In the rat, the hippocampus loses neurons with age, and cumulative exposure to glucocorticoids (GCs), the adrenocortical stress hormones, plays a major role in such exposure. My prior work suggests that GCs disrupt energy metabolism and thus compromise the ability of neurons to survive metabolic challenges. As evidence, varied insults that damage the hippocampus are more toxic in rates exposed to elevated GC concentrations and are less so in adrenalectomized rates. Such insults include the excittoxin kainic acid, the antimetabolite 3- acetylpyridine and hypoxia-ischemia. My proposed studies will 1) determine whether this model of GC- induced hippocampal damage applies to senescent neuron loss, 2) study the cellular mechanisms of this GC toxicity, and 3) examine the neuroendocrine consequences of the neuron loss. Part I: I will examine whether additional hippocampal insults also have their toxicities modulated by GC milieu. These will include epileptogenic excitotoxins and heavy metals. Since these acute insults may be of limited relevance to the gradual neuron loss of aging, I will then determine whether milder chronic insults also have their toxicities modulated by GCs. Part II: I will determine whether GCs are the sole damaging agents. I will expand my prior work with hippocampal neuron cultures to examine whether GCs endanger cells directly. I will study the steroidal and tissue specificity of the phenomenon, as well as identify the mediating receptors. Part III: I will study whether GCs exacerbate abnormal cellular parameters that accompany and may mediate neuron death. These will include excitatory neurotransmitter release, calcium influxes and lactic acidosis. Part IV: I will determine whether the aged hippocampus is preferentially sensitive to the synergy between GCs and varied insults, and whether GCs produce more extreme changes in the previously mentioned cellular parameters in the aged hippocampus. Part V: The hippocampus is a mediator the inhibitory negative feedback actions of GCs upon the adrenocortical axis. Using hypophysial portal cannulation methods, I will examine whether the hippocampal neuron loss of aging is associated with hypersecretion of corticotropic releasing factor or related peptides. If so, this would explain the GC hypersecretion of the aged rat which, in turn, further damages the hippocampus and impairs its function.
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