Anxiety-like behaviors and hippocampal nNOS in response to diet-induced obesity combined with exercise

Tobisawa, Yuki; Yoshimura, S.; Ra, Song‐Gyu; Goto, Rina; Kugimoto, Ikumi; Uehara, Yoshio; Kawanaka, Kentaro; Higaki, Yasuki

doi:10.1007/s12576-019-00686-5

Cited by 11 publications

(17 citation statements)

References 46 publications

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“…One day before the mice were sacrificed, we assessed anxiety-like behaviors using the elevated plus maze (EPM) test as previously described. 22,32 Mice were transferred to the testing room a minimum of 60 minutes prior to each test session. All tests were performed between 13:00 and 16:00, during the light period (80-100 lux).…”

Section: Behavioral Testmentioning

confidence: 99%

“…38,39 Our previous findings and other studies have also demonstrated that downregulation of hippocampal nNOS, which is one of the upstream regulators of BDNF, 21 also reduces anxiety-like behaviors. 20,22,33,40 It is considered that nNOS-derived nitric oxide is likely to regulate downstream signaling. 20,21 However, it is unclear whether an actual reduction in nNOS-derived nitric oxide regulates Bdnf promoter IV DNA methylation and/or its mRNA expression; thus, future studies are needed to investigate this concept.…”

Section: F I G U R Ementioning

confidence: 99%

“…21 Similarly, LTEx reduces excess hippocampal nNOS protein levels. 22,23 Interestingly, pharmacological reduction of NO metabolites increase PGC-1α protein expression. 24,25 In skeletal muscle, it has been proposed that PGC-1α might be at the crossroads of nNOS-mediated signaling and the associated adaptive response to physical activity.…”

Section: Introductionmentioning

confidence: 99%

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Short‐term running exercise alters DNA methylation patterns in neuronal nitric oxide synthase and brain‐derived neurotrophic factor genes in the mouse hippocampus and reduces anxiety‐like behaviors

Tobisawa

Sakai

et al. 2021

FASEB j.

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Running exercise has beneficial effects on brain health. However, the effects of relatively short-term running exercise (STEx) on behavior, and its underlying signaling pathways, are poorly understood. In this study, we evaluated the possibility that the regulation by STEx of brain-derived neurotrophic factor (BDNF) and neuronal nitric oxide synthase (nNOS, encoded by NOS1), which are important molecules for anxiety regulation, might involve mechanisms of epigenetic modification, such as DNA methylation. C57BL/6J male mice were divided into sedentary (SED, n = 12) and STEx (EX, n = 15) groups; STEx was conducted with the mice for a duration of 11 days. STEx reduced anxiety-like behaviors, and STEx reduced Nos1α and increased Bdnf exon I and IV mRNA levels in the hippocampus. Interestingly, behavioral parameters were associated with Bdnf exon I and IV and Nos1α mRNA levels in the ventral, but not dorsal, hippocampal region. However, STEx had no effect on peroxisome proliferator-activated receptor-γ coactivator 1α (Pgc-1α) or fibronectin type III domain-containing 5 (Fndc5) mRNA levels, which are relatively long-term exercise-induced upstream regulators of BDNF. In parallel with gene expression changes, we found, for the first time, that STEx downregulated Bdnf promoter IV and upregulated Nos1 DNA methylation levels in the hippocampus, and these patterns were partially different between the dorsal and ventral regions. These findings suggest that the beneficial effects of running exercise on mood regulation may be controlled by alterations in epigenetic mechanisms, especially in the ventral hippocampus. These effects occur even after a relatively short-term period of exercise. K E Y W O R D S anxiety, BDNF, DNA methylation, exercise, hippocampus, nNOS 2 of 15 | TOMIGA eT Al.How to cite this article: Tomiga Y, Sakai K, Ra S-G, et al. Short-term running exercise alters DNA methylation patterns in neuronal nitric oxide synthase and brain-derived neurotrophic factor genes in the mouse hippocampus and reduces anxiety-like behaviors.

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Section: Behavioral Testmentioning

confidence: 99%

Section: F I G U R Ementioning

confidence: 99%

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Short‐term running exercise alters DNA methylation patterns in neuronal nitric oxide synthase and brain‐derived neurotrophic factor genes in the mouse hippocampus and reduces anxiety‐like behaviors

Tobisawa

Sakai

et al. 2021

FASEB j.

