Modulation of the Hippocampal Noradrenergic System and Memory Processing by Peripheral Arousal

The peripheral hormone epinephrine is known to modulate memory for arousing experiences. So far, the mnemonic effects of epinephrine have been attributed almost exclusively to actions on amygdala noradrenergic systems. Epinephrine also increases neuronal activity in the locus coeruleus (LC), the primary source of norepinephrine to other limbic structures that process memory such as the hippocampus. The actions of epinephrine on the LC suggest that its memory-enhancing properties may also be mediated by influencing norepinephrine output in the hippocampus. To test this hypothesis, the series of experiments described in the present dissertation were designed and conducted. Following discussion of background and significance of the experiments conducted in Chapter 1, Chapter 2 presents in vivo microdialysis experiments to demonstrate that epinephrine not only modulates the noradrenergic activity in the amygdala but in the hippocampus as well, via activation of intermediary structures. The experiments in Chapter 3 observed neural activity in the vagus nerve following systemic injection of epinephrine using an electrophysiological method. The experiments in this chapter observed direct influences of epinephrine on vagal neural activity via b-adrenergic receptors. In Chapter 4, the effects of electrical stimulation of the vagus nerve on the hippocampal noradrenergic activity were examined with the microdialysis technique. Observed changes in norepinephrine levels following stimulation, similar to those observed after epinephrine injection, further confirm iii epinephrine's reliance on this peripheral nerve in modulating hippocampus noradrenergic activity. The functional significance of augmented release of norepinephrine in the hippocampus induced by peripheral epinephrine was ascertained in Chapter 5. An optimum dose of epinephrine was found to significantly improve retention in the hippocampus-mediated spatial 8-arm maze after an 18 hr delay. Furthermore, this memory enhancement produced by epinephrine was abolished by blocking hippocampal noradrenergic receptors, suggesting that epinephrine's memory-enhancing properties involves influences on noradrenergic activity in the hippocampus. Collectively, these findings indicate that the mnemonic effects of epinephrine reported in a wide range of learning conditions may not be mediated solely by norepinephrine release in the amygdala, but may also involve coactivation of the hippocampus norepinephrine system. Implications and significance of the present experiments are discussed in Chapter 6.

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