HOME  /  Research Programs  /  Research Team for Aging Neuroscience  /  Neurobiology of Aging

Neurobiology of Aging

Members

Theme Leader :
Hiroshi Nishimune, Ph.D.
Researcher :
Ritsuko Inoue, Ph.D., Kenji Takikawa, Ph.D.

Keywords

Synapse, neuromuscular junction, active zone, plasticity, fluorescent probe for neurotransmitters, Super–resolution imaging, motor neuron, exercise therapy, mesenchymal stem cells

Major Research Titles

  1. 1.Elucidation of molecular mechanisms causing synapse degeneration due to aging, dementia, and neurodegenerative diseases, primarily focusing on the losses of the synaptic vesicle release sites, the active zone.
  2. 2.Analysis of molecular mechanisms causing neuromuscular junction degeneration during aging and amyotrophic lateral sclerosis (ALS). Development of new intervention methods to ameliorate neuromuscular junction degeneration, including exercise therapy and injection of human umbilical cord-derived mesenchymal stem cells.
  3. 3.Analysis of age-related changes in neural activity of motor cortex and motor function decline.
  4. 4.YouTube Channel Link.

Profile

1. Our motor function, sensation, learning, and memory depend on the function of synapses that relay information between neurons or neurons and muscle fibers, for example. These synapses are essential for the nervous system function but degenerate or reduce their function due to aging, dementia, and neurodegenerative disease. We investigate the molecular mechanism of synapse degeneration, focusing on the loss of active zones, which are the synaptic vesicle release sites. We study these research projects using multidisciplinary approaches including super-resolution microscopy STED, genome-wide gene expression analysis, development of new fluorescent neurotransmitter probes.

2. Degeneration of motor neurons is known in aging and ALS. This degeneration seems to be preceded by the loss of neuromuscular junctions; however, the cause and the degeneration mechanism are not known well yet. We use approaches described in project 1 to study these degeneration mechanisms. Also, we aim to develop novel intervention approaches using exercise therapy and human umbilical cord-derived mesenchymal stem cells.

3. Aging is known to cause a decline in motor function; however, the role of the central nervous system in this impairment is not fully known. We hypothesize that age-related alteration of the motor cortex is involved in motor function decline. Administration of mitochondria coenzyme restores the motor function of aged animals to the young adult level and age-related electrophysiological alteration in the motor cortex. We study the mechanism of this effect using electrophysiology and super-resolution microscopy and aim to translate the outcome for prevention of the motor function decline in the elderly and the development of rehabilitation methods.

References

  1. 1.Nishimune, H., Sanes, J.R. & Carlson, S.S. A synaptic laminin-calcium channel interaction organizes active zones in motor nerve terminals. Nature 432, 580-587 (2004). (PMID 15577901).
  2. 2.Chen, J., Billings, S.E. & Nishimune, H. Calcium channels link the muscle-derived synapse organizer laminin beta2 to Bassoon and CAST/Erc2 to organize presynaptic active zones. J Neurosci 31, 512-525 (2011). (PMID 21228161).
  3. 3.Nishimune, H., Numata, T., Chen, J., Aoki, Y., Wang, Y., Starr, M.P., Mori, Y. & Stanford, J.A. Active zone protein Bassoon co-localizes with presynaptic calcium channel, modifies channel function, and recovers from aging related loss by exercise. PLoS One 7, e38029 (2012). (PMID 22701595).
  4. 4.Chen, J., Mizushige, T. & Nishimune, H. Active zone density is conserved during synaptic growth but impaired in aged mice. J Comp Neurol 520, 434-452 (2012). (PMID 21935939).
  5. 5.Nishimune, H., Badawi, Y., Mori, Y., & Shigemoto, K. Dual-color STED microscopy reveals sandwich structure of Bassoon and Piccolo in active zones of adult and aged mice. Scientific reports 6: 27935 (2016). (PMID 27321892).
  6. 6.Asanuma, D., Takaoka, Y., Namiki, S., Takikawa, K., Kamiya, M., Nagano, T., Urano, Y. & Hirose, K. Acidic-pH-activatable fluorescence probes for visualizing exocytosis dynamics. Angew Chem Int Ed Engl 53, 6085–6089 (2014). (PMID 24801356).
  7. 7.Takikawa, K., Asanuma, D., Namiki, S., Sakamoto, H., Ariyoshi, T., Kimpara, N. & Hirose, K. High-throughput development of a hybrid-type fluorescent glutamate sensor for analysis of synaptic transmission. Angew Chem Int Ed Engl 53, 13439–13443 (2014). (PMID 25297726).
  8. 8.Sakamoto, H., Ariyoshi, T., Kimpara, N., Sugao, K., Taiko, I., Takikawa, K., Asanuma, D., Namiki, S. & Hirose, K. Synaptic weight set by Munc13-1 supramolecular assemblies. Nat Neurosci 21, 41-49 (2018). (PMID 29230050).
  9. 9.Inoue, R., Suzuki, T., Nishimura, K. & Miura, M. Nicotinic acetylcholine receptor-mediated GABAergic inputs to cholinergic interneurons in the striosomes and the matrix compartments of the mouse striatum. Neuropharmacology 105, 318-328 (2016). (PMID 26808315).