Self Cite

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show abstract

“…Finally, two recent studies by Zemdegs' team [51,52] Neuronal nitric oxide synthase (nNOS) is a key regulator of emotional behaviour. Some experiments [62,102,103] found that anxiety caused by a HFD was associated with increased levels of nNOS in the hippocampus and cerebral cortex. The content of glutathione in the blood is used as a biomarker to reflect the redox state of mice [122].…”

Section: Neurotransmitters/neuromodulatorsmentioning

confidence: 99%

Dietary and metabolic risk of neuropsychiatric disorders: insights from animal models

et al. 2021

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Neuropsychiatric disorders are major causes of the global burden of diseases, frequently co-occurring with multiple comorbidities, especially obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease and its various risk factors in metabolic syndrome. While the determining factors of neuropsychiatric disorders are complex, recent studies have shown that there is a strong link between diet, metabolic state and neuropsychiatric disorders, including anxiety and depression. There is no doubt that rodent models are of great value for preclinical research. Therefore, this article focuses on a rodent model of chronic consumption of high-fat diet (HFD), and/or the addition of a certain amount of cholesterol or sugar. Meanwhile, summarizes the pattern of diet that induces anxiety/depressive-like behaviour and the underlying mechanism. We highlight how dietary and metabolic risk influence neuropsychiatric behaviour in animals. Changes in dietary patterns, especially HFD, can induce anxiety or depression-like behaviours, which may vary by diet exposure period, sex, age, species, and genetic background of the animals used. Furthermore, dietary patterns significantly aggravate anxiety/depression-like behaviour in animal models of neuropsychiatric disorders. The mechanisms by which diet induces anxiety/depressive-like behaviour may involve neuroinflammation, neurotransmitters/neuromodulators, neurotrophins, and the gut-brain axis. Future research should be focused on elucidating the mechanism and identifying the contribution of diet and diet-induced metabolic risk to neuropsychiatric disorders, which can form the basis for future clinical dietary intervention strategies for neuropsychiatric disorders.

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“…The increased incidence of obesity and obesity-associated comorbidities is a global health concern [4]. Although the adverse effects of obesity in the brain are unclear, studies have suggested that obesity and body fat deposition play an essential role in the pathogenesis of certain brain-related disorders [3,5,6]. Recent studies have also demonstrated that HFD consumption and obesity are correlated with cognitive damage and a raised chance of expanding dementia [7,8].…”

Section: Introductionmentioning

confidence: 99%

Effects of Hypericum scabrum extract on dentate gyrus synaptic plasticity in high fat diet-fed rats

et al. 2020

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High-fat diet (HFD) can induce deficits in neural function, oxidative stress, and decrease hippocampal neurogenesis. Hypericum (H.) scabrum extract (Ext) contains compounds that could treat neurological disorders. This study aimed to examine the neuroprotective impacts of the H. scabrum Ext on hippocampal synaptic plasticity in rats that were fed HFD. Fifty-four male Wistar rats (220 ± 10 g) were randomly arranged in six groups: (1) HFD group; (2) HFD + Ext300 group; (3) HFD + Ext100 group; (4) Control group; (5) Ext 300 mg/kg group; (6) Ext 100 mg/kg group. These protocols were administrated for 3 months. After this stage, a stimulating electrode was implanted in the perforant pathway (PP), and a bipolar recording electrode was embedded into the dentate gyrus (DG). Long-term potentiation (LTP) was provoked by high-frequency stimulation (HFS) of the PP. Field excitatory postsynaptic potentials (EPSP) and population spikes (PS) were recorded at 5, 30, and 60 min after HFS. The HFD group exhibited a large and significant decrease in their PS amplitude and EPSP slope as compared to the control and extract groups. In reverse, H. scabrum administration in the HFD + Ext rats reversed the effect of HFD on the PS amplitude and EPSP slope. The results of the study support that H. scabrum Ext can inhibit diminished synaptic plasticity caused by the HFD. These effects are probably due to the extreme antioxidant impacts of the Ext and its capability to scavenge free radicals.

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Anxiety-like behaviors and hippocampal nNOS in response to diet-induced obesity combined with exercise

Cited by 11 publications

References 46 publications

Short‐term running exercise alters DNA methylation patterns in neuronal nitric oxide synthase and brain‐derived neurotrophic factor genes in the mouse hippocampus and reduces anxiety‐like behaviors

Short‐term running exercise alters DNA methylation patterns in neuronal nitric oxide synthase and brain‐derived neurotrophic factor genes in the mouse hippocampus and reduces anxiety‐like behaviors

Dietary and metabolic risk of neuropsychiatric disorders: insights from animal models

Effects of Hypericum scabrum extract on dentate gyrus synaptic plasticity in high fat diet-fed rats

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