Symposium
Super crosstalk of metabolism and information processing
シンポジウム
脳内代謝回路と情報処理のクロストークの解明 |
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| 7月27日（土）16:30～16:50 第4会場（朱鷺メッセ 3F 301）
3S04e-1
代謝機能の光操作／光計測による脳情報解析と病態制御
Ko Matsui（松井 広）
東北大院生命科学超回路脳機能分野
Information processing in the brain is accomplished by signals conveyed by neurons. As the membrane potential of glial cells fluctuates only slightly, it has been considered that glial cells cannot serve as a medium of much information. However, using recently developed fluorescent probes, dynamic changes in glial ionic environment have been demonstrated. The presence of these neuron-to-glia communication has been shown before; but, because of the lack of a specific method for evoking glial activity, the presence of a signaling pathway leading back from glial-to-neuronal activity remained uncertain. To reveal the role of glia in brain function, the existence of glia-to-neuron signaling pathway triggered by such glial ionic changes needed to be shown.
Consciousness is lost within a minute from blood stream loss. This fact alone shows that complex information processing in the brain requires constant and precise supply of metabolic energy. Such super-network interaction between metabolism and information is likely to be the key link to body and mind connection. Neurons are never in direct contact with vascular components in the brain and astrocytes elements always come in between. Using electrophysiological and fluorescent imaging techniques, we have studied how neurons communicate with astrocytes. Super-fast communication pathway with kinetics comparable to neuronal synaptic transmission has been identified and it requires vesicular and ectopic releases of glutamate from presynaptic elements. We have also been studying the communication flowing in the opposite direction, from astrocytes to neurons, using specific and optogenetic activation of astrocytes. Classical transmitter can be released from astrocytes which appears to influence the function of the brain and lead to changes in behavior and learning. In addition, metabolites, which are not classically categorized as transmitters, also seem to be released from astrocytes. Metabolic alterations by optogenetic manipulation of astrocytes have a large impact on the information flow in neurons. In this talk, I will introduce our recent findings concerning this cross talk between metabolism and information processing. Possible future use of optogenetics in general systems biology will also be explored. | | 7月27日（土）16:50～17:10 第4会場（朱鷺メッセ 3F 301）
3S04e-2
脳梗塞における自然免疫の役割と脂質代謝
Takashi Shichita（七田 崇）
東京都医学研脳卒中ルネサンスプロジェクト
Microglia and infiltrating immune cells are pivotal players in the inflammation after ischemic stroke. Microglia and neutrophils/macrophages trigger the sterile inflammation after ischemic brain injury; however, these immune cells change their phenotype from inflammatory to pro-resolving around several days after stroke onset. On the other hand, intracerebral lipid metabolism is drastically changed after ischemic stroke. The metabolite of various lipids will be implicated in the time-dependent changes of innate immune response.
However, the relationships between intracerebral lipid metabolism and phenotypic change of cerebral myeloid cells remain to be clarified.
Infiltrating macrophages/neutrophils majorly produce inflammatory cytokines on day 3 after ischemic stroke onset (inflammatory phase); however, infiltrating macrophages and microglia produce neurotrophic factors and express scavenger receptors which efficiently remove inflammatory molecules from ischemic brain tissue on day 6 after stroke onset (resolution phase). This expression of scavenger receptor in myeloid cells can be enhanced by the administration of retinoids to mouse model of ischemic stroke. Furthermore, mass spectrometry analysis reveals the drastic changes of lipid metabolite between inflammatory and resolution phase. The expression levels of pro-resolving lipid mediators in ischemic brain increase in the resolution phase of ischemic brain injury, indicating the possibility that some lipid enzymes derived from ischemic brain have a key role in the resolution of cerebral post-ischemic inflammation. Retinoids and some pro-resolving lipid mediators have important roles in regulating cerebral post-ischemic inflammation. | | 7月27日（土）17:10～17:30 第4会場（朱鷺メッセ 3F 301）
3S04e-3
神経細胞内ATP動態のインビボ計測
Akiyo Natsubori（夏堀 晃世）
都医学研睡眠
