Cerebral hypoperfusion exacerbates traumatic brain injury in male but not female mice.

Mild-moderate traumatic brain injuries (TBIs) are prevalent, and while many individuals recover, there is evidence that a significant number experience long-term health impacts, including increased vulnerability to neurodegenerative diseases. These effects are influenced by other risk factors, such as cardiovascular disease. Our study tested the hypothesis that a pre-injury reduction in cerebral blood flow (CBF), mimicking cardiovascular disease, worsens TBI recovery. We induced bilateral carotid artery stenosis (BCAS) and a mild-moderate closed-head TBI in male and female mice, either alone or in combination, and analyzed CBF, spatial learning, memory, axonal damage, and gene expression. Findings showed that BCAS and TBI independently caused a ~10% decrease in CBF. Mice subjected to both BCAS and TBI experienced more significant CBF reductions, notably affecting spatial learning and memory, particularly in males. Additionally, male mice showed increased axonal damage with both BCAS and TBI compared to either condition alone. Females exhibited spatial memory deficits due to BCAS, but these were not worsened by subsequent TBI. Gene expression analysis in male mice highlighted that TBI and BCAS individually altered neuronal and glial profiles. However, the combination of BCAS and TBI resulted in markedly different transcriptional patterns. Our results suggest that mild cerebrovascular impairments, serving as a stand-in for preexisting cardiovascular conditions, can significantly worsen TBI outcomes in males. This highlights the potential for mild comorbidities to modify TBI outcomes and increase the risk of secondary diseases.

Mild traumatic brain injury induces pericyte detachment independent of stroke vulnerability.

Mild traumatic brain injury (mTBI) is an independent risk factor for ischemic stroke and can result in poorer outcomes- an effect presumed to involve the cerebral vasculature. Here we tested the hypothesis that mTBI-induced pericyte detachment from the cerebrovascular endothelium is responsible for worsened stroke outcomes. We performed a mild closed-head injury and/or treated C57/bl6 mice with imatinib mesylate, a tyrosine kinase inhibitor that induces pericyte detachment. The time course of pericyte detachment was assessed 7, 14, and 28 days post injury (DPI). To test the role of pericytes in TBI-induced exacerbation of ischemic stroke outcomes, we induced mTBI and/or treated mice with imatinib for one week prior to transient middle cerebral artery occlusion. We found that injury promoted pericyte detachment from the vasculature commensurate with the levels of detachment seen in imatinib-only treated animals, and that the detachment persisted for at least 14DPI, but recovered to sham levels by 28DPI. Further, mTBI, but not imatinib-induced pericyte detachment, increased infarct volume. Thus, we conclude that the transient detachment of pericytes caused by mTBI may not be sufficient to exacerbate subsequent ischemic stroke damage. These data have important implications for understanding cerebrovascular dysfunction following mTBI and potential mechanisms of increased risk for future ischemic strokes.

Pericyte dysfunction is a key mediator of the risk of cerebral ischemia.

Pericytes are critical yet understudied cells that are a central component of the neurovascular unit. They are connected to the cerebrovascular endothelium and help control vascular contractility and maintain the blood-brain barrier. Pericyte dysfunction has the potential to mediate many of the deleterious vascular consequences of ischemic stroke. Current therapeutics are designed to be administered after stroke onset and limit damage, but there are few options to target vascular risk factors pre-ischemia which likely contribute to stroke outcomes. Here, we focus on the role of pericytes in health and disease, and discuss how pericyte dysfunction can increase the risk of ischemic injury. Additionally, we note that despite the importance of pericytes in cerebrovascular disease, there are relatively few current therapeutic options that target pericyte function.

Exercise intensity and sex alter neurometabolic, transcriptional, and functional recovery following traumatic brain injury.

