シンポジウム
22 サブプレート神経活動のダイナミズムによる脳神経回路の発達機構
22 Formation of the earliest cortical neuronal circuits orchestrated by subplate neural activity
座長：丸山 千秋（公益財団法人東京都医学総合研究所・脳神経回路形成プロジェクト）・Molnár Zoltán（Department of Physiology, Anatomy & Genetics, University of Oxford） |
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| 2022年6月30日 9:02～9:27 ラグナガーデンホテル 羽衣：西 第10会場
1S10m-01
Shadows of the Subplate - Repurposed Cells of Development in the Adult Brain
*Zoltan Molnar(1,2)
1. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom, 2. Einstein Visiting Fellow, Charité-Universitätsmedizin Berlin, Berlin, Germany
Keyword: cerebral cortical development, subplate neurons, thalamocortical development, schizophrenia
The lowermost cell layer of the cerebral cortex that contains interstitial white matter cells in humans has great clinical relevance. These neurons are very abundant during development and express higher proportions of susceptibility genes linked to human cognitive disorders than any other cortical layer and their distribution is known to be altered in schizophrenia and autism (Hoerder Suabedissen et al., 2013; Bakken et al., 2016; Molnar et al., 2019; Swiegers et al., 2021). In spite of these clinical links, our current knowledge on the adult layer 6b is limited. These cells are the remnants of the subplate cells that are present in large numbers and play key role in the formation of cortical circuits but a large fraction of them die during postnatal development. The adult population that remains in all mammals to form interstitial white matter cells in human or layer 6b in mouse display unique conserved gene expression and connectivity. Members of my laboratory recently identified intracortical and thalamic projections from a subpopulation of layer 6b cells that might regulate both cortical and thalamic arousal of cortical areas that are involved in higher cortical functions (Hoerder Suabedissen, et al., 2018). We study their input and output using combined anatomical, genetic and physiological approaches. Selected cortical areas, relevant for sensory perception, arousal and sleep (V1, S1, M1, prefrontal cortex) are studied using chemogenetic and optogenetic methods. Our preliminary data suggest that 6b is not just a developmental remnant cell population in the adult, but a layer that plays a key role in cortical state control, integrating and modulating information processing (Guidi et al., 2016; Molnar et al., 2020; Krone et al., 2021; Horvath et al., 2021).
Molnar Z. (2019) Eur J Neurosci. 49(7):957-963.
Hoerder Suabedissen et al., (2013) Proc Natl Acad Sci U S A. 110(9):3555-60.
Molnar et al., (2019) J Anat. 235:432 451
Bakken et al., (2016) Nature. 535(7612):367 75.
Hoerder-Suabedissen et al., (2018) Cereb Cortex. 2018 28(5):1882 1897.
Guidi et al., (2016) SFN Abstract 634.16.
Molnar Z, Luhmann H, Kanold (2020) Science 370, 308
Krone et al., (2021) Nat Neurosci 24:1210 1215
Swiegers et al., (2021) J. Comp. Neurol. 529(14):3429 3452
Horvath TL, Molnar Z, Hirsh J (2021) Body Brain Behavior, Elsevier, isbn:9780128180938. | | 2022年6月30日 9:27～9:42 ラグナガーデンホテル 羽衣：西 第10会場
1S10m-02
マウスサブプレートニューロンの胎生期分子マーカーの同定と発生起源の探索
Identification of embryonic molecular markers of mouse subplate neurons and search for their developmental origins
*丸山 千秋(1)
1. 公益財団法人東京都医学総合研究所
*Chiaki Ohtaka-Maruyama(1)
1. Tokyo Metropolitan Institute of Medical Science
Keyword: SUBPLATE, CEREBRAL CORTEX, SINGLE-CELL ANALYSIS, DEVELOPMENTAL ORIGIN
The subplate layer is most developed and thickened between postconceptional weeks (PCW) 18 and 32 of humans and then largely disappears in the neonatal period. Subplate neurons (SpNs) are essential for forming the thalamocortical network, the first neural circuit in the developing cortex. We have also elucidated that SpNs have spontaneous neural activity and send signals via synaptic transmission to newborn neurons during radial neuronal migration in mice to facilitate migration mode conversion. Transcriptome analysis showed that autism-related genes were highly expressed in the subplate, and residual SpNs were frequently found in autism spectrum disorder (ASD) cases, suggesting that SpN dynamics are associated with developmental disorders. However, the detailed mechanism remains unclear. Most SpNs typically die before birth; however, some remain white matter cells in the lower part of the deepest layer in the neocortex (layer 6b). These cells exclusively respond to orexin, suggesting involvement in adult brain functions, including sleep-wake regulation. However, the details of SpN subtypes, molecular markers during fetal life, characteristics of neural activity, and correlation with EEG are still unknown, and comprehensive studies at the molecular level are needed. In this study, to understand the physiological significance of SpNs in brain development by analyzing their subtypes and roles, we isolated SpNs by FACS and identified novel markers of SpNs during fetal life by single-cell RNA-seq and clustering analysis. We analyze the expression patterns of the identified early marker candidate genes in detail by in situ hybridization, immunostaining, and spatial gene expression analysis (Visium). We also re-analyzed the recently published single-cell RNA seq data of cortical cells with Seurat to narrow down the genes specifically expressed in the preplate cells that will become subplate cells. We selected E10, E11, and E12 of mouse embryonic stages in the condition as Tbr1 + / Reelin- / Pax6- / Sox2-. Together with the identified candidate genes in these analyses, we will discuss the developmental origin of SpN. | | 2022年6月30日 9:42～9:59 ラグナガーデンホテル 羽衣：西 第10会場
