Abstract:Spaceflight entails various stressful environmental factors including microgravity. The effects of gravity changes have been studied extensively on skeletal, muscular, cardiovascular, immune and vestibular systems, but those on the nervous system are not well studied. The alteration of gravity in ground-based animal experiments is one of the approaches taken to address this issue. Here we investigated the effects of centrifugation-induced gravity changes on gene expression of brain-derived neurotrophic factor … Show more
“…After the treatments, all the mice were immediately killed through cervical dislocation, and their whole brains were removed. The brain samples were cut into 2 mm slices, and the medial prefrontal cortex, striatum, hippocampus, and hypothalamus were punched out, referring to the methods of Ishikawa et al [16].…”
Section: Experimental Conditions and Preparation Of Brain Samplesmentioning
Backgrounds
Sevoflurane is a most frequently used volatile anesthetics, but its molecular mechanisms of action remain unclear. We hypothesized that specific genes play regulatory roles in brain exposed to sevoflurane. Thus, we aimed to evaluate the effects of sevoflurane inhalation and identify potential regulatory genes by RNA-seq analysis.
Methods
Eight-week old mice were exposed to sevoflurane. RNA from medial prefrontal cortex, striatum, hypothalamus, and hippocampus were analysed using RNA-seq. Differently expressed genes were extracted and their gene ontology terms were analysed using Metascape. These our anesthetized mouse data and the transcriptome array data of the cerebral cortex of sleeping mice were compared. Finally, the activities of transcription factors were evaluated using a weighted parametric gene set analysis (wPGSA). JASPAR was used to confirm the existence of binding motifs in the upstream sequences of the differently expressed genes.
Results
The gene ontology term enrichment analysis result suggests that sevoflurane inhalation upregulated angiogenesis and downregulated neural differentiation in each region of brain. The comparison with the brains of sleeping mice showed that the gene expression changes were specific to anesthetized mice. Focusing on individual genes, sevoflurane induced Klf4 upregulation in all sampled parts of brain. wPGSA supported the function of KLF4 as a transcription factor, and KLF4-binding motifs were present in many regulatory regions of the differentially expressed genes.
Conclusions
Klf4 was upregulated by sevoflurane inhalation in the mouse brain. The roles of KLF4 might be key to elucidating the mechanisms of sevoflurane induced functional modification in the brain.
“…After the treatments, all the mice were immediately killed through cervical dislocation, and their whole brains were removed. The brain samples were cut into 2 mm slices, and the medial prefrontal cortex, striatum, hippocampus, and hypothalamus were punched out, referring to the methods of Ishikawa et al [16].…”
Section: Experimental Conditions and Preparation Of Brain Samplesmentioning
Backgrounds
Sevoflurane is a most frequently used volatile anesthetics, but its molecular mechanisms of action remain unclear. We hypothesized that specific genes play regulatory roles in brain exposed to sevoflurane. Thus, we aimed to evaluate the effects of sevoflurane inhalation and identify potential regulatory genes by RNA-seq analysis.
Methods
Eight-week old mice were exposed to sevoflurane. RNA from medial prefrontal cortex, striatum, hypothalamus, and hippocampus were analysed using RNA-seq. Differently expressed genes were extracted and their gene ontology terms were analysed using Metascape. These our anesthetized mouse data and the transcriptome array data of the cerebral cortex of sleeping mice were compared. Finally, the activities of transcription factors were evaluated using a weighted parametric gene set analysis (wPGSA). JASPAR was used to confirm the existence of binding motifs in the upstream sequences of the differently expressed genes.
Results
The gene ontology term enrichment analysis result suggests that sevoflurane inhalation upregulated angiogenesis and downregulated neural differentiation in each region of brain. The comparison with the brains of sleeping mice showed that the gene expression changes were specific to anesthetized mice. Focusing on individual genes, sevoflurane induced Klf4 upregulation in all sampled parts of brain. wPGSA supported the function of KLF4 as a transcription factor, and KLF4-binding motifs were present in many regulatory regions of the differentially expressed genes.
Conclusions
Klf4 was upregulated by sevoflurane inhalation in the mouse brain. The roles of KLF4 might be key to elucidating the mechanisms of sevoflurane induced functional modification in the brain.
“…It has been well studied that the vestibular system is greatly affected by altered gravity 21,22,[56][57][58] . The previous study implied that the vestibular organ was the main area influenced by HG in the brain 48 . Notably, the hippocampus, especially CA1, had electrophysiological and anatomical connections with the vestibular system [59][60][61][62][63][64][65][66] .…”
Section: Discussionmentioning
confidence: 95%
“…14 days 8 weeks C57BL/6J male mice Decreased brain-derived neurotrophic factor (BDNF) in the ventral hippocampus•Increased 5-HT receptor 1B in the ventral hippocampus 48 14 days 7 weeks Wistar male rats Impaired spatial memory (radial eight arms maze) The same serum cortisol level with the control Upregulation of insulin like growth factor binding protein 2 49 3,4G…”
The gravity is necessary for living organisms to operate various biological events including hippocampus-related functions of learning and memory. Until now, it remains inconclusive how altered gravity is associated with hippocampal functions. It is mainly due to the difficulties in generating an animal model experiencing altered gravity. Here, we demonstrate the effects of hypergravity on hippocampus-related functions using an animal behavior and electrophysiology with our hypergravity animal model. The hypergravity (4G, 4 weeks) group showed impaired synaptic efficacy and long-term potentiation in CA1 neurons of the hippocampus along with the poor performance of a novel object recognition task. Our studies suggest that altered gravity affects hippocampus-related cognitive functions, presumably through structural and functional adaptation to various conditions of gravity shift.
“…Hypergravity also alters rats' genetic expression of serotonin receptors in the ventral hippocampus, an effect mediated by the vestibular organs (Ishikawa et al, 2017). So the clinical efficacy of SSRI's may be due to a non-specific effect on the perception of gravity and non-depressive gravity-like behaviours.…”
Mental Gravity is a novel theory postulating that the mind actively simulates properties of physical gravity under different conditions, including when depressed. It describes how aspects of the brain, body, and self display characteristics analogous to the experience of gravitational force and underlying spacetime curvature as conceived in the general theory of relativity. It is systematically related to the Bayesian active inference account of brain behaviour, specifically neuronal gauge theories. Mental Gravity explains how “gravity priors” (i.e., the intuitive physics of heavy and falling objects) is mobilised for social/emotional communication, and also how it relates to autobiographical memory and the self. The theory models the interaction between present (experiential) and past (autobiographical) poles of the so-called “self-axis” as analogous to the interaction between two masses in a gravitational field. Depression represents a particularly salient form of Mental Gravity where the past self dominates present experience, leading to quasi-delusion beliefs or quasi-hallucinatory perceptions of increased gravity leading to gravity-like experiences of feeling down, low, heavy, and slow. A plausible neurobiological substrate for Mental Gravity is also proposed (relativistic pseudo-diffusion) to connect to the experience of subjective time dilation (slowing) in depression to the slowing/curavture of neural spacetime dynamics. Using a “common currency” approach, I therefore propose that Mental Gravity is fundamental to: 1) phenomenological experience of the self in space and time; 2) spatial and temporal perception and cognition; and 3) neurobiological spatiotemporal dynamics.
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