Physical exercise represents a potentially inexpensive, accessible, and optimizable rehabilitation approach to traumatic brain injury (TBI) recovery. However, little is known about the impact of post-injury exercise on the neurometabolic, transcriptional, and cognitive outcomes following a TBI. In the current study, we examined TBI outcomes in adolescent male and female mice following a controlled cortical impact (CCI) injury. Mice underwent a 10-day regimen of sedentary, low-, moderate-, or high-intensity treadmill exercise and were assessed for cognitive function, histopathology, mitochondrial function, and oxidative stress. Among male mice, low-moderate exercise improved cognitive recovery, and reduced cortical lesion volume and oxidative stress, whereas high-intensity exercise impaired both cognitive recovery and mitochondrial function. On the other hand, among female mice, exercise had an intermediate effect on cognitive recovery but significantly improved brain mitochondrial function. Moreover, single nuclei RNA sequencing of perilesional brain tissue revealed neuronal plasticity-related differential gene expression that was largely limited to the low-intensity exercise injured males. Taken together, these data build on previous reports of the neuroprotective capacity of exercise in a TBI model, and reveal that this rehabilitation strategy impacts neurometabolic, functional, and transcriptional outcome measures in an intensity- and sex-dependent manner.

Putting the Mind to Rest: A Historical Foundation for Rest as a Treatment for Traumatic Brain Injury.

Rest after traumatic brain injury (TBI) has been a part of clinical practice for more than a century but the use of rest as a treatment has ancient roots. In contemporary practice, rest recommendations have been significantly reduced but are still present. This advice to brain injured patients, on the face of it makes some logical sense but was not historically anchored in either theory or empirical data. The definition and parameters of rest have evolved over time but have encompassed recommendations including avoiding physical exercise, sensory stimulation, social contact, and even cognitive exertion. The goals and theoretical explanations for this approach have evolved and in modern conception include avoiding reinjury and reducing the metabolic demands on injured tissue. Moreover, as cellular and molecular understanding of the physiology of TBI developed, scientists and clinicians sometimes retroactively cited these new data in support of rest recommendations. Here, we trace the history of this approach and how it has been shaped by new understanding of the underlying pathology associated with brain injury.

Mild Traumatic Brain Injury Induces Time- and Sex-Dependent Cerebrovascular Dysfunction and Stroke Vulnerability.

Mild traumatic brain injury (mTBI) produces subtle cerebrovascular impairments that persist over time and promote increased ischemic stroke vulnerability. We recently established a role for vascular impairments in exacerbating stroke outcomes 1 week after TBI, but there is a lack of research regarding long-term impacts of mTBI-induced vascular dysfunction, as well as a significant need to understand how mTBI promotes stroke vulnerability in both males and females. Here, we present data using a mild closed head TBI model and an experimental stroke occurring either 7 or 28 days later in both male and female mice. We report that mTBI induces larger stroke volumes 7 days after injury, however, this increased vulnerability to stroke persists out to 28 days in female but not male mice. Importantly, mTBI-induced changes in blood-brain barrier permeability, intravascular coagulation, angiogenic factors, total vascular area, and glial expression were differentially altered across time and by sex. Taken together, these data suggest that mTBI can result in persistent cerebrovascular dysfunction and increased susceptibility to worsened ischemic outcomes, although these dysfunctions occur differently in male and female mice.

Ovarian Steroids Mediate Sex Differences in Alcohol Reward After Brain Injury in Mice.

Intoxication is a leading risk factor for injury, and TBI increases the risk for later alcohol misuse, especially when the injury is sustained in childhood. Previously, we modeled this pattern in mice, wherein females injured at postnatal day 21 drank significantly more than uninjured females, while we did not see this effect in males. However, the biological underpinnings of this sex difference have remained elusive. In this study, we utilize this preclinical model and traditional endocrine manipulations to assess the effect of perinatal sex steroids on post-injury ethanol response. We found that perinatal androgen administration and adult ovariectomy prevented the development of conditioned place preference to ethanol in females, while there was not an effect of gonadectomy either developmental time point on the severity of axonal degeneration. Finally, although TBI increased the number of microglia in males, there was no corresponding effect of gonadectomy, which suggests that males exhibit prolonged neuroinflammation after brain injury irrespective of circulating sex steroids. Taken together, our results indicate a potential role for ovarian sex steroids in the development of greater alcohol preference after a juvenile TBI in female mice.

