| プレナリーレクチャー |
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| 2022年6月30日 11:10～12:10 沖縄コンベンションセンター 劇場棟 第1会場
座長：池田 和司（奈良先端大）
1PL01
Decisions, movements and brains
*Churchland Anne(1)
*Anne Churchland(1)
1. University of California, Los Angeles, US
Keyword: Decisions, Movements, Brains
Understanding how cortical circuits generate complex behavior requires investigating how neurons within those circuits are modulated. Most efforts to understand neural activity during well-learned tasks focus on cognitive computations and task-related movements. We wondered whether mice making decisions explore a broader movement landscape, and how this impacts neural activity. We characterized movements using video and other sensors and measured neural activity using widefield and two-photon imaging. Cortex-wide activity was dominated by movements, especially uninstructed movements not required for the task. Next, we evaluated how the encoding of movement and task parameters varied across pyramidal neuron (PyN) types. Functional differences across PyN types have been observed within cortical areas, but it is not known whether these local differences extend throughout the cortex, nor whether additional differences emerge when larger-scale dynamics are considered. We used genetic and retrograde labeling to target pyramidal tract (PT), intratelencephalic (IT) and corticostriatal projection neurons and measured their cortex-wide activity. Each PyN type drove unique neural dynamics, both at the local and cortex-wide scale. Cortical activity and optogenetic inactivation during an auditory decision task also revealed distinct functional roles: all PyNs in parietal cortex were recruited during perception of the auditory stimulus, but, surprisingly, PT neurons had the largest causal role. In frontal cortex, all PyNs were required for accurate choices but showed distinct choice-tuning. Our results reveal that movements dominate neural activity in diverse PyN types, and that rich, cell-type-specific cortical dynamics shape perceptual decisions. | | 2022年7月1日 13:00～14:00 沖縄コンベンションセンター 劇場棟 第1会場
座長：竹居 光太郎（横浜市立大学）
2PL01
From the lab bench to clinical trials for a regeneration enhancing therapy for spinal cord injury
*Martin E. Schwab(1)
1. University of Zurich, CH
Keyword: Regeneration, spinal cord injury, growth inhibitor, Nogo-A
Following injury of the mammalian brain or spinal cord, lesioned nerve fibers can spontaneously grow and form new connections. This new ‘hardware’ can be fine tuned by intensive use and training during rehabilitation. The regrowing fibers are spatially restricted, however, to often less than a mm. Specific neurite growth inhibitory factors were found to restrict plastic and regenerative nerve fiber growth in the adult CNS. The membrane protein Nogo-A is a well characterized, potent neurite growth inhibitor in the CNS. Nogo-A activates an intracellular signalling cascade via multisubunit receptor complexes. Two binding sequences in the extracellular domains of Nogo-A interact with the receptor component S1PR2 and NgR1 which are in turn associated with additional membrane proteins (e.g. p75, Lingo1, tetraspanin3) and intracellular signal transducers. RhoA and ROCK are key signalling components of Nogo-A signalling, leading to cytoskeletal changes and transcriptional decrease of the cellular growth program. Ways to block Nogo-A function include antibodies against Nogo-A, the endogenous antagonist LOTUS, peptides, decoy receptors or pharmacological agents to block NOGO receptor components or the Rho – ROCK pathway, and knock out or knock down approaches. Our lab has used mainly function blocking antibodies against Nogo-A applied intrathecally to rats and macaque monkeys with spinal cord or cortical stroke lesions. In the spinal cord, injured fibers showed enhanced regenerative sprouting as well as long-distance regeneration. Spared fiber tracts showed enhanced compensatory sprouting. In animals with cortical strokes, intact-side corticobulbar or corticospinal fibers crossed the midline, supplying functional innervation to the denervated brain stem and spinal cord under the influence of anti-Nogo-A antibodies. Functional recovery was improved, including bladder function. - Different antibodies against human Nogo-A were produced, optimized and manufactured under GMP conditions. Their safety and tolerability after intrathecal infusion was tested in non-human primates. A Phase 1 clinical trial showed that repeated intrathecal injection into the lumbar CSF space over 30 days is well tolerated and safe in acute tetra- and paraplegic patients (Kucher et al., 2028). In a placebo controlled, randomized Phase 2 trial, >112 severe, acute tetraplegic patients have been treated up to now in a multinational European clinical trial network (NISCI). Arm – hand function (upper limb motor score), lower limb function, bladder and autonomic functions, pain and quality of life scores are being evaluated over 6 mts. The trial will reach its projected number of patients in Q2/3-2022, and results will be available from Q2-2023 on. | | 2022年7月2日 13:00～14:00 沖縄コンベンションセンター 劇場棟 第1会場
座長：合田 裕紀子（理化学研究所 脳神経科学研究センター）
3PL01
Localized mRNAs and Protein Synthesis at Neuronal Synapses.
*Erin M. Schuman(1)
1. Max Planck Institute for Brain Research, DE
Keyword: synapse, protein synthesis, local translation, mRNA
The complex morphology of neurons, with synapses located hundreds of microns from the cell body, necessitates the localization of important cell biological machines, including ribosomes, within dendrites and axons. Local translation of mRNAs is important for the function and plasticity of synapses. Using advanced sequencing and imaging techniques we have updated our understanding of the local transcriptome and identified the local translatome- identifying over 800 transcripts for which local translation is the dominant source of protein. In addition, we have explored the unique mechanisms neurons use to meet protein demands at synapses, identifying surprising features of neuronal and synaptic protein synthesis. | | | |
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