Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Psychiatry, University of Genoa, Genoa, Italy.
IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
Mol Psychiatry. 2020 Jan;25(1):82-93. doi: 10.1038/s41380-019-0406-4. Epub 2019 Apr 5.
Alterations in brain intrinsic activity-as organized in resting-state networks (RSNs) such as sensorimotor network (SMN), salience network (SN), and default-mode network (DMN)-and in neurotransmitters signaling-such as dopamine (DA) and serotonin (5-HT)-have been independently detected in psychiatric disorders like bipolar disorder and schizophrenia. Thus, the aim of this work was to investigate the relationship between such neurotransmitters and RSNs in healthy, by reviewing the relevant work on this topic and performing complementary analyses, in order to better understand their physiological link, as well as their alterations in psychiatric disorders. According to the reviewed data, neurotransmitters nuclei diffusively project to subcortical and cortical regions of RSNs. In particular, the dopaminergic substantia nigra (SNc)-related nigrostriatal pathway is structurally and functionally connected with core regions of the SMN, whereas the ventral tegmental area (VTA)-related mesocorticolimbic pathway with core regions of the SN. The serotonergic raphe nuclei (RNi) connections involve regions of the SMN and DMN. Coherently, changes in neurotransmitters activity impact the functional configuration and level of activity of RSNs, as measured by functional connectivity (FC) and amplitude of low-frequency fluctuations/temporal variability of BOLD signal. Specifically, DA signaling is associated with increase in FC and activity in the SMN (hypothetically via the SNc-related nigrostriatal pathway) and SN (hypothetically via the VTA-related mesocorticolimbic pathway), as well as concurrent decrease in FC and activity in the DMN. By contrast, 5-HT signaling (via the RNi-related pathways) is associated with decrease in SMN activity along with increase in DMN activity. Complementally, our empirical data showed a positive correlation between SNc-related FC and SMN activity, whereas a negative correlation between RNi-related FC and SMN activity (along with tilting of networks balance toward the DMN). According to these data, we hypothesize that the activity of neurotransmitter-related neurons synchronize the low-frequency oscillations within different RSNs regions, thus affecting the baseline level of RSNs activity and their balancing. In our model, DA signaling favors the predominance of SMN-SN activity, whereas 5-HT signaling favors the predominance of DMN activity, manifesting in distinct behavioral patterns. In turn, alterations in neurotransmitters signaling (or its disconnection) may favor a correspondent functional reorganization of RSNs, manifesting in distinct psychopathological states. The here suggested model carries important implications for psychiatric disorders, providing novel and well testable hypotheses especially on bipolar disorder and schizophrenia.
大脑内活动的改变——如在静息态网络（RSN）中组织的改变，如感觉运动网络（SMN）、突显网络（SN）和默认模式网络（DMN）——以及神经递质信号的改变，如多巴胺（DA）和血清素（5-HT），在双相情感障碍和精神分裂症等精神疾病中已经被独立检测到。因此，本工作的目的是通过综述该主题的相关工作并进行补充分析，来研究健康人群中这些神经递质和 RSN 之间的关系，以便更好地理解它们的生理联系，以及它们在精神疾病中的改变。根据综述的数据，神经递质核向 RSN 的皮质下和皮质区域弥散投射。具体而言，多巴胺能黑质致密部（SNc）相关的黑质纹状体通路在结构和功能上与 SMN 的核心区域相连，而腹侧被盖区（VTA）相关的中脑边缘通路与 SN 的核心区域相连。5-羟色胺能中缝核（RNi）的连接涉及到 SMN 和 DMN 的区域。一致地，神经递质活性的变化影响 RSN 的功能结构和活动水平，如功能连接（FC）和低频波动/血氧水平依赖信号的时间变异性的幅度所测量的。具体而言，DA 信号与 SMN（假设通过 SNc 相关的黑质纹状体通路）和 SN（假设通过 VTA 相关的中脑边缘通路）的 FC 和活动的增加有关，以及 DMN 的 FC 和活动的同时减少。相比之下，5-HT 信号（通过 RNi 相关通路）与 SMN 活动的减少有关，同时与 DMN 活动的增加有关。此外，我们的实证数据显示，SNc 相关 FC 与 SMN 活动之间呈正相关，而 RNi 相关 FC 与 SMN 活动之间呈负相关（同时网络平衡向 DMN 倾斜）。根据这些数据，我们假设与神经递质相关的神经元的活动同步不同 RSN 区域内的低频振荡，从而影响 RSN 活动的基线水平及其平衡。在我们的模型中，DA 信号有利于 SMN-SN 活动的优势，而 5-HT 信号有利于 DMN 活动的优势，表现出不同的行为模式。相反，神经递质信号的改变（或其断开）可能有利于 RSN 的相应功能重组，表现出不同的精神病理状态。这里提出的模型对精神疾病具有重要意义，提供了新的、可很好验证的假设，特别是对双相情感障碍和精神分裂症。
