Optical Methods for the Study of Brain Metabolism In Situ.

From its inception, the International Society of Oxygen Transport to Tissue (ISOTT) included several core members who were intrigued by the possibility of using light to probe the metabolic state of the cerebral cortex. This 50th anniversary review will focus on optical methods (UV, Visible, NIR) used to study brain oxygen metabolism in the intact brain. Chance, Lübbers, and Jöbsis did fundamental work in the 1970s and 1980s.

Environmental Enrichment Improved Cognitive Performance in Mice under Normoxia and Hypoxia.

The mammalian brain modulates its microvascular network to accommodate tissue energy demand in a process referred to as angioplasticity. There is an aging effect on cognitive function and adaptive responses to hypoxia. Hypoxia-induced angiogenesis is delayed in the aging mouse brain.

Effect of 3-Day and 21-Day Hypoxic Preconditioning on Recovery Following Cerebral Ischemia in Rats.

We have previously reported that in a rat model of chronic hypoxia, HIF-1α and its target genes have significantly accumulated by 3 days of exposure, whereas no significant increase in capillary density has occurred; there is a significant increase in capillary density at 21 days of chronic hypoxic exposure. In this study we hypothesize that by utilizing 3 days and 21 days of hypoxic preconditioning, we would distinguish between the relative neuroprotective contributions of the accumulation of HIF-1α and its target genes and angiogenic adaptation in a rat middle cerebral artery occlusion (MCAO) model. Rats were randomly assigned to either hypoxic precondition groups (3-day and 21-day hypoxia) or normoxic control group.

Altered Behavioral Performance in the Neuron-Specific HIF-1- and HIF-2-Deficient Mice Following Chronic Hypoxic Exposure.

Hypoxia-inducible factors (HIFs) are transcriptional regulators that mediate in mice for HIF-1 and HIF-2. The objective of this study was to investigate the effect of neuronal deletion of HIF-1 and HIF-2 in hypoxic adaptation by using the neuron-specific knockout (KO) mice. The floxed control and KO mice were used.

Chronic Ketosis Modulates HIF1α-Mediated Inflammatory Response in Rat Brain.

Hypoxia inducible factor alpha (HIF1α) is associated with neuroprotection conferred by diet-induced ketosis, but the underlying mechanism remains unclear. In this study, we use a ketogenic diet in rodents to induce a metabolic state of chronic ketosis, as measured by elevated blood ketone bodies. Chronic ketosis correlates with neuroprotection in both aged and following focal cerebral ischemia and reperfusion (via middle cerebral artery occlusion, MCAO) in mouse and rat models.

Neurovascular and cortical responses to hyperoxia: enhanced cognition and electroencephalographic activity despite reduced perfusion.

Key Points: Extreme aviation is accompanied by ever-present risks of hypobaric hypoxia and decompression sickness. Neuroprotection against those hazards is conferred through fractional inspired oxygen ( ) concentrations of 60-100% (hyperoxia). Hyperoxia reduces global cerebral perfusion (gCBF), increases reactive oxygen species within the brain and leads to cell death within the hippocampus.

Increased cerebral vascularization and decreased water exchange across the blood-brain barrier in aquaporin-4 knockout mice.

Aquaporin-4 (AQP4) plays an important role in regulating water exchange across the blood-brain barrier (BBB) and brain-cerebrospinal fluid interface. Studies on AQP-4 knockout mice (AQP4-KO) have reported considerable protection from brain edema induced by acute water intoxication and ischemic stroke, identifying AQP4 as a potential target for therapeutic interventions. However, the long-term effects of chronic AQP4 suppression are yet to be elucidated.

Functionalized Phenylbenzamides Inhibit Aquaporin-4 Reducing Cerebral Edema and Improving Outcome in Two Models of CNS Injury.

Cerebral edema in ischemic stroke can lead to increased intracranial pressure, reduced cerebral blood flow and neuronal death. Unfortunately, current therapies for cerebral edema are either ineffective or highly invasive. During the development of cytotoxic and subsequent ionic cerebral edema water enters the brain by moving across an intact blood brain barrier and through aquaporin-4 (AQP4) at astrocyte endfeet.