1S10m-03
マウス視覚野サブプレートニューロンの視覚反応選択性
Visual response selectivity in subplate neurons of mouse visual cortex
*吉村 由美子(1)
1. 自然科学研究機構 生理学研究所
*Yumiko Yoshimura(1)
1. National Institute for Physiological Sciences
Keyword: Visual cortex, Subplate neurons, Visual responses
Cortical neurons are functionally and neurochemically heterogeneous. For example, excitatory neurons expressing FoxP2 in layer 6 provide feedback inputs to the thalamus in the primary visual cortex. A subset of subplate neurons residing in the deeper part of layer 6 or the vicinity of the white matter express CTGF, a subplate neuronal marker. A recent study using a 3-photon microscopy has demonstrated that subplate neurons respond to visual stimuli in the primary visual cortex of adult mice. Excitatory neuron subtypes in each cortical layer may have distinct visual response properties. However, the properties in each excitatory neuron subtype are not well characterized in deep layer neurons, including subplate neurons. We analyzed visual responses in individual excitatory neurons across cortical layers in the primary visual cortex of juvenile mice under awake conditions. We established a method to record visual responses in multiple neuronal subtypes from the same mice by combining calcium imaging with a conventional two-photon microscopy and a tissue clearing method. GCaMP was selectively expressed in excitatory neurons under a CaMKII promoter. Visual response properties were compared between excitatory subplate neurons and pyramidal neurons in layer 2/3 or layer 6a. Orientation selectivity was broader in excitatory subplate neurons than pyramidal neurons in layer 2/3 or layer 6a, consistent with a previous report in adult mice. We found that the subplate neurons were more binocular than excitatory neurons in other layers. These results suggest that excitatory subplate neurons in the developing visual cortex exhibit distinct visual response properties. | | 2022年6月30日 9:59～10:24 ラグナガーデンホテル 羽衣：西 第10会場
1S10m-04
Role of subplate neurons in the construction and deconstruction of the cerebral cortex
*Heiko J. Luhmann(1)
1. University Medical Center Mainz, Germany
Keyword: neocortex, development, subplate, neurophysiology
During early development, the cerebral cortex of all mammals, including humans, shows a transient neuronal cell layer between the white matter and the cortical plate / layer 6 (Kanold and Luhmann, 2010). Subplate neurons show relatively mature morphological and functional properties allowing them to act as "amplifiers" of neuronal activity in the developing neocortex (Luhmann et al., 2009). Furthermore, the subplate plays central roles in the development of thalamocortical connections and transient cortical circuits and in shaping the columnar architecture of the neocortex (Molnár et al., 2020). Finally, experimental animal studies and clinical data strongly suggest that early disturbances in subplate function have, both, an immediate and a long-term impact on cortical maturation, which may cause neurological and psychiatric disorders (Kostovic, 2020).
This presentation aims to give a comprehensive overview on the unique functional properties of subplate neurons in early cortical development and how the subplate controls spontaneous and sensory evoked network activity (Luhmann et al., 2018). Subplate neurons can discharge at relatively high frequencies and receive a functionally mature glutamatergic synaptic input from the thalamus. Furthermore, they receive GABAergic and other glutamatergic inputs from neighboring subplate neurons and developing neurons in the cortical plate, indicating that the subplate represents an important cortical hub during early development. This assumption is supported by the local and long-range projections of subplate neurons connecting developing cortical networks.
In sensory cortical areas of newborn rodents and preterm human infants specific spontaneous and sensory evoked activity patterns can be recorded, namely spindle burst / delta brush activity (Colonnese et al., 2010). This unique activity pattern seems to support or even controls the maturation of cortical columns, since it can be recorded at early stages and initially synchronizes the activity of a local columnar network. Any disturbances in this activity (e.g. from maternal drug abuse, anesthetics, in utero infection) may have long-term consequences.