The role of the stress system in recovery after traumatic brain injury: A tribute to Bruce S. McEwen.

Traumatic brain injury (TBI) represents a major public health concern. Although the majority of individuals that suffer mild-moderate TBI recover relatively quickly, a substantial subset of individuals experiences prolonged and debilitating symptoms. An exacerbated response to physiological and psychological stressors after TBI may mediate poor functional recovery. Individuals with TBI can suffer from poor stress tolerance, impairments in the ability to evaluate stressors, and poor initiation (and cessation) of neuroendocrine stress responses, all of which can exacerbate TBI-mediated dysfunction. Here, we pay tribute to the pioneering neuroendocrinologist Dr. Bruce McEwen by discussing the ways in which his work on stress physiology and allostatic loading impacts the TBI patient population both before and after their injuries. Specifically, we will discuss the modulatory role of hypothalamic-pituitary-adrenal axis responses immediately after TBI and later in recovery. We will also consider the impact of stressors and stress responses in promoting post-concussive syndrome and post-traumatic stress disorders, two common sequelae of TBI. Finally, we will explore the role of early life stressors, prior to brain injuries, as modulators of injury outcomes.

Mild traumatic brain injury increases vulnerability to cerebral ischemia in mice.

Recent studies have reported that TBI is an independent risk factor for subsequent stroke. Here, we tested the hypothesis that TBI would exacerbate experimental stroke outcomes via alternations in neuroimmune and neurometabolic function. We performed a mild closed-head TBI and then one week later induced an experimental stroke in adult male mice. Mice that had previously experienced TBI exhibited larger infarcts, greater functional deficits, and more pronounced neuroinflammatory responses to stroke. We hypothesized that impairments in central metabolic physiology mediated poorer outcomes after TBI. To test this, we treated mice with the insulin sensitizing drug pioglitazone (Pio) after TBI. Pio prevented the exacerbation of ischemic outcomes induced by TBI and also blocked the induction of insulin insensitivity by TBI. However, tissue respiratory function was not improved by Pio. Finally, TBI altered microvascular responses including promoting vascular accumulation of serum proteins and significantly impairing blood flow during the reperfusion period after stroke, both of which were reversed by treatment with Pio. Thus, TBI appears to exacerbate ischemic outcomes by impairing metabolic and microvascular physiology. These data have important implications because TBI patients experience strokes at greater rates than individuals without a history of head injury, but these data suggest that those strokes may also cause greater tissue damage and functional impairments in that population.

Moderate Intensity Treadmill Exercise Increases Survival of Newborn Hippocampal Neurons and Improves Neurobehavioral Outcomes after Traumatic Brain Injury.

Physician-prescribed rest after traumatic brain injury (TBI) is both commonplace and an increasingly scrutinized approach to TBI treatment. Although this practice remains a standard of patient care for TBI, research of patient outcomes reveals little to no benefit of prescribed rest after TBI, and in some cases prolonged rest has been shown to interfere with patient well-being. In direct contrast to the clinical advice regarding physical activity after TBI, animal models of brain injury consistently indicate that exercise is neuroprotective and promotes recovery. Here, we assessed the effect of low and moderate intensity treadmill exercise on functional outcome and hippocampal neural proliferation after brain injury. Using the controlled cortical impact (CCI) mouse model of TBI, we show that 10 days of moderate intensity treadmill exercise initiated after CCI reduces anxiety-like behavior, improves hippocampus-dependent spatial memory, and promotes hippocampal proliferation and newborn neuronal survival. Pathophysiological measures including lesion volume and axon degeneration were not altered by exercise. Taken together, these data reveal that carefully titrated physical activity may be a safe and effective approach to promoting recovery after brain injury.

