Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and Β-Arrestin-1–regulated Lactate Metabolism

BACKGROUND: Stress is a conserved physiological response in mammals. Whereas moderate stress strengthens memory to improve reactions to previously experienced difficult situations, too much stress is harmful.METHODS: We used specific beta-adrenergic agonists, as well as beta(2)-adrenergic receptor (beta 2AR) and arrestin knockout models, to study the effects of adaptive beta 2AR activation on cognitive function using Morris water maze and object recognition experiments. We used molecular and cell biological approaches to elucidate the signaling subnetworks.RESULTS: We observed that the duration of the adaptive beta 2AR activation determines its consequences on learning and memory. Short-term formoterol treatment, for 3 to 5 days, improved cognitive function; however, prolonged beta 2AR activation, for more than 6 days, produced harmful effects. We identified the activation of several signaling networks downstream of beta 2AR, as well as an essential role for arrestin and lactate metabolism in promoting cognitive ability. Whereas Gs-protein kinase A-cyclic adenosine monophosphate response element binding protein signaling modulated monocarboxylate transporter 1 expression, beta-arrestin-1 controlled expression levels of monocarboxylate transporter 4 and lactate dehydrogenase A through the formation of a beta-arrestin-1/phospho-mitogen-activated protein kinase/hypoxia-inducible factor-1 alpha ternary complex to upregulate lactate metabolism in astrocyte-derived U251 cells. Conversely, long-term treatment with formoterol led to the desensitization of beta 2ARs, which was responsible for its decreased beneficial effects.CONCLUSIONS: Our results not only revealed that beta-arrestin-1 regulated lactate metabolism to contribute to beta 2AR functions in improved memory formation, but also indicated that the appropriate management of one specific stress pathway, such as through the clinical drug formoterol, may exert beneficial effects on cognitive abilities.