Sex-dependent perturbations in risky choice behavior and prefrontal tyrosine hydroxylase levels induced by repetitive mild traumatic brain injury.

Head trauma often impairs cognitive processes mediated within the prefrontal cortex (PFC), leading to impaired decision making and risk-taking behavior. Mild traumatic brain injury (mTBI) accounts for approximately 80 % of reported head injury cases. Most neurological symptoms of a single mTBI are transient; however, growing evidence suggests that repeated mTBI (rmTBI) results in more severe impairments that worsen with each subsequent injury.

Perturbations in risk/reward decision making and frontal cortical catecholamine regulation induced by mild traumatic brain injury.

Mild traumatic brain injury (mTBI) disrupts cognitive processes that influence risk taking behavior. Little is known regarding the effects of repetitive mild injury (rmTBI) or whether these outcomes are sex specific. Risk/reward decision making is mediated by the prefrontal cortex (PFC), which is densely innervated by catecholaminergic fibers.

Repeated mild closed head injury in neonatal rats results in sustained cognitive deficits associated with chronic microglial activation and neurodegeneration.

Abusive head trauma in infants is a consequence of multiple episodes of abuse and results in axonal injury, brain atrophy, and chronic cognitive deficits. Anesthetized 11-day-old rats, neurologically equivalent to infants, were subjected to 1 impact/day to the intact skull for 3 successive days. Repeated, but not single impact(s) resulted in spatial learning deficits (p < 0.

Glucocorticoid Receptor Overexpression in the Dorsal Hippocampus Attenuates Spatial Learning and Synaptic Plasticity Deficits after Pediatric Traumatic Brain Injury.

Traumatic brain injury (TBI) in children <4 years of age leads to long-term deficits in cognitive and learning abilities that can persist or even worsen as these children age into adolescence. In this study, the role of glucocorticoid receptor (GR) function in the dorsal hippocampus (DH) in hippocampal-dependent cognitive function and synaptic plasticity were assessed following injury to the 11-day-old rat. Brain injury produced significant impairments in spatial learning and memory in the Morris water maze in male and female rats at 1-month post-injury (adolescence), which was accompanied by impairments in induction and maintenance of long-term potentiation (LTP) in the CA1 region of the DH.

Sex and estrous-phase dependent alterations in depression-like behavior following mild traumatic brain injury in adolescent rats.

Following mild traumatic brain injury (TBI), high school and collegiate-aged females tend to report more emotional symptoms than males. Adolescent male and female rats (35 days old) were subjected to mild TBI and evaluated for anxiety- and depression-like behaviors using the elevated plus maze and forced swim test (FST), respectively, and cellular alterations. Injured brains did not exhibit an overt lesion, atrophy of tissue or astrocytic reactivity underneath the impact site at 6-week post-injury, suggestive of the mild nature of trauma.

Trajectory of Long-Term Outcome in Severe Pediatric Diffuse Axonal Injury: An Exploratory Study.

Pediatric severe traumatic brain injury (TBI) is one of the leading causes of disability and death. One of the classic pathoanatomic brain injury lesions following severe pediatric TBI is diffuse (multifocal) axonal injury (DAI). In this single institution study, our overarching goal was to describe the clinical characteristics and long-term outcome trajectory of severe pediatric TBI patients with DAI.

A Pro-social Pill? The Potential of Pharmacological Treatments to Improve Social Outcomes After Pediatric Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of injury-induced disability in young children worldwide, and social behavior impairments in this population are a significant challenge for affected patients and their families. The protracted trajectory of secondary injury processes triggered by a TBI during early life-alongside ongoing developmental maturation-offers an extended time window when therapeutic interventions may yield functional benefits. This mini-review explores the scarce but promising pre-clinical literature to date demonstrating that social behavior impairments after early life brain injuries can be modified by drug therapies.

Intranasal Administration of Oxytocin Attenuates Social Recognition Deficits and Increases Prefrontal Cortex Inhibitory Postsynaptic Currents following Traumatic Brain Injury.

Pediatric traumatic brain injury (TBI) results in heightened risk for social deficits that can emerge during adolescence and adulthood. A moderate TBI in male and female rats on postnatal day 11 (equivalent to children below the age of 4) resulted in impairments in social novelty recognition, defined as the preference for interacting with a novel rat compared with a familiar rat, but not sociability, defined as the preference for interacting with a rat compared with an object in the three-chamber test when tested at four weeks (adolescence) and eight weeks (adulthood) postinjury. The deficits in social recognition were not accompanied by deficits in novel object recognition memory and were associated with a decrease in the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) recorded from pyramidal neurons within Layer II/III of the medial prefrontal cortex (mPFC).

A Role for the Amygdala in Impairments of Affective Behaviors Following Mild Traumatic Brain Injury.

Mild traumatic brain injury (TBI) results in chronic affective disorders such as depression, anxiety, and fear that persist up to years following injury and significantly impair the quality of life for patients. Although a great deal of research has contributed to defining symptoms of mild TBI, there are no adequate drug therapies for brain-injured individuals. Preclinical studies have modeled these deficits in affective behaviors post-injury to understand the underlying mechanisms with a view to developing appropriate treatment strategies.

Stem Cell Therapy for Pediatric Traumatic Brain Injury.

There has been a growing interest in the potential of stem cell transplantation as therapy for pediatric brain injuries. Studies in pre-clinical models of pediatric brain injury such as Traumatic Brain Injury (TBI) and neonatal hypoxia-ischemia (HI) have contributed to our understanding of the roles of endogenous stem cells in repair processes and functional recovery following brain injury, and the effects of exogenous stem cell transplantation on recovery from brain injury. Although only a handful of studies have evaluated these effects in models of pediatric TBI, many studies have evaluated stem cell transplantation therapy in models of neonatal HI which has a considerable overlap of injury pathology with pediatric TBI.