Amino Acid Nanofibers Improve Glycemia and Confer Cognitive Therapeutic Efficacy to Bound Insulin.

Diabetes poses a high risk for debilitating complications in neural tissues, regulating glucose uptake through insulin-dependent and predominantly insulin-independent pathways. Supramolecular nanostructures provide a flexible strategy for combinatorial regulation of glycemia. Here, we compare the effects of free insulin to insulin bound to positively charged nanofibers comprised of self-assembling amino acid compounds (AACs) with an antioxidant-modified side chain moiety (AAC2) in both in vitro and in vivo models of type 1 diabetes. Free AAC2, free human insulin (hINS) and AAC2-bound-human insulin (AAC2-hINS) were tested in streptozotocin (STZ)-induced mouse model of type 1 diabetes. AAC2-hINS acted as a complex and exhibited different properties compared to free AAC2 or hINS. Mice treated with the AAC2-hINS complex were devoid of hypoglycemic episodes, had improved levels of insulin in circulation and in the brain, and increased expression of neurotransmitter taurine transporter, Slc6a6. Consequently, treatment with AAC2-hINS markedly advanced both physical and cognitive performance in mice with STZ-induced and genetic type 1 diabetes compared to treatments with free AAC2 or hINS. This study demonstrates that the flexible nanofiber AAC2 can serve as a therapeutic platform for the combinatorial treatment of diabetes and its complications.

Sex, Drugs, and TBI: The Role of Sex in Substance Abuse Related to Traumatic Brain Injuries.

Traumatic brain injuries (TBI) are a significant public health problem costing billions of dollars in healthcare costs and lost productivity while simultaneously reducing the quality of life for both patients and caregivers. Substance abuse is closely interconnected with TBI, as intoxicated individuals are at a greater risk of suffering brain injuries, and TBI may serve as a risk factor for the subsequent development of substance use disorders. There are also prominent sex differences in the etiology, epidemiology, and consequences of TBI. For instance, men are more likely to be injured on sporting fields or in auto accidents, while women are disproportionately likely to suffer TBI associated with intimate partner violence. Moreover, while men are much more likely to suffer TBI during late adolescence-young adulthood, sex differences in the incidence of TBI are much less prominent during other developmental epochs. Further, there are prominent sex differences in substance abuse biology; for example, while more men meet diagnostic criteria for substance abuse disorders, women tend to advance from casual use to addiction more quickly. In this paper, we will discuss the emerging clinical and preclinical evidence that these sex differences in TBI and substance abuse interact and may be prominent determinates of long-term outcomes.

Dim light at night exacerbates stroke outcome.

Circadian rhythms are endogenous biological cycles that synchronize physiology and behaviour to promote optimal function. These ~24-hr internal rhythms are set to precisely 24 hr daily by exposure to the sun. However, the prevalence of night-time lighting has the potential to dysregulate these biological functions. Hospital patients may be particularly vulnerable to the consequences of light at night because of their compromised physiological state. A mouse model of stroke (middle cerebral artery occlusion; MCAO) was used to test the hypothesis that exposure to dim light at night impairs responses to a major insult. Stroke lesion size was substantially larger among animals housed in dLAN after reperfusion than animals maintained in dark nights. Mice housed in dLAN for three days after the stroke displayed increased post-stroke anxiety-like behaviour. Overall, dLAN amplified pro-inflammatory pathways in the CNS, which may have exacerbated neuronal damage. Our results suggest that exposure to LAN is detrimental to stroke recovery.

Is Pediatric Traumatic Brain Injury Associated with Adult Alcohol Misuse?