Post-resuscitation Arterial Blood Pressure on Survival and Change of Capillary Density Following Cardiac Arrest and Resuscitation in Rats.

Transient global brain ischemia, induced by cardiac arrest and resuscitation, results in reperfusion injury leading to delayed selective neuronal cell loss and post-resuscitation mortality. This study determined the effects of post-resuscitation hypotension and hypothermia on long-term survival following cardiac arrest and resuscitation. The capillary density was also determined.

Impact of Aging on Metabolic Changes in the Ketotic Rat Brain: Glucose, Oxidative and 4-HNE Metabolism.

Neuroprotection by ketosis is thought to be associated with improved mitochondrial function, decreased reactive oxygen species (ROS) and apoptotic and inflammatory mediators, and increased protective pathways. Oxidative injury to cells is often associated with lipid peroxidation. Accumulation of intermediary products of lipid peroxidation includes 4-hydroxynonenal (HNE; a toxic lipid peroxidation intermediate).

Cerebral Angioplasticity: The Anatomical Contribution to Ensuring Appropriate Oxygen Transport to Brain.

In order to maintain proper function, mammalian brain requires a significant fraction of the energy provided through whole body oxygen consumption and oxidative phosphorylation. This has been fairly well known for a long time. More recently there has been an increased appreciation that, while whole brain blood flow remains fairly constant, there are large regional changes in local blood flow to account for spatial and temporal heterogeneity of neuronal activity.

Correction to: Oxygen Transport to Tissue XL.

The chapters "Changes in Cytochrome-C-Oxidase Account for Changes in Attenuation of Near-Infrared Light in the Healthy Infant Brain" and "Fibreless Multiwavelength NIRS System for Imaging Localised Changes in Cerebral Oxidised Cytochrome C Oxidase" are made as open access as per the author's request in this revised version of the book.

Diet-Induced Ketosis Protects Against Focal Cerebral Ischemia in Mouse.

Over the past decade we have consistently shown that ketosis is neuroprotective against ischemic insults in rats. We reported that diet-induced ketotic rats had a significant reduction in infarct volume when subjected to middle cerebral artery occlusion (MCAO), and improved survival and recovery after cardiac arrest and resuscitation. The neuroprotective mechanisms of ketosis (via ketogenic diet; KG) include (i) ketones are alternate energy substrates that can restore energy balance when glucose metabolism is deficient and (ii) ketones modulate cell-signalling pathways that are cytoprotective.

Environmental Enrichment Induces Increased Cerebral Capillary Density and Improved Cognitive Function in Mice.

Enrichment provides an environment that fosters increased physical activity and sensory stimulation as compared to standard housing. Promoting and sustaining stimulation increases neuronal activity and, consequently, brain oxygen demand. The mammalian brain modulates its microvascular network to accommodate tissue energy demand in a process referred to as angioplasticity.

Brain Tissue PO Measurement During Normoxia and Hypoxia Using Two-Photon Phosphorescence Lifetime Microscopy.

Key to the understanding of the principles of physiological and structural acclimatization to changes in the balance between energy supply (represented by substrate and oxygen delivery, and mitochondrial oxidative phosphorylation) and energy demand (initiated by neuronal activity) is to determine the controlling variables, how they are sensed and the mechanisms initiated to maintain the balance. The mammalian brain depends completely on continuous delivery of oxygen to maintain its function. We hypothesized that tissue oxygen is the primary sensed variable.

Gender differences in hypoxic acclimatization in cyclooxygenase-2-deficient mice.

The aim of this study was to determine the effect of cyclooxygenase-2 (COX-2) gene deletion on the adaptive responses during prolonged moderate hypobaric hypoxia. Wild-type (WT) and COX-2 knockout (KO) mice of both genders (3 months old) were exposed to hypobaric hypoxia (~0.4 ATM) or normoxia for 21 days and brain capillary densities were determined.

Protective Effect of Dl-3-n-Butylphthalide on Recovery from Cardiac Arrest and Resuscitation in Rats.

