Hormetic and Non-Hormetic Dose-Response Functions in Stress Effects on Memory and Synaptic Plasticity: Issues and Mechanisms

Over a century of behavioral research has shown that stress can exert both positive and negative effects on memory. We have explored the idea that the complex effects of stress on learning and memory can be characterized by hormetic- and non-hormetic dose-response functions, in which stress may either stimulate or impair brain memory mechanisms, depending, in part, on the timing and duration of the stress experience. Extensive work has shown that acute stress or corticosteroid administration has a biphasic effect specifically on hippocampus-dependent learning, memory and synaptic plasticity. We suggest that brief stress exerts a rapid enhancement of memory-related functions of the hippocampus, produced by the amygdala-induced activation of hippocampal synaptic plasticity in conjunction with excitatory effects of neuromodulators, including glucocorticoids, norepinephrine, corticotropin-releasing hormone, acetylcholine and dopamine. We propose that the rapid stress-induced activation of the amygdala-hippocampus brain memory system results in a linear (non-hormetic) dose-response relation between emotional strength and memory formation. In response to more prolonged stress, a delayed inhibition of hippocampal function develops, which can be attributed to compensatory cellular responses which protect hippocampal neurons from excitotoxicity. The inhibition of hippocampal functioning in response to prolonged stress is potentially relevant to the well-described curvilinear (hormetic) dose-response relationship between arousal and memory. In summary, our emphasis on the temporal features of stress-brain interactions addresses how stress can activate, as well as impair, hippocampal functioning to produce differently shaped (nonhormetic/hormetic) stress-memory dose response functions.