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.

主要抑郁症（MDD）的药理学治疗方面的成功将得到促进通过改善对前额叶皮层的情绪调节机制的知识，很大程度上可以（PFC）及其连接。 MDD的药物疗法是基于单胺 - 有关神经元功能的相关药物；但是，这些药物只是部分有效的。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，可能有助于沮丧。因此，为增强前额叶功能的抑郁症设计更有效的治疗方法确定PFC中神经胶质功能障碍的机制至关重要设计新的治疗方法。在PFC的形态和神经化学改变中 MDD中的星形胶质细胞和少突胶质细胞，我们发现水平和组织分布急剧下降 Connexin 43（CX43），星形胶质细胞的主要间隙连接蛋白。在大脑皮层中，CX43形成差距星形胶质细胞和这些结合与少突胶质细胞之间的结合。因此，相互作用的星形胶质细胞和少突胶质细胞病理可能会导致PFC连通性改变。重要的是，受长慢性的大鼠不可预测的压力（CUS）是一种类似抑郁症行为的模型，可显着减少CX43 PFC，而施加到PFC的间隙连接器会导致抑郁样行为。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类似抑郁症的行为中起着重要作用。这有证据表明，即使在非 - 灾难性的，骨髓可塑性的限制变化。因此，PFC与其他大脑区域的连通性可能是受到连接蛋白相关的髓鞘可塑性或维护的影响，从而有助于抑郁症状，例如运动迟缓，决策障碍或情绪调节异常。我们假设降低CX43和CX30的降低（PLC，大鼠PFC的一个分裂）为了响应CUS或通过分子手段，会破坏髓磷脂完整性，并导致抑郁状行为。相比之下，CX43或髓磷脂的PFC靶向增强应减轻抑郁症 CU引起的行为。这些假设将以三个特定目的进行测试：特定目标1：cus 将导致类似抑郁症行为的诱导，并降低星形胶质细胞和少突胶质细胞蛋白参与髓磷脂维持。特定目标2：CX43表达和大鼠PLC中的髓磷脂将导致类似抑郁的行为，以及星形胶质细胞和少突胶质细胞蛋白参与髓磷脂维持。特定目标3：CX43或 PLC中的髓磷脂蛋白MBP将导致抑郁症样行为和认知障碍减少由CUS以及髓鞘维持中涉及的蛋白质增加引起的。