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Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and ?-Arrestin-1-Regulated Lactate Metabolism.

ABSTRACT: 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.We used specific ?-adrenergic agonists, as well as ?2-adrenergic receptor (?2AR) and arrestin knockout models, to study the effects of adaptive ?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.We observed that the duration of the adaptive ?2AR activation determines its consequences on learning and memory. Short-term formoterol treatment, for 3 to 5 days, improved cognitive function; however, prolonged ?2AR activation, for more than 6 days, produced harmful effects. We identified the activation of several signaling networks downstream of ?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, ?-arrestin-1 controlled expression levels of monocarboxylate transporter 4 and lactate dehydrogenase A through the formation of a ?-arrestin-1/phospho-mitogen-activated protein kinase/hypoxia-inducible factor-1? ternary complex to upregulate lactate metabolism in astrocyte-derived U251 cells. Conversely, long-term treatment with formoterol led to the desensitization of ?2ARs, which was responsible for its decreased beneficial effects.Our results not only revealed that ?-arrestin-1 regulated lactate metabolism to contribute to ?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.

SUBMITTER: Dong JH

PROVIDER: S-EPMC6088385 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and β-Arrestin-1-Regulated Lactate Metabolism.

Dong Jun-Hong JH Wang Yi-Jing YJ Cui Min M Wang Xiao-Jing XJ Zheng Wen-Shuai WS Ma Ming-Liang ML Yang Fan F He Dong-Fang DF Hu Qiao-Xia QX Zhang Dao-Lai DL Ning Shang-Lei SL Liu Chun-Hua CH Wang Chuan C Wang Yue Y Li Xiang-Yao XY Yi Fan F Lin Amy A Kahsai Alem W AW Cahill Thomas Joseph TJ Chen Zhe-Yu ZY Yu Xiao X Sun Jin-Peng JP

Biological psychiatry 20161013 8

<h4>Background</h4>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.<h4>Methods</h4>We used specific β-adrenergic agonists, as well as β<sub>2</sub>-adrenergic receptor (β2AR) and arrestin knockout models, to study the effects of adaptive β2AR activation on cognitive function using Morris water maze and object recognition experiments. We used molecula ...[more]

PMID: 27916196

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Project description:BackgroundTendon injuries are common problems among athletes. Complete recovery of the mechanical structure and function of ruptured tendons is challenging. It has been demonstrated that upregulation of glycolysis and lactate production occurs in wounds, inflammation sites, and cancerous tumors, and these metabolic changes also control growth and differentiation of stem and progenitor cells. Similar metabolic changes have been reported in human healing tendons. In addition, lactate production has increased in progenitors isolated from injured tendons after treatment with IL-1β. It is thought that the metabolic changes play a role in tendon healing after injury.HypothesisGlucose metabolism is altered during tendon injury and healing, and modulation of this altered metabolism improves tendon repair.Study designControlled laboratory study.MethodsThe authors used the tendon injury model involving a complete incision of the Achilles tendon in C57BL/6J female mice and studied alterations of glucose metabolism in injured tendons with [U-13C]glucose and metabolomics analysis 1 and 4 weeks after surgery. They also examined the effects of dichloroacetate (DCA; an indirect lactate synthesis inhibitor) treatment on the recovery of structure and mechanical properties of injured tendons 4 weeks after surgery in the same mouse model.ResultsSignificant changes in glucose metabolism in tendons after injury surgery were detected. 13C enrichment of metabolites and intermediates, flux through glycolysis, and lactate synthesis, as well as tricarboxylic acid cycle activity, were acutely increased 1 week after injury. Increased glycolysis and lactate generation were also found 4 weeks after injury. DCA-treated injured tendons showed decreased cross-sectional area and higher values of modulus, maximum stress, and maximum force when compared with vehicle-treated injured tendons. Improved alignment of the collagen fibers was also observed in the DCA group. Furthermore, DCA treatment reduced mucoid accumulation and ectopic calcification in injured tendons.ConclusionThe findings indicate that injured tendons acutely increase glycolysis and lactate synthesis after injury and that the inhibition of lactate synthesis by DCA is beneficial for tendon healing.Clinical relevanceChanging metabolism in injured tendons may be a therapeutic target for tendon repair.

Dataset Information

Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and ?-Arrestin-1-Regulated Lactate Metabolism.

Publications

Adaptive Activation of a Stress Response Pathway Improves Learning and Memory Through Gs and β-Arrestin-1-Regulated Lactate Metabolism.

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