A role for norepinephrine in arousal, emotion and learning?: limbic modulation by norepinephrine and the Kety hypothesis.

1. Kety hypothesized that forebrain norepinephrine acted to selectively enhance cell firing in neurons receiving environmental inputs during affectively important events. He further suggested that norepinephrine could act to induce a 'persistent facilitation' of the inputs which accompany affectively important events and would thus promote a memory for these events. 2. The electrophysiological actions of norepinephrine at the time Kety proposed his hypothesis were thought to be inhibitory. More recent evidence has demonstrated that norepinephrine in neocortex and cerebellum enhances both excitatory and inhibitory evoked activity much as Kety proposed. This has been termed norepinephrine neuromodulation. 3. The locus coeruleus-norepinephrine system which gives rise to neocortical and cerebellar norepinephrine innervation also innervates, even more densely, areas of the limbic system. A review of norepinephrine actions, particularly in limbic cortex, indicates that locus coeruleus-norepinephrine also enhances transmission of evoked inputs in these structures. 4. A long-lasting enhancement of evoked inputs by locus coeruleus-norepinephrine has been demonstrated in the hippocampus. This long-lasting enhancement of inputs is reviewed in detail since it appears to directly support Kety's hypothesized 'persistent facilitation' effect of norepinephrine. It is suggested that norepinephrine-induced long-lasting enhancement may underlie numerous demonstrations of norepinephrine-dependent memory and neural plasticity in the forebrain. 5. The relationship of norepinephrine neuromodulation to possible candidate mechanisms and to activation of specific norepinephrine receptors is briefly discussed.