Evidence suggests that pediatric traumatic brain injury (TBI) may be causally related to alcohol misuse later in life; however, the nature and extent of the association has not been well described. This study examined the relationship between pediatric TBI and adult alcohol misuse in a population sample ≥20 years of age. We sought to determine (1) whether first self-reported incidence of TBI with loss of consciousness (LOC) before the age of 20 increased the risk for alcohol misuse later in life; and (2) whether sex, injury severity, and age at time of injury modified the association. We found a greater likelihood of binge but not heavy drinking for those whose first self-reported TBI with LOC occurred before the age of 20 when compared with those whose first self-reported TBI with LOC occurred later in life (28.5% vs. 20.4%, p = 0.003). When limited to those with only mild TBI, the relationship to binge drinking remained significant (31.9% vs. 19.3%, p < 0.001) and was evident for both males (38.4% vs. 25.6%, p = 0.016) and females (20.9% vs. 12.4%, p = 0.044). When controlling for sex, age, and race/ethnicity, reporting a first TBI with LOC before age 20 was associated with binge drinking only for those with mild TBI (adjusted odds ratio [AOR] = 1.32; 95% confidence interval [CI] = 1.00-1.74). Results also showed that those with first TBI with LOC occurring between the ages of 10 and 19 years were more likely to binge drink as adults than those first injured earlier in life, regardless of TBI severity. Further research is needed at both the epidemiological and pre-clinical levels to better understand this relationship.

Lifelong consequences of brain injuries during development: From risk to resilience.

Traumatic brain injuries in children represent a major public health issue and even relatively mild injuries can have lifelong consequences. However, the outcomes from these injuries are highly heterogeneous, with most individuals recovering fully, but a substantial subset experiencing prolonged or permanent disabilities across a number of domains. Moreover, brain injuries predispose individuals to other kinds of neuropsychiatric and somatic illnesses. Critically, the severity of the injury only partially predicts subsequent outcomes, thus other factors must be involved. In this review, we discuss the psychological, social, neuroendocrine, and autonomic processes that are disrupted following traumatic brain injury during development, and consider the mechanisms the mediate risk or resilience after traumatic brain injury in this vulnerable population.

Does pediatric traumatic brain injury cause adult alcohol misuse: Combining preclinical and epidemiological approaches.

Traumatic brain injury (TBI) is closely interrelated with alcohol use disorders. This is mediated, in part, by the large number of individuals who are intoxicated at the time of their injuries. However, there is also evidence, both preclinically and epidemiologically that TBI, particularly when it occurs early in life can increase the incidence of alcohol use disorders later on. This is extremely important because drinking after TBI has been associated with much poorer long-term outcomes as compared to individuals who do not drink. However, for a number of reasons including potential confounders and a relatively long time between injury and onset of drinking it has been difficult to definitively assign causality. Here, we utilize a framework derived from the toxicology literature to determine whether a causal relationship between pediatric TBI and subsequent alcohol abuse is evident. In order for there to be a high likelihood of a causal relationship between an environmental factor and a health outcome, this framework indicates that an epidemiological relationship be present in humans and that analogous relationship has to exist in a preclinical model system and that the mechanism(s) of action that are identified in the model system must also be plausibly active in humans. In this review we discuss the epidemiological evidence for increased drinking in humans. Further, we discuss, the animal models for increased drinking after TBI and the potential mechanistic insights that have been derived from those animal models. We conclude, based on the framework described, that it is possible that pediatric TBI causes alcohol use disorders in humans.

Dim light at night impairs recovery from global cerebral ischemia.

Nighttime lighting is one of the great conveniences of modernization; however, there is mounting evidence that inopportune light exposure can disrupt physiological and behavioral functions. Hospital patients may be particularly vulnerable to the consequences of light at night due to their compromised physiological state. Cardiac arrest/cardiopulmonary resuscitation (CA) was used to test the hypothesis in mice that exposure to dim light at night impairs central nervous system (CNS) recovery from a major pathological insult. Mice exposed to dim light at night (5 lx) had higher mortality in the week following cardiac arrest compared to mice housed in dark nights (0 lx). Neuronal damage was significantly greater in surviving mice exposed to dim light at night after CA versus those housed in dark nights. Dim light at night may have elevated neuronal damage by amplifying pro-inflammatory pathways in the CNS; Iba1 immunoreactivity (an indication of microglia activation) and pro-inflammatory cytokine expression were elevated in mice exposed to dim light at night post-CA. Furthermore, selective inhibition of IL-1ß or TNFα ameliorated damage in mice exposed to dim light at night. The effects of light at night on CA outcomes were also prevented by using a wavelength of nighttime light that has minimal impact on the endogenous circadian clock, suggesting that replacing broad-spectrum nighttime light with specific circadian-inert wavelengths could be protective. Together, these data indicate that exposure to dim light at night after global cerebral ischemia increases neuroinflammation, in turn exacerbating neurological damage and potential for mortality.

