Astrocyte gap junctions,myelin integrity and depression-like behaviors

星形胶质细胞间隙连接、髓磷脂完整性和抑郁样行为

基本信息

批准号：
9519123
负责人：
JOSE JAVIER MIGUEL-HIDALGO
金额：
$ 38.13万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9519123
关键词：
Affect Animal Model Animals Antidepressive Agents Area Astrocytes Axon Behavior Behavioral Behavioral Assay Brain Brain region Cerebral cortex Characteristics Chronic Complementary DNA Connexin 43 Connexins Decision Making Demyelinations Drug or chemical Tissue Distribution Electron Microscopy Functional disorder GJB6 gene Gap Junctions Immunohistochemistry Impaired cognition Impairment Infusion procedures Knowledge Lysophosphatidylcholines Maintenance Major Depressive Disorder Measures Mental Depression Molecular Morphology Motor Myelin Myelin Proteins Neuroglia Neurons Oligodendroglia Pathology Pattern Pharmaceutical Preparations Pharmacological Treatment Pharmacotherapy Play Prefrontal Cortex Proteins Rattus Research Role Stress Subfamily lentivirinae Testing base cognitive function depression model depressive symptoms design effective therapy emotion regulation improved in vivo indexing monoamine neurochemistry novel therapeutic intervention overexpression response small hairpin RNA success

项目摘要

Success in the pharmacological treatment of major depressive disorder (MDD) would be facilitated greatly by improved knowledge of the mechanisms underlying emotional regulation by the prefrontal cortex (PFC) and its connections. Pharmacotherapies for MDD are based on the putative effects of monoamine- related drugs on neuronal function; however, these drugs are only partially efficacious. Our research has shown that PFC glial cells, including astrocytes and oligodendrocytes, may contribute to the pathophysiology of depression. Thus, to design more effective treatments for depression that enhance prefrontal function, it is critical to determine the mechanisms underpinning glial dysfunction in the PFC and how they can be leveraged to design new therapeutic approaches. Among the morphological and neurochemical alterations in PFC astrocytes and oligodendrocytes in MDD, we have found a dramatic decrease in levels and tissue distribution of connexin 43 (Cx43), the major gap junction protein of astrocytes. In the cerebral cortex, Cx43 forms gap junctions between astrocytes and of these with the oligodendrocytes. Thus, interacting astrocyte and oligodendrocyte pathology may result in altered PFC connectivity. Importantly, rats subjected to chronic unpredictable stress (CUS), a model for depression-like behaviors, undergo significant Cx43 reduction in the PFC, while gap junction blockers applied to the PFC result in depression-like behaviors. Furthermore, suppression of astrocyte Cx43 and Cx30 disrupts myelin in animal models. Recent animal studies suggest that specific myelin or gap junction disruption in the PFC plays a significant role in depression-like behaviors. This evidence fits with findings that brain connectivity patterns can be significantly altered even after non- catastrophic, restricted changes in myelin plasticity. Thus, PFC connectivity to other brain areas could be deeply affected by connexin-related changes in myelin plasticity or maintenance, thereby contributing to depression symptoms such as motor retardation, impaired decision-making or abnormal emotional regulation. We hypothesize that reduction in Cx43 and Cx30 in the prelimbic cortex (PLC, a division of the rat PFC) in response to CUS, or by molecular means, will disrupt myelin integrity and result in depression-like behaviors. By contrast, PFC-targeted enhancement of Cx43 or myelin should mitigate depression-like behaviors induced by CUS. These hypotheses will be tested with three specific aims: Specific aim 1: CUS will result in the induction of depression-like behaviors and reduction in the levels of astrocyte and oligodendrocyte proteins involved in myelin maintenance. Specific aim 2: Disruption of Cx43 expression and myelin in the rat PLC will result in depression-like behaviors along with reduction in the levels of astrocyte and oligodendrocyte proteins involved in myelin maintenance. Specific aim 3: Overexpression of Cx43 or the myelin protein MBP in the PLC will result in reduction of depression-like behaviors and cognitive impairment caused by CUS along with an increase proteins involved in myelin maintenance.

将促进重度抑郁症（MDD）药物治疗的成功大大提高了对前额叶皮层情绪调节机制的了解（PFC）及其连接。 MDD 的药物治疗基于单胺类药物的推定作用影响神经功能的相关药物；然而，这些药物仅部分有效。我们的研究有表明 PFC 神经胶质细胞，包括星形胶质细胞和少突胶质细胞，可能有助于病理生理学沮丧。因此，为了设计更有效的抑郁症治疗方法来增强前额叶功能，对于确定 PFC 中神经胶质细胞功能障碍的机制以及如何利用它们至关重要设计新的治疗方法。 PFC 的形态和神经化学变化 MDD 中的星形胶质细胞和少突胶质细胞，我们发现其水平和组织分布急剧下降连接蛋白 43 (Cx43)，星形胶质细胞的主要间隙连接蛋白。在大脑皮层，Cx43形成间隙星形胶质细胞之间以及星形胶质细胞与少突胶质细胞之间的连接。因此，相互作用的星形胶质细胞和少突胶质细胞病理学可能导致 PFC 连接性改变。重要的是，遭受慢性不可预测的压力（CUS）是一种类似抑郁行为的模型，在 PFC，而应用于 PFC 的间隙连接阻滞剂会导致抑郁样行为。此外，星形胶质细胞 Cx43 和 Cx30 的抑制会破坏动物模型中的髓磷脂。最近的动物研究表明 PFC 中特定的髓磷脂或间隙连接破坏在抑郁样行为中起着重要作用。这证据与以下发现相符：即使在非髓磷脂可塑性发生灾难性的、有限的变化。因此，PFC 与其他大脑区域的连接可能是髓磷脂可塑性或维护方面深受连接蛋白相关变化的影响，从而有助于抑郁症状，例如运动迟缓、决策受损或情绪调节异常。我们假设前边缘皮质（PLC，大鼠 PFC 的一个部分）中 Cx43 和 Cx30 的减少对 CUS 的反应或通过分子手段，会破坏髓磷脂的完整性并导致抑郁症样症状行为。相比之下，PFC 靶向增强 Cx43 或髓磷脂应该可以减轻抑郁样症状 CUS 诱发的行为。这些假设将通过三个具体目标进行检验：具体目标 1：CUS 将导致抑郁样行为的诱发以及星形胶质细胞和星形胶质细胞水平的降低少突胶质细胞蛋白参与髓磷脂的维持。具体目标 2：破坏 Cx43 表达并大鼠 PLC 中的髓磷脂会导致抑郁样行为，同时星形胶质细胞和星形胶质细胞水平降低。少突胶质细胞蛋白参与髓磷脂的维持。具体目标 3：Cx43 或 PLC 中的髓磷脂蛋白 MBP 将减少抑郁样行为和认知障碍由 CUS 引起，以及参与髓磷脂维持的蛋白质增加。