preclinical studies, carried out in both male and female rats, will advance our understanding of neurobehavioral and histopathological alterations in survivors of brain trauma living with comorbid hypertension, as well as facilitate identifying mechanisms through which therapeutic and rehabilitative approaches may be targeted to relevant symptoms in the clinic.