Adenosine 5'-triphosphate (ATP) is a metabolic molecule which is used for many subcellular processes as an energy source. It is synthesized in each cell and a requirement for many subcellular processes in the brain, such as synaptic transmission, housekeeping activities, action potentials, and resting membrane potential. Furthermore, neuronal intracellular ATP concentration could potentially affect its electrical activity via ATP-sensitive K channels. Previous study showed that the intracellular ATP levels were decreased during the electrical activity in cultured neurons in a frequency-dependent manner due to energy consumption. However, these mechanisms might be different in the brains of living animals, because the neuronal electrical activity couples brain metabolic activities such as hemodynamics to maintain energy homeostasis. Moreover, in vivo brain intracellular ATP dynamics could be affected by sleep-wake states of animals, in which energy consuming and coupled producing activities change. To elucidate in vivo brain intracellular ATP dynamics, we conducted optical measurement of neuronal intracellular ATP levels using genetically-encoded fluorescent ATP probes (Thy1-ATeam: Trevisiol A. et al., 2017, eLife) and our fiber photometric system (Natsubori A. et al., 2017, J.Neurosci). We observed that the intracellular ATP levels in pyramidal neurons in cortical layer 5 were significantly decreased in rapid eye movement (REM) sleep compared with those in wake and non-REM sleep, suggesting a high energy expenditure during REM sleep. The neuronal intracellular ATP dynamics showed state-dependent phase relationship with cerebral blood flow (CBF), which has a role in energy supply and used for non-invasive measurable parameter for brain activities. We observed that the neuronal ATP response to local electrical stimulation was also state-dependent, which could be involved in state-dependent volume transmission such as acetylcholine. These unique characteristics of neuronal intracellular ATP dynamics could to be helpful for understanding not only physiological but also pathological brain metabolic conditions, such as cerebral ischemia and metabolic and neurodegenerative disorders in the future. | | 7月27日（土）17:30～17:50 第4会場（朱鷺メッセ 3F 301）
3S04e-4
光遺伝学による脳血流制御法
Kenji Tanaka（田中 謙二）
慶應大医精神・神経科学
It is well known that the neuronal activation triggers a blood flow change. However, little is known about whether the blood flow dynamics regulate neuronal activities. To address this question, we first generated the tool to manipulate the regional cerebral blood flow in behaving animals. We realized that the combination of parvalbumin promoter - tTA BAC transgenic and KENGE-tet yielded the strong gene induction in smooth muscles in blood vessels, thus, we exploited this system to target smooth muscles. To avoid gene induction in neuronal cells, we deleted KENGE-tet cassette by crossing pan-neuron Cre line. In this triple transgenic approach (PV-tTA::KENGE-tet; neuron-Cre), ChR2 or photoactivatable adenylate cyclase (PAC) was expressed only in smooth muscle cells. Blue light illumination induced contraction of blood vessels in ChR2 mice or relaxation in PAC mice. The response to the light quickly occurred but the vessel diameter changes lasted over 30 seconds even after light-off. Optogenetics-mediated blood vessel contraction or relaxation induced cerebral blood flow decrease or increase. These effects were observed not only in the cerebral cortex but also in the ventral striatum. We now use these mice to manipulate the blood flow that dominates the ventral striatum and examine how a regional blood flow regulates the neuronal activity and the motivated behavior. | | 7月27日（土）17:50～18:30 第4会場（朱鷺メッセ 3F 301）
3S04e-5
Dynamics of energy metabolites in brain cells.
Johannes Hirrlinger（Hirrlinger Johannes）1,2，Andrea Trevisiol（Trevisiol Andrea）2，Ulrike Winkler（Winkler Ulrike）1，Susanne Kohler（Kohler Susanne）1
1University of Leipzig, Carl-Ludwig-Institute for Physiology
2Max-Planck-Institute for Experimental Medicine, Dept. of Neurogenetics
Brain function crucially depends on an appropriate supply of energy and failure of energy metabolism will very quickly severely impair proper activity of this vital organ. Complex interactions of neurons, astrocytes and oligodendrocytes are essential for maintaining brain energy homeostasis. To study the dynamics of metabolites at high spatial and temporal resolution we took advantage of genetically encoded fluorescence sensors for metabolites, which convert the concentration of a metabolite of interest into a fluorescence signal. We focussed on the dynamics of metabolites like ATP or the NADH/NAD+-redox state in neurons and astrocytes both in vitro and in situ under basal and stimulated conditions. Our results show that intracellular metabolite levels are indeed subject to fast and reversible changes during physiological activity in brain cells and that these changes are diverse in different types of cells but also within the same type of cells in different brain regions. Furthermore, the dynamics of energy metabolites are modified in mouse models of diseases suggesting that these metabolic changes might contribute to pathophysiology. In summary, these studies provide new insights into the dynamics of energy metabolites in the brain, which allows for a deeper understanding of the contribution of brain energy metabolism to brain function both under physiological and pathophysiological conditions. | | | |
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