References:
Colonnese, M.T., … Khazipov, R. (2010) Neuron 67, 480-498. Kanold, P.O., Luhmann, H.J. (2010) Annu. Rev. Neurosci 33, 23-48.
Kostovic, I. (2020) Prog Neurobiol, 101883. 10.1016/j.pneurobio.2020.101883.
Luhmann, H.J., Kilb, W., Hanganu-Opatz, I.L. (2009) Front Neuroanat 3, 19ff.
Luhmann, H.J., Kirischuk, S., Kilb, W. (2018) Frontiers in Neuroanatomy 12, 97.
Molnár, Z., Luhmann, H.J., Kanold, P.O. (2020) Science 370. 10.1126/science.abb2153. | | 2022年6月30日 10:24～10:41 ラグナガーデンホテル 羽衣：西 第10会場
1S10m-05
発達期の脳波にみられるデルタブラッシュ
Delta brush on electroencephalogram during early human brain development
*城所 博之(1)
1. 名古屋大学大学院医学系研究科
*Hiroyuki Kidokoro(1)
1. Grad Sch Med, Nagoya University, Nagoya, Japan
Keyword: subplate neuron, preterm infants, delta brush, electroencephalogram
Spontaneous brain activity is crucial for early brain development, including neurogenesis, neuronal migration, cortical architecture, and network formation. Electrical activity is the driving force of brain development and strongly regulates neural genes. The delta brush, a well-known characteristic waveform of the human preterm electroencephalogram, represents one of the spontaneous electrical activities. Recent experimental animal model evidence suggests that delta brushes are not only spontaneous intrinsic activity but are also evoked by external sensory stimulation or spontaneous movement. They are also likely to reflect the activity of subplate neurons, which play an important role in early brain development and network organization. Here, evidence about delta brushes in human preterm electroencephalogram is provided along with future perspectives. | | 2022年6月30日 10:41～10:58 ラグナガーデンホテル 羽衣：西 第10会場
1S10m-06
ヒト胎児皮質における長距離連合線維形成：サブプレート仮説
A model for subplate-mediated formation of long association fibers in human fetal cortex
*多賀 厳太郎(1)、堀部 和也(2)、藤本 仰一(2)
1. 東京大学大学院教育学研究科、2. 大阪大学理学研究科
*Gentaro Taga(1), Kazuya Horibe(2), Koichi Fujimoto(2)
1. Graduate School of Education, The University of Tokyo, Japan, 2. Graduate School of Sciences, Osaka University, Osaka, Japan
Keyword: human, fetus, connectivity, subplate
The human cerebral cortex is composed of a large number of gyri, brain regions divided by the sulci, and white matter fiber bundles connecting them. The macroscopic geometry and network are unique to humans, on which functions such as perception, cognition, and language emerge in infants (Taga et al. 2003; Watanabe et al. 2008; Homae et al. 2010). Anatomy and brain imaging studies are revealing the process by which the basic morphology of the cortex, including the subplate, is formed from fetal to infancy (Pogledic et al. 2020; Terashima et al. 2021). However, the principles of cortical morphology and network formation remain unclear.Recently a concept of “tangential subplate nexus (TSN)" of interregional connectivity was proposed (Kostovic 2020). In contrast to radial organization of the cortical plate, a tangentially extended structural continuum of the TSN allows a latetral propagation of signals and spontaneous activity across the tangential plane, which mediate formation of transient intereregional connections before establishement of long cortico-cortical association fibers. On the other hand, a theoretical study showed that excitatory activity is likely to be generated along the geodesic in a medium on a curved surface (Horibe et al. 2019). Thus, we hypothesized that a long-distance network would be formed to take the shortest distance along the surface shape of the subplate in the early fetal period.To test the hypothesis, we used 3D mesh data of the brain surface prepared from MRI of a preterm infant with 28 gestational weeks (Garcia et al. 2018). Two points on the brain surface were randomly selected and a geodesic line was determined. After the repetition of this process, we identified the regions where the geodesic line passed frequently. We founud that many geodesics pass through the peri-sylvian regions on the lateral surface, the cingulate gyrus on the medial surface, and the insula within the Sylvian fissure. Furthermore, the bundles of geodesic lines can be associated with major long association fibers such as arcuate, uncinate, inferior fronto-occipital, inferior longitudinal fasciculi and cingulum.The results suggest that the major long associative fibers of the human cortex are tangentially formed according to the macroscopic geometry of the subplates before the onset of multiple sulci formation in the fetal period. The spontaneous activity of the subplate neurons are possibly take a crucial role in the network formation (Molnár et al. 2020). In particular, the arcuate fasciculus, which highly develops in humans and is involved in language function, may originate from the higly dense network mediated by the fetal TSN. | |
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