Life science
Medicine, Drug discovery

Revealing the neuropathology of ASD based on circuit
formation processes in the cerebral neocortex
Department of Anatomy and Neuroscience, Graduate School of Medicine /United Graduate School of Child development
Professor Makoto Sato

Researchmap https://researchmap.jp/read0185568

Lecturer Yuichiro Oka

Researchmap https://researchmap.jp/okayLife science

Abstract
The cerebral neocortex consists of multiple functional areas with
distinct functions, which are connected via direct neuronal connection called association projections. Long association projections,which connect the two areas residing in different cortical lobes, arethought to be involved in higher-order cortical functions such as
multi-modal sensory integration and regulation of voluntary movements. However, organization and development of long association
projections are not fully understood at cellular level. We established a model system to specifically visualize the long association projection from the primary somatosensory cortex (S1, in theparietal lobe) to the primary motor cortex (M1, in the frontal lobe)
in the mouse. Using this system, we examined the developmental
processes of axons in long association projection at the single
neuron resolution. We found that long association neurons project
not only to M1 but also to the corpus callosum that bridges the bilateral hemispheres (Fig.1), and that the projection to M1 is one of
the many collateral branches sprouting from the earlier-projecting
axons to the corpus callosum (Fig.2).

projection patterns and their disorders at early postnatal stages invarious mouse models for ASD should pave the way to clarify theneuropathology of and to develop therapeutic approaches to distinct symptoms.

ABrostrallateralBrain
primary
somatosensory
cortexFlattened cortex
tocorpus
callosum▍ Background & Results
Cerebral neocortex consists of several dozens of functional areas with different functions. Information processed in a functional
area is transferred to another area via neuronal connection calledassociation projection. Long association projections connect twoareas on different cortical lobes and are thought to be involved in
integration of sensory information in multiple modalities, regulationof voluntary movements, and so on. However, how the long association projections are formed during the developmental processes
is yet to be fully elucidated. We examined the developmental processes of the projections from S1 to M1 in mice as a model of longassociation projections. First, we identified the Plxnd1 gene as amarker expressed in 80% of long association neurons. Next, usinga plasmid vector to express GFP in Plxnd1-expressing neurons
and in utero electroporation, we established a method to selectively visualize the long association neurons and their axons. After thebrains were sampled at different postnatal stages, cortices wereflattened and optically cleared, and imaged with confocal microscopy. Our analysis at the single neuron resolution revealed that at
postnatal day 7, each long association neuron are dual-projection
neurons with projections both to M1 and to the corpus callosum.
We also found that the projection to M1 is one and the fastest-extending of the collateral branches sprouted from the earlier-projecting callosal axon.

primary
motorcortex

optically cleared

Fig. 1 A. Cerebral cortex was removed from the brain tissue, flattened and optically cleared for confocal imaging. B. Examples of dual-projection neurons visualized with GFP.

Postnatal day 3

Primary motor cortex
Cerebralneocortex

Primary somatosensory cortex

Postnatal day 5

Postnatal day 7▍ Significance of the research and Future perspective
Recent fMRI studies showed that the functional connectivity
patterns between cortical areas in infants highly accurately predict the symptoms that later emerge in ASD. Thus, classifying theFig.2 Long association projection between cortical areas is formed as the longest
collateral branch (red arrow) sprouted from the earlier-projecting callosal axon.

P a t e n t Japanese Patent Application No. 2019-072782
Oka, Yuichiro; Doi, Miyuki; Taniguchi, Manabu et al. Interstitial Axon Collaterals of Callosal Neurons Form Association Projections from the Primary SomaTr e a t i s etosensory to Motor Cortex in Mice. Cerebral Cortex. 2021; 31(11): 5225-5238. doi: 10.1093/cercor/bhab153
UR
L https://resou.osaka-u.ac.jp/ja/research/2021/20210713_2
K e y w o r d neuroscience, neural circuit formation, cerebral neocortex, neurodevelopment disorder, developmental coordination disorder