Repetitive Brain Injury of Juvenile Mice Impairs Environmental Enrichment-Induced Modulation of REM Sleep in Adulthood.

Traumatic brain injuries (TBIs) are a common and costly ongoing public health concern. Injuries that occur during childhood development can have particularly profound and long-lasting effects. One common consequence and potential mediator of negative outcomes of TBI is sleep disruption which occurs in a substantial proportion of TBI patients. These individuals report greater incidences of insomnia and sleep fragmentation combined with a greater overall sleep requirement meaning that many patients are chronically sleep-deprived. We sought to develop an animal model of developmental TBI-induced sleep dysfunction. Specifically, we tested the hypothesis that early (postnatal day 21), repeated closed head injuries in Swiss-Webster mice, would impair basal and homeostatic sleep responses in adulthood. Further, we asked whether environmental enrichment (EE), a manipulation that improves functional recovery following TBI and has been shown to alter sleep physiology, would prevent TBI-induced sleep dysfunction and alter sleep-modulatory peptide expression. In contrast to our hypothesis, the mild, repeated head injury that we used did not significantly alter basal or homeostatic sleep responses in mice housed in standard laboratory conditions. Sham-injured mice housed in enriched environments exhibited enhanced rapid eye movement (REM) sleep and expression of the REM-promoting peptide pro-melanin-concentrating hormone, an effect that was not apparent in TBI mice housed in enriched environments. Thus, TBI blocked the REM-enhancing effects of EE. This work has important implications for the management and rehabilitation of the TBI patient population.

Minocycline blocks traumatic brain injury-induced alcohol consumption and nucleus accumbens inflammation in adolescent male mice.

Alcohol use is a well characterized risk factor for traumatic brain injury (TBI); however, emerging clinical and experimental research suggests that TBI may also be an independent risk factor for the development of alcohol use disorders. In particular, TBIs incurred early in life predict the development of problem alcohol use and increase vulnerability to neuroinflammation as a consequence of alcohol use. Critically, the neuroinflammatory response to alcohol, mediated in large part by microglia, may also function as a driver of further alcohol use. Here, we tested the hypothesis that TBI increases alcohol consumption through microglia-mediated neuroinflammation. Mice were injured as juveniles and alcohol consumption and preference were assessed in a free-choice voluntary drinking paradigm in adolescence. TBI increased alcohol consumption; however, treatment with minocycline, an inhibitor of microglial activation, reduced alcohol intake in TBI mice to sham levels. Moreover, a single injection of ethanol (2 g/kg) significantly increased microglial activation in the nucleus accumbens and microglial expression of the proinflammatory cytokine IL-1ß in TBI, but not sham or minocycline-treated, mice. Our data implicate TBI-induced microglial activation as a possible mechanism for the development of alcohol use disorders.

Alcohol Use Disorder and Traumatic Brain Injury.

Alcohol use and traumatic brain injury (TBI) are inextricably and bidirectionally linked. Alcohol intoxication is one of the strongest predictors of TBI, and a substantial proportion of TBIs occur in intoxicated individuals. An inverse relationship is also emerging, such that TBI can serve as a risk factor for, or modulate the course of, alcohol use disorder (AUD). Critically, alcohol use after TBI is a key predictor of rehabilitation outcomes, prognosis, and additional head injuries. This review provides a general overview of the bidirectional relationship between TBI and AUD and a discussion of potential neuropsychological and neurobiological mechanisms that might underlie the relationship.