Progesterone treatment following traumatic brain injury in the 11-day-old rat attenuates cognitive deficits and neuronal hyperexcitability in adolescence.

Traumatic brain injury (TBI) in children younger than 4 years old results in cognitive and psychosocial deficits in adolescence and adulthood. At 4 weeks following closed head injury on postnatal day 11, male and female rats exhibited impairment in novel object recognition memory (NOR) along with an increase in open arm time in the elevated plus maze (EPM), suggestive of risk-taking behaviors. This was accompanied by an increase in intrinsic excitability and frequency of spontaneous excitatory post-synaptic currents (EPSCs), and a decrease in the frequency of spontaneous inhibitory post-synaptic currents in layer 2/3 neurons within the medial prefrontal cortex (PFC), a region that is implicated in both object recognition and risk-taking behaviors.

Depletion of microglia immediately following traumatic brain injury in the pediatric rat: Implications for cellular and behavioral pathology.

The inflammatory response is a significant component of the pathophysiology of pediatric traumatic brain injury. High levels of inflammatory mediators have been found in the cerebrospinal fluid of brain-injured children which have been linked to poor prognosis. Targeting aspects of the inflammatory response in the hopes of finding a viable post-injury therapeutic option has gained attention.

Therapeutic strategies to target acute and long-term sequelae of pediatric traumatic brain injury.

Pediatric traumatic brain injury (TBI) remains one of the leading causes of morbidity and mortality in children. Experimental and clinical studies demonstrate that the developmental age, the type of injury (diffuse vs. focal) and sex may play important roles in the response of the developing brain to a traumatic injury.

Factors affecting increased risk for substance use disorders following traumatic brain injury: What we can learn from animal models.

Recent studies have helped identify multiple factors affecting increased risk for substance use disorders (SUDs) following traumatic brain injury (TBI). These factors include age at the time of injury, repetitive injury and TBI severity, neurocircuits, neurotransmitter systems, neuroinflammation, and sex differences. This review will address each of these factors by discussing 1) the clinical and preclinical data identifying patient populations at greatest risk for SUDs post-TBI, 2) TBI-related neuropathology in discrete brain regions heavily implicated in SUDs, and 3) the effects of TBI on molecular mechanisms that may drive substance abuse behavior, like dopaminergic and glutamatergic transmission or neuroimmune signaling in mesolimbic regions of the brain.

Strong Correlation of Genome-Wide Expression after Traumatic Brain Injury In Vitro and In Vivo Implicates a Role for SORLA.

The utility of in vitro models of traumatic brain injury (TBI) depends on their ability to recapitulate the in vivo TBI cascade. In this study, we used a genome-wide approach to compare changes in gene expression at several time points post-injury in both an in vitro model and an in vivo model of TBI. We found a total of 2073 differentially expressed genes in our in vitro model and 877 differentially expressed genes in our in vivo model when compared to noninjured controls.

Minocycline Transiently Reduces Microglia/Macrophage Activation but Exacerbates Cognitive Deficits Following Repetitive Traumatic Brain Injury in the Neonatal Rat.

Elevated microglial/macrophage-associated biomarkers in the cerebrospinal fluid of infant victims of abusive head trauma (AHT) suggest that these cells play a role in the pathophysiology of the injury. In a model of AHT in 11-day-old rats, 3 impacts (24 hours apart) resulted in spatial learning and memory deficits and increased brain microglial/macrophage reactivity, traumatic axonal injury, neuronal degeneration, and cortical and white-matter atrophy. The antibiotic minocycline has been effective in decreasing injury-induced microglial/macrophage activation while simultaneously attenuating cellular and functional deficits in models of neonatal hypoxic ischemia, but the potential for this compound to rescue deficits after impact-based trauma to the immature brain remains unexplored.

Neuroprotective Effects of the Glutamate Transporter Activator (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) following Traumatic Brain Injury in the Adult Rat.

Traumatic brain injury (TBI) in humans and in animals leads to an acute and sustained increase in tissue glutamate concentrations within the brain, triggering glutamate-mediated excitotoxicity. Excitatory amino acid transporters (EAATs) are responsible for maintaining extracellular central nervous system glutamate concentrations below neurotoxic levels. Our results demonstrate that as early as 5 min and up to 2 h following brain trauma in brain-injured rats, the activity (Vmax) of EAAT2 in the cortex and the hippocampus was significantly decreased, compared with sham-injured animals.

Combination Therapies for Traumatic Brain Injury: Retrospective Considerations.

Patients enrolled in clinical trials for traumatic brain injury (TBI) may present with heterogeneous features over a range of injury severity, such as diffuse axonal injury, ischemia, edema, hemorrhage, oxidative damage, mitochondrial and metabolic dysfunction, excitotoxicity, inflammation, and other pathophysiological processes. To determine whether combination therapies might be more effective than monotherapy at attenuating moderate TBI or promoting recovery, the National Institutes of Health funded six preclinical studies in adult and immature male rats to evaluate promising acute treatments alone and in combination. Each of the studies had a solid rationale for its approach based on previous research, but only one reported significant improvements in long-term outcomes across a battery of behavioral tests.

Cathepsin L Mediates the Degradation of Novel APP C-Terminal Fragments.

Alzheimer's disease (AD) is characterized by the deposition of amyloid β (Aβ), a peptide generated from proteolytic processing of its precursor, amyloid precursor protein (APP). Canonical APP proteolysis occurs via α-, β-, and γ-secretases. APP is also actively degraded by protein degradation systems.