Human Systems Neuroscience Laboratory, Department of Health Sciences, Boston University, 635 Commonwealth Ave., Room 401D, Boston, MA, 02215, USA.
Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, USA.
Mol Autism. 2020 Oct 20;11(1):83. doi: 10.1186/s13229-020-00390-x.
The human orbitofrontal cortex (OFC) is involved in assessing the emotional significance of events and stimuli, emotion-based learning, allocation of attentional resources, and social cognition. Little is known about the structure, connectivity and excitatory/inhibitory circuit interactions underlying these diverse functions in human OFC, as well as how the circuit is disrupted in individuals with autism spectrum disorder (ASD).
We used post-mortem brain tissue from neurotypical adults and individuals with ASD. We examined the morphology and distribution of myelinated axons across cortical layers in OFC, at the single axon level, as a proxy of excitatory pathways. In the same regions, we also examined the laminar distribution of all neurons and neurochemically- and functionally-distinct inhibitory neurons that express the calcium-binding proteins parvalbumin (PV), calbindin (CB), and calretinin (CR).
We found that the density of myelinated axons increased consistently towards layer 6, while the average axon diameter did not change significantly across layers in both groups. However, both the density and diameter of myelinated axons were significantly lower in the ASD group compared with the Control group. The distribution pattern and density of the three major types of inhibitory neurons was comparable between groups, but there was a significant reduction in the density of excitatory neurons across OFC layers in ASD.
This study is limited by the availability of human post-mortem tissue optimally processed for high-resolution microscopy and immunolabeling, especially from individuals with ASD.
The balance between excitation and inhibition in OFC is at the core of its function, assessing and integrating emotional and social cues with internal states and external inputs. Our preliminary results provide evidence for laminar-specific changes in the ratio of excitation/inhibition in OFC of adults with ASD, with an overall weakening and likely disorganization of excitatory signals and a relative strengthening of local inhibition. These changes likely underlie pathology of major OFC communications with limbic or other cortices and the amygdala in individuals with ASD, and may provide the anatomic basis for disrupted transmission of signals for social interactions and emotions in autism.
人类眶额皮层（OFC）参与评估事件和刺激的情绪意义、基于情绪的学习、注意力资源的分配以及社会认知。目前对于人类 OFC 中这些不同功能的结构、连接和兴奋性/抑制性回路相互作用，以及在自闭症谱系障碍（ASD）个体中回路如何被破坏，知之甚少。
我们使用来自神经典型成年人和 ASD 个体的死后脑组织。我们在单个轴突水平上检查了 OFC 皮质层中髓鞘化轴突的形态和分布，作为兴奋性通路的代表。在相同区域，我们还检查了所有神经元以及表达钙结合蛋白 parvalbumin (PV)、calbindin (CB) 和 calretinin (CR) 的神经化学和功能上不同的抑制性神经元的分层分布。
我们发现，髓鞘化轴突的密度朝着 6 层持续增加，而在两组中，平均轴突直径在各层之间没有明显变化。然而，与对照组相比，ASD 组的髓鞘化轴突密度和直径均显著降低。三种主要类型抑制性神经元的分布模式和密度在组间相当，但 ASD 中 OFC 各层兴奋性神经元的密度显著降低。
本研究受到可用于高分辨率显微镜和免疫标记的最佳处理的人类死后组织的可用性限制，特别是来自 ASD 个体的组织。
OFC 中兴奋和抑制的平衡是其功能的核心，它评估和整合情绪和社会线索与内部状态和外部输入。我们的初步结果为 ASD 成人 OFC 中兴奋/抑制比的层特异性变化提供了证据，表现为兴奋性信号整体减弱且可能紊乱，而局部抑制相对增强。这些变化可能是 ASD 个体中 OFC 与边缘或其他皮质和杏仁核的主要通讯病理学的基础，并且可能为自闭症中社交互动和情绪信号的传递中断提供解剖学基础。