In this study we investigated the effect of Dl-3-n-butylphthalide (NBP), a clinically used drug for stroke patients in China, on the recovery following cardiac arrest and resuscitation in rats. Male Wistar rats (3-month old) underwent cardiac arrest (12 min) and resuscitation. Rats were randomly assigned to the following groups: sham non-arrested group, vehicle group (vehicle-treated, 7 days before cardiac arrest and 4 days post-resuscitation), NBP pre-treated group (NBP-treated, 7 days before cardiac arrest), and NBP post-treated group (NBP-treated, 4 days post-resuscitation).

Aging Effect on Post-recovery Hypofusion and Mortality Following Cardiac Arrest and Resuscitation in Rats.

In this study we investigated the effect of aging on brain blood flow following transient global ischemia. Male Fisher rats (6 and 24 months old) underwent cardiac arrest (15 min) and resuscitation. Regional brain (cortex, hippocampus, brainstem and cerebellum) blood flow was measured in non-arrested rats and 1-h recovery rats using [14C] iodoantipyrene (IAP) autoradiography; the 4-day survival rate was determined in the two age groups.

HIF-1α/COX-2 expression and mouse brain capillary remodeling during prolonged moderate hypoxia and subsequent re-oxygenation.

Dynamic microvascular remodeling maintains an optimal continuous supply of oxygen and nutrients to the brain to account for prolonged environmental variations. The objective of this study was to determine the relative time course of capillary regression during re-oxygenation after exposure to prolonged moderate hypoxia and expression of the primary signaling factors involved in the process. Four-month old male C57BL/6 mice were housed and maintained in a hypobaric chamber at 290 Torr (0.

Short-term hypoxic preconditioning improved survival following cardiac arrest and resuscitation in rats.

Cardiac arrest and resuscitation produces delayed mortality and hippocampal neuronal death in rats. Hypoxic preconditioning has been to shown to protect the brain from ischemic insults. We have previously reported that with chronic hypobaric hypoxia, the accumulation of hypoxic-inducible factor-1 alpha (HIF-1α) and its target genes was increased for the first several days of hypoxic exposure, and returned to baseline level by 3 weeks when angiogenesis is completed.

Defining the role of HIF and its downstream mediators in hypoxic-induced cerebral angiogenesis.

Now that some of the basic mechanisms that underlie hypoxia-induced cerebral angiogenesis have been described, it has become clear that the hypoxia-inducible transcription factors, HIF-1 and HIF-2, play an important role in the process by causing the upregulation of vascular endothelial growth factor (VEGF). The heterogeneity of the brain parenchyma means that further progress in understanding capillary pathophysiology requires techniques that allow determination of the roles of individual components of the neurovascular unit. Multi-stain fluorescence co-localization techniques provide one such approach.

Hypoxia-induced angiogenesis and capillary density determination.

Chronic exposure to moderate hypoxia elicits structural and functional changes in the microvascular network of the mammalian CNS. Hypoxia-induced angiogenesis can be elicited and studied by a relatively simple experimental method. Rats or mice can be exposed to mild hypoxia in a hypobaric chamber, or alternatively in a normobaric hypoxia chamber.

Increased HIF-1α and HIF-2α accumulation, but decreased microvascular density, in chronic hyperoxia and hypercapnia in the mouse cerebral cortex.

The partial pressure of oxygen in the brain parenchyma is tightly controlled, and normal brain function is delicately sensitive to continuous and controlled oxygen delivery. The objective of this study was to determine brain angiogenic adaptive changes during chronic normobaric hyperoxia and hypercapnia in mice. Four-month-old C56BL/6 J mice were kept in a normobaric chamber at 50 % O2 and 2.

Mitochondrial abnormalities in a streptozotocin-induced rat model of sporadic Alzheimer's disease.

This study aimed to show that the rat model of sporadic Alzheimer's disease (sAD) generated by the intracerebroventricular (icv) injection of a sub-diabetogenic dose of streptozotocin (icvSTZ) is characterized by brain mitochondrial abnormalities. Three-month-old male Wistar rats were investigated 5 weeks after a single bilateral icv injection of STZ (3 mg/ Kg) or vehicle. icvSTZ administration induced a decrease in brain weight and cognitive decline, without affecting blood glucose levels.