STRUCTURE/FUNCTION OF SUBCORTICAL WHITE MATTER NEURONS

皮层下白质（SCWM）神经元是灵长类动物新皮层的共同特征，在人类中大量存在。这些细胞被认为是亚板的残余物，可能在新皮层发育过程中起着路标的作用。SCWM神经元在成人中的功能尚不清楚，然而，由于它们在出生后的早期生活中具有广泛的轴突过程，它们可能能够影响成年后皮层大区域的活动。尽管其意义尚不清楚，但SCWM神经元数量在多种神经系统疾病中也有所增加，包括精神分裂症、癫痫形式，也许还有阿尔茨海默病。因此，检查这些细胞的突触组织和生理对于全面了解正常和病理皮质功能是很重要的。这个项目的目的是为了验证SCWM神经元被整合到新皮层回路中的假设。这项研究特别适合使用人体组织进行，原因有两个；1) SCWM神经元的密度随着生物体的复杂性而增加，因此在啮齿动物或猫等动物中进行的研究可能不适用于人类；2)在非人类灵长类动物身上进行这样一项研究的费用将是令人望而却步的。为治疗顽固性癫痫而切除患者的组织是常规可用的。这些切除通常包括与癫痫发作有关的区域以及与这些区域相邻的相对正常的组织。我们将使用解剖学和生理学技术的结合来检查SCWM神经元是否整合到神经元回路中。如果这个假设是有效的，那么这些细胞和新皮层之间的突触输入和输出应该是有证据的。将对该组织进行电子显微镜研究，以检查这些细胞的体细胞和近端树突上是否有突触，这些突触来自皮层。此外，这些细胞的突触输出将通过检查生物细胞素填充细胞的轴突来测定。SCWM细胞的突触靶点将通过双标记研究来确定。生理研究将通过视觉识别的SCWM神经元进行记录。除了从生理上表征这些细胞外，我们还将研究这些细胞是否接受来自新皮层的自发或诱发的突触活动，以及任何突触活动背后可能的递质。所有生理研究的细胞都将被标记为生物细胞素，以使我们能够验证细胞类型并用于解剖实验。这些研究将首次提供这些细胞在成人新皮层功能中可能发挥的作用的信息。考虑到这些细胞可能与多种神经系统疾病有关，对这些细胞进行完全表征是至关重要的。

Subcortical white matter (SCWM) neurons are a common feature in the primate neocortex and are present in large numbers in the human. These cells are believed to be the remnant of the subplate and may have served guidepost functions during neocortical development. The function of SCWM neurons in the adult is unknown, however because they have extensive axonal processes in early postnatal life, they may be able to affect the activity of large regions of cortex into adulthood. Although the significance is not yet known, there are also increased numbers of SCWM neurons in a variety of neurological diseases, including schizophrenia, forms of epilepsy and, perhaps, Alzheimer's disease. It is important, therefore, to examine the synaptic organization and physiology of these cells for a complete understanding of both normal and pathological cortical function. The goal of this project is to test the hypothesis that SCWM neurons are integrated into the neocortical circuitry. This study is uniquely suited to be carried out using human tissue for two reasons; 1) the density of SCWM neurons increases with the complexity of the organism, therefore studies carried out in animals such as rodents or cats may not be applicable to humans; 2) the costs of carrying out such a study in non-human primates would be prohibitive. Tissue from patients undergoing resection for the treatment of intractable epilepsy is routinely available. These resections typically include areas involved in seizure generation as well as relatively normal tissue adjacent to these areas. We will examine whether SCWM neurons are integrated into the neuronal circuitry using a combination of anatomical and physiological techniques. If this hypothesis is valid, there should be evidence for both synaptic inputs and outputs between these cells and the neocortex. Electron microscopic studies of this tissue will be performed to examine whether there are synapses onto the soma and proximal dendrites of these cells that arise from the cortex. In addition, the synaptic output of these cells will be assayed by examining the axonal arbors of biocytin- filled cells. The synaptic targets of SCWM cells will be identified using double labeling studies. Physiological studies will be performed by recording from visually identified SCWM neurons. In addition to characterizing these cells physiologically, we will examine whether these cells receive spontaneous or evoked synaptic activity from the neocortex and the possible transmitter(s) underlying any synaptic activity. All cells studied physiologically will be labeled with biocytin to allow us to verify the cell type and for use in the anatomical experiments. These studies will provide the first information on the possible role of these cells in the function of the adult neocortex. Given the possible involvement of these cells in a variety of neurological disorders, it is critical to characterize these cells completely.