Regional diversity of cortical white matter neurons in adult and infant rhesus monkey

 描述(申请人提供)：白质(WM)神经元在系统发育上是保守的；在灵长类动物和其他具有大脑回脑的物种中，大量的WM神经元持续存在于早期发育之后。它们在神经化学和形态上是不同的。在发育过程中，已知这些神经元在丘脑和皮质回路的建立中起着重要作用，并且 与脑回形成有关(Suarez-Sola等人，2009；Kanold和Luhmann，2010；Zilles等人，2013；Sun和Hevner，2014)。在成人中，人们对这些神经元知之甚少，除了至少有一些神经元被整合到大脑皮层回路这一事实之外。强烈建议一组一氧化氮合酶阳性的WM神经元在血管调节中发挥重要作用(Barbaresi等人，2014年)。此外，WM神经元引起了人们的兴趣，因为与对照组相比，一些精神分裂症受试者大脑中浅层WM神经元的密度增加(Connor等人，2011年；Yang等人，2011年)。自闭症受试者大脑中WM神经元密度的增加也被报道(McFadden和Minshew，2013)。目前的建议是基于这样的假设，即WM神经元在成人中仍然具有重要的功能，并且非人类灵长类动物模型将为进一步的细胞、分子和电路水平的研究提供富有成效的机会。之所以需要猴子模型，是因为与人类相比，猴子更容易接受实验操作，而且灵长类动物和啮齿动物之间在发育和回路方面存在许多差异(Judas等人，2010b)。实验设计的关键部分是1)对成年恒河猴不同皮质区域的浅层和深层WM群体进行系统的定量分析，并根据兴奋性和抑制性亚群进行评分，以及2)围产期和婴儿猴(12个月)的可比性分析，以确定WM神经元数量下降的区域和细胞类型差异。WM亚群的可视化将通过免疫组织化学NeuN和其他标准细胞类型标记物在组织切片的大脑中进行。成功将被定义为确定成人和婴儿大脑中都存在区域特定差异，正如已经在 人脑(Garcia-Marin等人，2010年)。预计在最终的R01中，下一步将是解决WM亚群的网络连通性和突触后靶点，并调查WM种群在整个生命周期以及疾病和其他疾病的猴子模型中的解剖学差异。

 DESCRIPTION (provided by applicant): White matter (WM) neurons are phylogenetically conserved; and in primates and other species with large gyrencephalic brains, substantial numbers of WM neurons persist beyond early development. These are neurochemically and morphologically heterogeneous. During development, these neurons are known to have essential roles in the establishment of both thalamocortical and corticocortical circuitry, and are implicated in gyral formation (Suarez-Sola et al., 2009; Kanold and Luhmann, 2010; Zilles et al., 2013; Sun and Hevner, 2014). In the adult, very little is known about these neurons, beyond the fact that at least some of these are incorporated into cortical circuitry. An important role in vascular regulation is strongly suggested for a contingent of NOS-positive WM neurons (Barbaresi et al., 2014). Further, WM neurons have attracted interest since the density of superficial WM neurons is increased in brains of some schizophrenic subjects as compared with controls (Connor et al., 2011; Yang et al., 2011). Increased density of WM neurons is also reported in the brains of autistic subjects (McFadden and Minshew, 2013). The present proposal is motivated by the hypothesis that WM neurons remain functionally important in the adult and that a nonhuman primate model will offer productive opportunities for further cellular, molecular, and circuit-level investigations. A monkey model is needed because of the greater accessibility of monkeys, as opposed to humans, to experimental manipulations, and because of the many developmental and circuitry differences between primates and rodents (Judas et al., 2010b). Key parts of the experimental design are 1) a systematic quantitative analysis of the superficial and deep WM populations in the adult rhesus monkey, sampled across different cortical regions and scored in terms of excitatory and inhibitory subpopulations, and 2) a comparable analysis in the perinatal and infant monkey (<12 months), to determine region- and cell-type differences in the numerical fall-off of WM neurons. Visualization of WM subpopulations will be by immunohistochemistry for NeuN and other standard cell type markers, in histologically sectioned brains. Success will be defined as identifying that region specific differences occur in both the adult and infant brain, as is predicted by region specific differences already reported in the human brain (Garcia-Marin et al., 2010). Anticipated next steps, in an eventual R01, would be to address network connectivity and postsynaptic targets of WM subpopulations, and to investigate anatomical differences in the WM populations across the lifespan and in monkey models of disease and other conditions.