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    Nerve gas-induced seizures: Role of basal forebrain cholinergic projections in rapid neuronal and glial activation in the brain

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    Author
    Zimmer, Lee Alexander
    Advisor
    Shipley, Michael T.
    Date
    1999
    Type
    dissertation
    
    Metadata
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    Abstract
    Soman, an, irreversible inhibitor of cholinesterase, causes intense convulsions, neuropathology and, ultimately, death. We used the immediate early gene product, Fos, as a marker for neuronal activity to pinpoint the earliest brain regions involved in the initiation and maintenance of soman-induced convulsions. The rapid induction of Fos in the piriform, cortex (PC) and the pontine nucleus locus coeruleus (LC), taken together with previous anatomical, electrophysiological, and neurochemical studies, suggests that prolonged, excessive exposure to synaptically released acetylcholine (ACh) and norepinephrine triggers seizures in PC and subsequently in other cortical and subcortical structures. By 24 hr following soman injection, there is marked neuropathology in the PC. Using immunocytochemical markers specific for astrocytes (GFAP) and glia (OX-42), we aimed to determine if soman-induced seizures also cause selective, rapid activation of astrocytes and microglia in the PC and other brain regions. The results demonstrate that: (i) there is a rapid increase (45--60 min) in GFAP staining in astrocytes of the piriform restricted to the same layers in which neurons express Fos; (ii) between 1 and 8 hr, ramified microglia in PC and hippocampus alter their morphology to resemble active then reactive microglia. These results suggest that intensely active neurons provide local signals triggering reactive changes in neighboring glia. To investigate the role of ACh in soman-induced seizures, cholinergic neurons in the nucleus of the diagonal band (NDB) were lesioned unilaterally with 192 IgG-saporin. NDB lesions inhibited the rapid activation of Fos in PC and inhibited changes in GFAP staining induced by staining. Electrical stimulation electrodes were implanted unilaterally in the NDB to focally activate projections to PC. Stimulation of NDB induced Fos and GFAP staining in PC identical to those following soman. Fos and GFAP staining elicited by NDB stimulation was blocked by scopolamine. These results suggest that ACh release from NDB terminals in PC triggers the initiation of seizures and gliosis following soman administration via a muscarinic receptor mechanism. Next, we examined the role of microglia during CNS injury using an in vitro slice paradigm that eliminated blood-borne monocytes and other serum factors before injury. Our findings indicate that resting microglia transform into macrophage-like cells following brain injury in the absence of monocytes and other serum factors. Finally, the effects of stimulation of the NDB on the spontaneous discharge of neurons and evoked field potentials in PC were investigated in anesthetized rats. The results of this study suggest that activation of cholinergic inputs to PC increases the excitability of pyramidal cells, probably by a disinhibitory mechanism involving muscarinic receptor activation.
    Description
    University of Maryland, Baltimore. Ph.D. 1999
    Keyword
    Biology, Molecular
    Biology, Neuroscience
    Biology, Animal Physiology
    Basal Forebrain
    Seizures
    Soman--adverse effects
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/1320
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    Theses and Dissertations School of Medicine
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