Key epigenetic and signaling factors in the formation and maintenance of the blood-brain barrier.

The blood-brain barrier (BBB) controls the movement of molecules into and out of the central nervous system (CNS). Since a functional BBB forms by mouse embryonic day E15.5, we reasoned that gene cohorts expressed in CNS endothelial cells (EC) at E13.

The evolving pathophysiology of TBI and the advantages of temporally-guided combination therapies.

Several clinical and experimental studies have demonstrated that traumatic brain injury (TBI) activates cascades of biochemical, molecular, structural, and pathological changes in the brain. These changes combine to contribute to the various outcomes observed after TBI. Given the breadth and complexity of changes, combination treatments may be an effective approach for targeting multiple detrimental pathways to yield meaningful improvements.

4R-cembranoid suppresses glial cells inflammatory phenotypes and prevents hippocampal neuronal loss in LPS-treated mice.

Chronic neuroinflammation has been implicated in neurodegenerative disease pathogenesis. A key feature of neuroinflammation is neuronal loss and glial activation, including microglia and astrocytes. 4R-cembranoid (4R) is a natural compound that inhibits hippocampal pro-inflammatory cytokines and increases memory function in mice.

Traumatic brain injury-associated epigenetic changes and the risk for neurodegenerative diseases.

Epidemiological studies have shown that traumatic brain injury (TBI) increases the risk for developing neurodegenerative diseases (NDs). However, molecular mechanisms that underlie this risk are largely unidentified. TBI triggers widespread epigenetic modifications.

Enhanced presynaptic mitochondrial energy production is required for memory formation.

Some of the prominent features of long-term memory formation include protein synthesis, gene expression, enhanced neurotransmitter release, increased excitability, and formation of new synapses. As these processes are critically dependent on mitochondrial function, we hypothesized that increased mitochondrial respiration and dynamics would play a prominent role in memory formation. To address this possibility, we measured mitochondrial oxygen consumption (OCR) in hippocampal tissue punches from trained and untrained animals.

Caudal DMN neurons innervate the spleen and release CART peptide to regulate neuroimmune function.

Background: Inflammation is a fundamental biological response to injury and infection, which if unregulated can contribute to the pathophysiology of many diseases. The vagus nerve, which primarily originates from the dorsal motor nucleus (DMN), plays an important role in rapidly dampening inflammation by regulating splenic function. However, direct vagal innervation of the spleen, which houses the majority of immune and inflammatory cells, has not been established.

Optogenetic Stimulation of CA1 Pyramidal Neurons at Theta Enhances Recognition Memory in Brain Injured Animals.

The hippocampus plays a prominent role in learning and memory formation. The functional integrity of this structure is often compromised after traumatic brain injury (TBI), resulting in lasting cognitive dysfunction. The activity of hippocampal neurons, particularly place cells, is coordinated by local theta oscillations.

Epigenetic Modifications and Their Potential Contribution to Traumatic Brain Injury Pathobiology and Outcome.

Epigenetic information is not permanently encoded in the DNA sequence, but rather consists of reversible, heritable modifications that regulate the gene expression profile of a cell. Epigenetic modifications can result in cellular changes that can be long lasting and include DNA methylation, histone methylation, histone acetylation, and RNA methylation. As epigenetic modifications are reversible, the enzymes that add (epigenetic writers), the proteins that decode (epigenetic readers), and the enzymes that remove (epigenetic erasers) these modifications can be targeted to alter cellular function and disease biology.

Impaired Experience-Dependent Refinement of Place Cells in a Rat Model of Alzheimer's Disease.

Background: Hippocampal place cells play an integral role in generating spatial maps. Impaired spatial memory is a characteristic pathology of Alzheimer's disease (AD), yet it remains unclear how AD influences the properties of hippocampal place cells.

Objective: To record electrophysiological activity in hippocampal CA1 neurons in freely-moving 18-month-old male TgF344-AD and age-matched wild-type (WT) littermates to examine place cell properties.

Metformin Reduces Repeat Mild Concussive Injury Pathophysiology.

Mild traumatic brain injury (mTBI) can initiate complex pathophysiological changes in the brain. Numerous cellular and molecular mechanisms underlying these pathologic changes are altered after injury, including those involved in energy utilization, excitotoxicity, ionic disturbances, and inflammation. It is thought that targeting multiple mechanisms may be necessary to produce meaningful reductions in brain pathology and to improve outcome.

Insulin-Like Growth Factor-2 (IGF-2) Does Not Improve Memory in the Chronic Stage of Traumatic Brain Injury in Rodents.

