Division of Multicellular Circuit Dynamics
Member
Analysis of physiological changes in multicellular circuit dynamics responsible for higher brain
The Division Multicellular Circuit Dynamics aims to elucidate the circuitry mechanism of neuron and glia cells in central nervous system. For this purpose, 1. We focus on the glial physiological functions that affect on the neuronal circuits and ultimately on the behavior output. 2. We focus on the functional connectivity of the local multi cellular circuits and quantify the connectivity by our developed holographic microscope to modulate the circuits. Please see below for the detail.1. Aim of Research
(1) Project to reveal physiological functions of glial cells
(a) Microglia : We previously showed that microglia directly contact on synapse to monitor their functions using two photon microscope (Wake et al., 2009). Our recent research showed that microglia contact on synapse via P2Y12 signaling to modulate their function and thus to regulate the synchronization of neuronal circuits (Akiyoshi et al., 2018, Badimon et al., 2020).
In addition, we focused on blood brain barrier (BBB) permeability with systemic inflammation. Microglia migrate on blood vessels with the induction of systemic inflammation and expressed Cldn5 to form tight junction with endothelial cells to protect their permeability. However, with the progression of inflammation, microglia start to express CD68 to phagocyte astrocyte endfeet and thus increase the BBB permeability (Haruwaka et al., 2019). We are currently studying microglial contribution on motor learning and cross modal plasticity.
(b) Oligodendrocyte : We focused on activity dependent myelination and the responsible functional response of oligodendrocyte using two-photon microscope and electrophysiological methods. Oligodendrocyte was expressed GCaMP6 to see their modulation. We found glutamate signaling is essential to regulate the temporal pattern of action potential distributions of different axons.
(2) Development of holographic microscope
To manipulate neuronal and glial circuits with higher temporal and spatial resolution, we developed holographic microscope. Using this system, we measured the local circuit connectivity by stimulating single cell with simultaneous imaging of neuronal populational activity and studied the connectivity change in pain model (Okada et al., 2021). We further measured the connectivity in autism and schizophrenia mouse model.
Figure 1 Microglia which respond to inflammation by migrating toward and accumulationg around BBB maintain BBB integrity during the early phase of inflammation. Microglia phagocytosis of astrocytic end-feet impaired BBB function in the late phase.
Figure 2 In the primary somatosensory cortex during the acute phase of pain, holographic stimulation shows an increase of responses of surrounding neurons to single-cell stimulation, resulting in enhanced functional connectivity.
Selected publications
*Okada et al., Sci Adv, (2021)*Badimon et al., Nature, (2020)
*Kato et al., Glia, (2020)
*Haruwaka et al., Nat Commun, (2019)
*Wake et al., Nat Commun (2015)
*Wake et al., Science (2011)