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Studies on Functions of Npas4 during the Sensory Input-Dependent Olfactory Bulb Development

Studies on Functions of Npas4 during the Sensory Input-Dependent Olfactory Bulb Development
Sunghwan Kim
DGIST Authors
Kim, Sunghwan; Rah, Jong-Cheol; Moon, Cheil
Jong Cheol Rah
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Sensory input is essential for brain development. It is well known that odor-evoked activity affects the development of olfactory bulb (OB) interneurons. However, little is known about how odor-induced activity regulates the development of OB interneurons. Here, I investigated whether the immediate early gene (IEG)-transcription factor, Npas4, acted as a developmentary regulator for OB interneurons. Olfactory deprivation at the postnatal day 0 (P0) reduced the expression of an interneuron marker, GAD67 during the first 14 days. However, specific subtypes of OB Interneurons were differently affected sensory input. Next, I observed where and when Npas4 was mainly expressed in mouse OB. Npas4 was mainly expressed interneuron specific layers, and Npas4 was more expressed in the early-postnatal stages rather than the adult stages. Furthermore, naris occlusion also reduced the expression of Npas4 and putative downstream molecules that had protective effects in other brain regions. Taken together, these data suggest that activity-induced Npas4 regulates downstream molecules in the early-postnatal stage, and which have protective effects, during sensory input-dependent OB interneuron development. |외부로부터의 감각의 유입은 동물이 삶을 살아가는 데 있어 중요한 역할을 할 뿐만 아니라, 뇌의 발달에 있어서도 중요한 역할을 한다고 알려져 있다. 여러 감각들 중, 후각 자극은 후구(olfactory bulb)의 발달에 중요한 역할을 한다고 잘 알려져 있다. 하지만, 냄새에 의한 자극이 후구의 발달에 어떻게 영향을 미치는지에 대한 분자적인 작용기전은 알려진 것이 거의 없다. 본 연구에서 우리는 급속 초기 발현 유전자(immediate early gene)-전사인자인 Npas4가 후각 자극에 의한 후구 중간신경세포 (interneuron)의 발달의 조절자로서 역할을 할 것이라고 제시한다. 막 태어난 마우스의 한쪽 코를 막은 후구에서는 14일이 지난 후 관찰 결과, 중간신경세포 표지자(marker) 인 GAD67이 현저히 감소하는 한다는 것을 관찰할 수 있었다. 이를 통해 신생 마우스에서 후각자극이 후구의 중간신경세포의 발달에 영향을 끼친 다는 것을 밝혔다. 또한, 중간신경세포에서 발현하는 여러 단백질들이 후각자극에 의해 다르게 영향을 받는 다는 것을 밝혀냈다. 이를 통해, 후각자극이 중간신경세포 모두에게 같은 영향을 주지는 않는 다는 것을 알 수 있었다. Npas4의 발현 패턴을 관찰 결과, Npas4는 후구의 중간 신경 세포층 들에서 관찰되었다. 또한 Npas4는 신생 마우스에서 성체시기의 마우스보다 더 많이 발현한다는 것을 밝혔다. 게다가, 신생 마우스에서 후각인지상실은 Npas4와 다른 뇌 부위에서 보호효과(protective effect)를 가지는 Npas4의 하위경로 분자들의 expression 감소를 유발한다는 것을 밝혔다. 이러한 사실들을 종합해서, Npas4가 신생마우스의 후구 중간신경세포의 발달에 자극 의존적으로 영향을 끼칠 수 있다는 것을 제시한다.
Table Of Contents
CONTENTS ABSTRACT I CONTENTS ii LIST OF FIGURES iii LIST OF TABLES iii INTRODUCTION 1 MATERIALS AND METHODS 5 RESULTS 9 1.Influence of sensory input to the olfactory bulb development 9 1.1 OB volume is reduced by neonatal sensory deprivation. 1.2.Sensory deprivation differently affects each type of neurons. 1.3. Sensory deprivation differently affects each type of interneurons. 2.Npas4 mRNA and protein expression pattern in the OB 19 2.1.Early developmental stage of OB more expresses Npas4 mRNA than adult stage. 2.2. Npas4 is expressed in the nucleus/cytosol. 3.Regulation of Npas4 and putative stream by the sensory input 24 3.1 Sensory deprivation reduces Npas4 mRNA and protein expression level. 3.2 In the OB, Npas4 may have a protective effect. DISCUSSION 28 FURTHER STUDIES 32 REFERENCES 34 ABSTRACT IN KOREAN 39 APPENDIX 40 LIST OF FIGURES Figure 1 Effect of unilateral naris occlusion on the OB volume. Figure 2 Effect of unilateral naris occlusion on OB interneurons and projection neurons. Figure 3 Effect of unilateral naris occlusion on subtype of OB interneurons. Figure 4 Npas4 is highly expressed in the early developmental stage. Figure 5 Npas4 protein is mainly expressed in the OB interneurons. Figure 6 Npas4 mRNA and protein level are downregulated by sensory input in the OB. Figure 7 Npas4 putative downstream molecules mRNA level is differently regulated by sensory input in the OB. Figure 8 Npas4 has nuclear export sequence (NES). LIST OF TABLES Table 1. List of well-known interneuron subtypes in the olfactory bulb. Table 2. List of well-known IEGs and/ or transcription factors in the OB. Table 3. List of Functions of Npas4.
Brain and Cognitive Sciences
Related Researcher
  • Author Moon, Cheil Laboratory of Chemical Senses
  • Research Interests Brain convergent science based on chemical senses; olfaction; 감각신경계 기반 뇌융합과학; 후각 신경계
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