Browsing by Subject "Hippocampus (Brain)"
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Item Adenosine and blood flow regulatory mechanisms in hippocampal ischemia(Texas Tech University, 2002-05) Gervitz, Leon MAccording to the National Institutes of Health (NIH), stroke affects more than 700,000 people annually, making it the third leading cause of death and the most common cause of adult disability in the United States. The success of medical intervention after a stroke depends on its being started soon after the insult. Defined as an acute neurological disorder caused by disturbances of the cerebral blood supply, stroke can rapidly lead to the development of ischemic brain tissue that is comprised of a nonviable, necrotic core surrounded by a penumbral region. Although functionally depressed, the penumbral region remains metabolically intact making it potentially salvageable during the post-ischemic therapeutic window. As such, it is considered a promising target for acute therapeutic intervention. The limited success of current early interventions, however, argues for a greater understanding of the regulatory mechanisms governing the physiology of the ischemic brain. Of particular interest are the regulatory mechanisms governing neuronal function and blood flow within the ischemic hippocampus. An integral part of the limbic system that is involved in the processing of short-term memory, the hippocampus is a bilateral structure that is exquisitely sensitive to hypoxia and/or ischemia. It is well established that an early response to cerebral hypoxic and/or ischemic conditions is a reversible inhibition of evoked synaptic potentials. The suppression of synaptic function is thought to serve as a neuroprotective mechanism to reduce energy expenditure during metabolic stress, i.e. hypoxia/ischemia. There is substantial evidence in in vitro preparations that the initial reversible loss of synaptic activity during exposure to hypoxia or ischemic-like conditions in the hippocampus is due to the release of endogenous adenosine acting at neuronal Ai receptors. Such roles for adenosine in in vivo preparations, however, have not been as convincingly demonstrated. Using a rat model of unilateral common carotid artery occlusion coupled with hypoxia, this dissertation examines the regulatory mechanisms of hippocampal blood flow and the contribution of adenosine to the early hypoxic/ischemic inhibition of synaptic transmission in an in vivo model of ischemic penumbra, and additionally examines the role of adenosine in the initiation of a post-ischemic, anti-apoptotic signal transduction pathway, Akt/Protein Kinase B. Animals were placed in a stereotaxic apparatus and evoked excitatory postsynaptic potentials (fEPSPs) were recorded from CAl of the rat hippocampus. Additionally, body temperature, systemic blood pressure, arterial blood gases, and hippocampal blood flow using laser Doppler flowmetry were monitored during experiments. Akt/PKB activation was examined using Western blot analysis. We demonstrate for the first time in an in vivo preparation, that A1 receptor activation plays a central role in the early hypoxic-ischemic depression of the evoked hippocampal synaptic potentials. Moreover, we demonstrate that while hypoxia is a potent stimulus for the adenosine-mediated depression of the synaptic potentials in vitro, reduced hippocampal tissue p02 alone does not appear to be sufficient to induce an adenosine-mediated depression of synaptic transmission in vivo. There must be, it seems, an accompanying reduction in local hippocampal blood flow. Moreover, the adenosine A1- mediated depression of synaptic depression occurs in proportion to reductions in local cerebral blood flow over a wide range of flows typical of penumbra. We also demonstrated that A] receptor activation leads to the activation of the neurotrophic/anti-apoptotic protein kinase Akt/Protein Kinase B (PKB). This result suggest that Akt/PKB activation may play a heretofore unappreciated role in adenosine A1-mediated signal transduction and, therefore, in adenosine A 1-mediated neuroprotection. We conclude from this work that adenosine acts as both an endogenous mediator and a sensitive indicator of penumbral conditions throughout the range of penumbral blood flows, and is an important mediator of the cellular response to survivable levels of ischemia.Item Brain region gene expression responds discretely to chronic alcohol withdrawal with specific disruption of the hippocampus during intoxication(2005) Berman, Ari Ethan; Bergeson, Susan E.Alcoholism is a chronic, progressive and heritable disease that affects millions of Americans and costs the United States hundreds of billions of dollars per year in medical expenditures, property damage, and loss of productivity. Alcohol dependence is the result of long-lasting cellular and molecular changes in the brain that are initiated and maintained by the repeated ingestion of intoxicating amounts of alcohol. Withdrawal symptoms from alcohol occur when alcohol intake is reduced or halted and the brain enters a period of extended hyperactivity. Animal models for alcohol-related behaviors were previously developed and characterized in both mice and rats, including mouse strains that were particularly sensitive to alcohol withdrawal. Mice from a strain that is highly sensitive to withdrawal from alcohol, DBA/2J, were given a chronic dose of ethanol by inhalation and comparative microarray analysis was performed. A suite of microarray analysis software was written to facilitate the large amount of data collected from this experiment, and a robust web-based database system, the Alcohol Research Integrator, was developed to serve both as a storage and as a high-level analysis medium. Here we show that detectable gene expression changes occur in a discrete fashion between gross anatomical brain regions at various stages of withdrawal, and that the hippocampus shows a markedly greater level of gene expression change during intoxication than any of the other brain regions suggesting a particular vulnerability to the intoxicating effects of alcohol.Item Membrane binding characteristics of choline-o-acetyltransferase in rat hippocampal nerve terminals(Texas Tech University, 1992-12) Smith, L. KeithCholine-0-acetyltransferase (ChAT; EC 2.3.1.6.) is the enzyme which catalyzes the formation of the excitory neurotransmitter acetylcholine. Although most of the ChAT in central cholinergic nerve terminals is soluble, some is also non-ionically associated with membranes. The major objective of this dissertation research was to determine how this membrane-bound detergent soluble form of ChAT (D-ChAT) was anchored to membranes in rat hippocampal nerve terminals. I tested the hypothesis that D-ChAT was anchored to membranes by a glycosylphosphatidylinositol (GPI) anchor. ChAT appeared to possess three characteristics common to many GPI-anchored proteins: (1) phosphatidylinositol specific-phospholipase C (PI-PLC) selectively released it from membranes, (2) PI-PLC treatment converted it from a detergent soluble into an aqueous form, and (3) an antibody to an epitope on the GPI anchor (anti-CRD) immunoreacted with the cytosolic form of ChAT (S3-ChAT) on Western blots. I also tested the possibility that D-ChAT might be one of the first intracellular GPI-anchored proteins described by internalizing PI-PLC into synaptosomes and determining if it would release D-ChAT from membranes into the cytosol. Internalized PI-PLC increased the amount of ChAT found in the cytosol, while reducing the amount of D-ChAT associated with membranes. In some tissues, endogenous glycosyl-phosphatidylinositol-specific phospholipase Cs (GPI-PLCs) function to release GPI-anchored proteins from membranes. To determine if an endogenous GPI-PLC might function to release D-ChAT from membranes, I utilized the GPI-PLC inhibitor zinc. Zinc inhibited an endogenous temperature-dependent release of ChAT from rat hippocampal minces, an endogenous release of ChAT from intracellular membranes into the cytosol of synaptosomes, and an endogenous conversion of ChAT from a detergent into an aqueous form in a plasma membrane enriched subcellular fraction (P4). These results suggest that some of the D-ChAT in rat hippocampal nerve terminals is GPI-anchored intracellularly, and that an endogenous GPI-PLC-like enzyme releases it from membranes into the cytosol.Item The effect of hippocampal lesions upon activity and learning(Texas Tech University, 1966-08) Jackson, William JamesNot available