Association of impaired neuronal migration with cognitive deficits in extremely preterm infants
Ken-ichiro Kubo, Kimiko Deguchi, Taku Nagai, Yukiko Ito, Keitaro Yoshida, Toshihiro Endo, Seico Benner, Wei Shan, Ayako Kitazawa, Michihiko Aramaki, Kazuhiro Ishii, Minkyung Shin, Yuki Matsunaga, Kanehiro Hayashi, Masaki Kakeyama, Chiharu Tohyama, Kenji F. Tanaka, Kohichi Tanaka, Sachio Takashima, Masahiro Nakayama, Masayuki Itoh, Yukio Hirata, Barbara Antalffy, Dawna D. Armstrong, Kiyofumi Yamada, Ken Inoue, Kazunori Nakajima
Ken-ichiro Kubo, Kimiko Deguchi, Taku Nagai, Yukiko Ito, Keitaro Yoshida, Toshihiro Endo, Seico Benner, Wei Shan, Ayako Kitazawa, Michihiko Aramaki, Kazuhiro Ishii, Minkyung Shin, Yuki Matsunaga, Kanehiro Hayashi, Masaki Kakeyama, Chiharu Tohyama, Kenji F. Tanaka, Kohichi Tanaka, Sachio Takashima, Masahiro Nakayama, Masayuki Itoh, Yukio Hirata, Barbara Antalffy, Dawna D. Armstrong, Kiyofumi Yamada, Ken Inoue, Kazunori Nakajima
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Research Article Development Neuroscience

Association of impaired neuronal migration with cognitive deficits in extremely preterm infants

Abstract

Many extremely preterm infants (born before 28 gestational weeks [GWs]) develop cognitive impairment in later life, although the underlying pathogenesis is not yet completely understood. Our examinations of the developing human neocortex confirmed that neuronal migration continues beyond 23 GWs, the gestational week at which extremely preterm infants have live births. We observed larger numbers of ectopic neurons in the white matter of the neocortex in human extremely preterm infants with brain injury and hypothesized that altered neuronal migration may be associated with cognitive impairment in later life. To confirm whether preterm brain injury affects neuronal migration, we produced brain damage in mouse embryos by occluding the maternal uterine arteries. The mice showed delayed neuronal migration, ectopic neurons in the white matter, altered neuronal alignment, and abnormal corticocortical axonal wiring. Similar to human extremely preterm infants with brain injury, the surviving mice exhibited cognitive deficits. Activation of the affected medial prefrontal cortices of the surviving mice improved working memory deficits, indicating that decreased neuronal activity caused the cognitive deficits. These findings suggest that altered neuronal migration altered by brain injury might contribute to the subsequent development of cognitive impairment in extremely preterm infants.

Authors

Ken-ichiro Kubo, Kimiko Deguchi, Taku Nagai, Yukiko Ito, Keitaro Yoshida, Toshihiro Endo, Seico Benner, Wei Shan, Ayako Kitazawa, Michihiko Aramaki, Kazuhiro Ishii, Minkyung Shin, Yuki Matsunaga, Kanehiro Hayashi, Masaki Kakeyama, Chiharu Tohyama, Kenji F. Tanaka, Kohichi Tanaka, Sachio Takashima, Masahiro Nakayama, Masayuki Itoh, Yukio Hirata, Barbara Antalffy, Dawna D. Armstrong, Kiyofumi Yamada, Ken Inoue, Kazunori Nakajima

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Figure 9

Mild maternal hypothermia mitigated neurodevelopmental damages.

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Mild maternal hypothermia mitigated neurodevelopmental damages. (A) A sh...
(A) A sham operation (Control) or maternal uterine artery occlusion (Occluded and Hypothermia) was performed at E16.5. During the occlusion period, the dam was maintained on a warmer set at a temperature of 37.5°C (Occluded) or 25.5°C (Hypothermia). Brains were analyzed 12 hours after occlusion. Sections were immunostained with anti-PH3 antibody. Scale bar: 200 μm. (B) The numbers of PH3-positive cells in the VZ and SVZ are shown (n = 7, respectively). **P < 0.01, ***P < 0.001, Tukey-Kramer test. (C) GFP plasmid was transfected at E16.5 and immediately followed by performance of a sham operation (Control) or maternal uterine artery occlusion (Occluded and Hypothermia). During the occlusion period, the dam was maintained on a warmer set at a temperature of 37.5°C (Occluded) or 25.5°C (Hypothermia) as in A. Brains were analyzed at P3.5. Sections were counterstained with DAPI (blue). Scale bar: 200 μm. (D) Cell distribution was evaluated by bin analysis. (E) Relative migration distances (%) from the ventricle are shown (n = 7, each). ***P < 0.001, Tukey-Kramer test. (F) Performance in the novel object recognition test (NORT). Top: exploratory index. Bottom: total exploration time. Values are mean ± SEM (n = 11 each). ***P < 0.001, repeated-measures ANOVA followed by Bonferroni post-hoc test. (G) The graph indicates the spontaneous alteration behavior in the Y-maze test (Control: n = 13, Occluded: n = 14, Hypothermia: n = 15). ***P < 0.001, Tukey-Kramer test. (B, E, F, and G) Each point represents an individual mouse. Box-and-whisker plots were used to graphically represent the median (line within box), upper and lower quartiles (bounds of box), and maximum and minimum values (top and bottom bars).