成年哺乳类大脑皮质浅层未成熟神经元起源与发育

One of the most challenging and exciting tasks for modern scientific research is to decode the biological mechanisms underlying the development, evolution, plasticity and function of the cerebral cortex, the highest comand center of the brain. This basic research is also crucial for understanding the etiology of many neurological and psychiatric disorders, and for innovating mechanism-based disease intervention. We have shown a novel population of cortical neurons expressing doublecortin (DCX+) and other typical immature neuronal markers in different mammals (guinea pig, cat, monkey and human) at adulthood and even old ages. These neurons occur in the superficial cortical layers especially at the border between layers I and II. They are more numerous in larger mammals relative to mouse and rat wherein these type of cells exist only in the piriform cortex. Works by us and other groups have defined these cells as immature and developing neurons. However, it remains unclear, and in several areas, controversy, regarding their origin, development and destiny. Little is currently known whether, and if so, how, these neurons are incoporated into neuronal circuitry and paticipate in synaptoplasticity. We carried out pilot studies in guinea pigs, suggesting that these immature neurons can be generated in postnatal/adult stages, likely from layer I. Using a modified cell birth-dating approach, in this application we propose to address several basic issues about these novel cortical neurons, via the following goals: (1) To determine the site of origin, developmental trajectory and fate of these neurons in adult guinea pig and cat cortices;（2）To characterize the cell cycle dynamics of these cells and/or their precursors; (3) To determine their synaptogenesis and circuitry integration relative to somal and process morphogenesis in adult guinea pig and cat cortices. The proposed investigations are expected to promote the understainding of the cellular basis and mechanism underlying mammalian cortical and cortical neuronal plasticity during adulthood.

解码大脑皮质发育、进化、塑形和功能之谜是当今最具挑战性的科学研究使命之一，也是揭示很多神经精神疾患的病理机制和开拓新的诊疗手段的关键。我们在成年甚至老年哺乳动物（包括豚鼠、猫、灵长类）大脑皮质浅层发现未成熟神经元，表达doublecortin (DCX+)等标记物且具有分化成熟趋势。目前对这些神经元的起源、分化过程、去向、与皮质种系进化的关系，以及是否及如何整合至功能神经网络等知之甚少。本申请将通过在体细胞定时标记（birth-dating）示踪，结合光、电镜免疫细胞化学技术，采用豚鼠和猫为模型，实现如下研究目标（1）确定和比较在上述两种动物这类皮质DCX+神经元的起源、分化过程和命运;(2)探讨这些神经元或/和前体的细胞周期动力学特征;（3）确定这些DCX+神经元形态成熟和突触发生的关系及它们的神经突触联系特征。本研究将加深对成年哺乳类皮质和皮质神经元塑形细胞基础和机制的认识。

Putative neural precursors, and cells expressing doublecortin (DCX+) and other immature neuronal markers, exist at the superficial cortex in mammals, with their biological implications remained elusive. Supported by this grant, we carried studies, primarily in guinea pigs, to understand the role of these cells, using BrdU-birth-dating and immunolabeling methods. We found: (1) Maturation of layer II DCX+ cells in the primary olfactory cortex is modulated by physiological neuronal activity; (2) Layer II DCX+ cells are largely produced during prenatal stage, with a few generated postnatally; (3) Type I nitric oxide-producing neurons are produced during early corticogenesis, while type II cells can be produced across the entire prenatal period; (4) Putative quiescent neural precursors in layer I of adult guinea pig and human cerebral cortex express Sp8, a mature interneuron marker. These findings provide new mechanism for cortical neuroplasticity in mammals in health and disease.