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TLR7 and IL-6 differentially regulate the effects of rotarod exercise on the transcriptomic profile and neurogenesis to influence anxiety and memory.

ABSTRACT: Voluntary exercise is well known to benefit brain performance. In contrast, forced exercise induces inflammation-related stress responses and may cause psychiatric disorders. Here, we unexpectedly found that rotarod testing, a frequently applied assay for evaluating rodent motor coordination, induces anxiety and alters spatial learning/memory performance of mice. Rotarod testing upregulated genes involved in the unfolded protein response and stress responses and downregulated genes associated with neurogenesis and neuronal differentiation. It impacts two downstream pathways. The first is the IL-6-dependent pathway, which mediates rotarod-induced anxiety. The second is the Toll-like receptor 7 (TLR7)-dependent pathway, which is involved in the effect of rotarod exercise on gene expression and its impact on contextual learning and memory of mice. Thus, although rotarod exercise does not induce systemic inflammation, it influences innate immunity-related responses in the brain, controls gene expression and, consequently, regulates anxiety and contextual learning and memory.

SUBMITTER: Hung YF

PROVIDER: S-EPMC8082089 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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TLR7 and IL-6 differentially regulate the effects of rotarod exercise on the transcriptomic profile and neurogenesis to influence anxiety and memory.

Hung Yun-Fen YF Hsueh Yi-Ping YP

iScience 20210331 4

Voluntary exercise is well known to benefit brain performance. In contrast, forced exercise induces inflammation-related stress responses and may cause psychiatric disorders. Here, we unexpectedly found that rotarod testing, a frequently applied assay for evaluating rodent motor coordination, induces anxiety and alters spatial learning/memory performance of mice. Rotarod testing upregulated genes involved in the unfolded protein response and stress responses and downregulated genes associated wi ...[more]

PMID: 33981972

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Project description:Our six-week treadmill running training (forced exercise) model has revealed that mild exercise (ME) with an intensity below the lactate threshold (LT) is sufficient to enhance spatial memory, while intense exercise (IE) above the LT negates such benefits. To help understand the unrevealed neuronal and signaling/molecular mechanisms of the intensity-dependent cognitive change, in this rat model, we here investigated plasma corticosterone concentration as a marker of stress, adult hippocampal neurogenesis (AHN) as a potential contributor to this ME-induced spatial memory, and comprehensively delineated the hippocampal transcriptomic profile using a whole-genome DNA microarray analysis approach through comparison with IE. Results showed that only IE had the higher corticosterone concentration than control, and that the less intense exercise (ME) is better suited to improve AHN, especially in regards to the survival and maturation of newborn neurons. DNA microarray analysis using a 4 × 44 K Agilent chip revealed that ME regulated more genes than did IE (ME: 604 genes, IE: 415 genes), and only 41 genes were modified with both exercise intensities. The identified molecular components did not comprise well-known factors related to exercise-induced AHN, such as brain-derived neurotrophic factor. Rather, network analysis of the data using Ingenuity Pathway Analysis algorithms revealed that the ME-influenced genes were principally related to lipid metabolism, protein synthesis and inflammatory response, which are recognized as associated with AHN. In contrast, IE-influenced genes linked to excessive inflammatory immune response, which is a negative regulator of hippocampal neuroadaptation, were identified. Collectively, these results in a treadmill running model demonstrate that long-term ME, but not of IE, with minimizing running stress, has beneficial effects on increasing AHN, and provides an ME-specific gene inventory containing some potential regulators of this positive regulation. This evidence might serve in further elucidating the mechanism behind ME-induced cognitive gain.

Project description:Mild exercise (ME) with an intensity below the lactate threshold (LT) is sufficient to enhance hippocampal function, while intense exercise (IE) above the LT negates such benefits. However, the question as to why ME more effectively enhances hippocampal function than does IE remains to be clarified. Here, we investigated adult hippocampal neurogenesis (AHN) as a mechanism of ME-induced cognitive improvement, and comprehensively delineated the transcriptomic profile of the hippocampus, using a rat whole-genome microarray approach through comparison with IE. Immunohistochemical results showed that less intense exercise (ME) is better suited to improve AHN, especially in regards to the survival and maturation of newborn neurons. DNA microarray analysis revealed that ME regulated more genes than did IE (ME: 604 genes, IE: 415 genes), and only 44 genes were modified with both exercise intensities. The identified molecular components did not comprise well-known factors related to exercise-induced AHN, such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF1), probably due to the timing of hippocampal tissue collection after the last training session and the technical feature of microarray. Rather, network analysis of the microarray data using Ingenuity Pathway Analysis algorithms revealed that the ME-influenced genes were principally related to lipid metabolism, protein synthesis and inflammatory response, which are recognized as associated with hippocampal neuroadaptations including AHN. In contrast, IE-influenced genes linked to immune response, a negative regulatory system of AHN and hippocampal function, were identified. Collectively, these results support our hypothesis that AHN could explain why ME enhances hippocampal function, and provide the ME-specific gene list that contain some potential regulators of this positive regulation. The list will become a foundation to elucidate the molecular pathway involving the ME-induced cognitive gain.

Dataset Information

TLR7 and IL-6 differentially regulate the effects of rotarod exercise on the transcriptomic profile and neurogenesis to influence anxiety and memory.

Publications

TLR7 and IL-6 differentially regulate the effects of rotarod exercise on the transcriptomic profile and neurogenesis to influence anxiety and memory.

Similar Datasets

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