Persistent cognitive impairment(s) can be a significant consequence of traumatic brain injury (TBI) and can markedly compromise quality of life. Unfortunately, identifying effective treatments to alleviate memory impairments in the chronic stage of TBI has proven elusive. Several studies have demonstrated that insulin-like growth factor-2 (IGF-2) can enhance memory in both normal animals and in experimental models of disease.

Hypothermia for Patients Requiring Evacuation of Subdural Hematoma: A Multicenter Randomized Clinical Trial.

Background: Hypothermia is neuroprotective in some ischemia-reperfusion injuries. Ischemia-reperfusion injury may occur with traumatic subdural hematoma (SDH). This study aimed to determine whether early induction and maintenance of hypothermia in patients with acute SDH would lead to decreased ischemia-reperfusion injury and improve global neurologic outcome.

4R-cembranoid confers neuroprotection against LPS-induced hippocampal inflammation in mice.

Background: Chronic brain inflammation has been implicated in the pathogenesis of various neurodegenerative diseases and disorders. For example, overexpression of pro-inflammatory cytokines has been associated with impairments in hippocampal-dependent memory. Lipopolysaccharide (LPS) injection is a widely used model to explore the pathobiology of inflammation.

Selective Endothelial Hyperactivation of Oncogenic KRAS Induces Brain Arteriovenous Malformations in Mice.

Objective: Brain arteriovenous malformations (bAVMs) are a leading cause of hemorrhagic stroke and neurological deficits in children and young adults, however, no pharmacological intervention is available to treat these patients. Although more than 95% of bAVMs are sporadic without family history, the pathogenesis of sporadic bAVMs is largely unknown, which may account for the lack of therapeutic options. KRAS mutations are frequently observed in cancer, and a recent unprecedented finding of these mutations in human sporadic bAVMs offers a new direction in the bAVM research.

P-glycoprotein Expression Is Upregulated in a Pre-Clinical Model of Traumatic Brain Injury.

Athletes participating in contact sports are at risk for sustaining repeat mild traumatic brain injury (rmTBI). Unfortunately, no pharmacological treatment to lessen the pathophysiology of brain injury has received U.S.

A method for assessing tissue respiration in anatomically defined brain regions.

The survival and function of brain cells requires uninterrupted ATP synthesis. Different brain structures subserve distinct neurological functions, and therefore have different energy production/consumption requirements. Typically, mitochondrial function is assessed following their isolation from relatively large amounts of starting tissue, making it difficult to ascertain energy production/failure in small anatomical locations.

Early versus Late Profiles of Inflammatory Cytokines after Mild Traumatic Brain Injury and Their Association with Neuropsychological Outcomes.

Despite pre-clinical evidence for the role of inflammation in traumatic brain injury (TBI), there is limited data on inflammatory biomarkers in mild TBI (mTBI). In this study, we describe the profile of plasma inflammatory cytokines and explore associations between these cytokines and neuropsychological outcomes after mTBI. Patients with mTBI with negative computed tomography and orthopedic injury (OI) controls without mTBI were prospectively recruited from emergency rooms at three trauma centers.

Traumatic brain injury and hippocampal neurogenesis: Functional implications.

In the adult brain, self-renewing radial-glia like (RGL) progenitor cells have been shown to reside in the subventricular zone and the subgranular zone of the hippocampus. A large body of evidence shows that experiences such as learning, enriched environment and stress can alter proliferation and differentiation of RGL progenitor cells. The progenitor cells present in the subgranular zone of the hippocampus divide to give rise to newborn neurons that migrate to the dentate gyrus where they differentiate into adult granule neurons.

Sarm1 loss reduces axonal damage and improves cognitive outcome after repetitive mild closed head injury.

One of the consistent pathologies associated with both clinical and experimental traumatic brain injury is axonal injury, especially following mild traumatic brain injury (or concussive injury). Several lines of experimental evidence have demonstrated a role for NAD+ metabolism in axonal degeneration. One of the enzymes that metabolizes NAD+ in axons is Sarm1 (Sterile Alpha and TIR Motif Containing 1), and its activity is thought to play a key role in axonal degeneration.

Loss of PTEN-induced kinase 1 (Pink1) reduces hippocampal tyrosine hydroxylase and impairs learning and memory.

Phosphatase and tensin homolog (PTEN)-induced kinase 1 (Pink1) is involved in mitochondrial quality control, which is essential for maintaining energy production and minimizing oxidative damage from dysfunctional/depolarized mitochondria. Pink1 mutations are the second most common cause of autosomal recessive Parkinson's disease (PD). In addition to characteristic motor impairments, PD patients also commonly exhibit cognitive impairments.