Role of COP1 in dendritic spines, cognition and stress resilience

COP1 在树突棘、认知和应激恢复中的作用

• 批准号: 10592899
• 负责人: Xin-Ming Ma
• 金额: $ 24.77万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-02 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10592899
• 关键词: Adult; Affect; Anxiety; Area; Bipolar Disorder; Brain; Brain-Derived Neurotrophic Factor; Chronic; Chronic stress; Cognition; Cognitive; Cognitive deficits; DLG4 gene; Data; Dendritic Spines; Dependovirus; Development; Disease; Ensure; Excision; Frequencies; Hippocampus; Impaired cognition; Impairment; Intervention; Knockout Mice; Label; Learning; Maintenance; Medial; Mediating; Memory; Mental Depression; Mental Health; Mental disorders; Microscope; Mus; Mutation; Neurons; Outcome Study; Pathology; Play; Prefrontal Cortex; Prosencephalon; Proteins; Proteomics; Regulation; Research Domain Criteria; Risk Factors; Rodent; Role; Shapes; Stress; Synapses; Synaptic plasticity; Synaptophysin; System; Testing; Time; Ubiquitin; Vertebral column; Visualization; Whole-Cell Recordings; autism spectrum disorder; biological adaptation to stress; cognitive enhancement; cognitive function; cognitive system; conditional knockout; constitutive expression; density; gene gun; genome wide association study; hippocampal pyramidal neuron; information processing; male; memory recognition; multicatalytic endopeptidase complex; novel; object recognition; overexpression; postnatal; postsynaptic; promoter; protein degradation; resilience; response; sex; spatial memory; stress related disorder; stress resilience; synaptic function; synaptogenesis; ubiquitin-protein ligase

Maintenance of healthy dendritic spine and synapse function is essential for normal brain function. The number of dendritic spines is precisely controlled and coordinated by synaptic activity to ensure functional brain network integrity. It is well-established that disruptions of the density, shape and size of dendritic spines are associated with psychiatric disorders. The medial prefrontal cortex (mPFC) is an information processing center and forms brain circuit with hippocampus. The hippocampus is well established as an important brain area for cognition. This cognitive dysfunction found in psychiatric disorders may result from disruptions of the hippocampal-prefrontal cortex circuit. The hippocampus and mPFC are vulnerable to stress. Stress is a risk factor for psychiatric disorders such as depression. Chronic stress-induced cognitive deficit is accompanied by a decrease in spine density and impaired synaptic plasticity in the pyramidal neurons of the rodent mPFC and hippocampal CA1 area. But the underlying mechanisms are poorly understood. Tight regulation of protein degradation is critical for normal brain function. Maintaining normal ubiquitin-proteasome system (UPS), which regulates protein degradation, is necessary for proper development of the brain, synapse formation and plasticity. Dysregulation of UPS results in diseases, e.g. mutations in E3 ligase cause psychiatric disorders. Constitutive photomorphogenesis protein 1 (COP1), an E3 ubiquitin ligase, is a critical and negative regulator of its various substrates. COP1 plays an essential role in mouse brain development, but function of COP1 in the adult brain is unknown. Genome-wide association studies showed that COP1 is a risk factor for anxiety, bipolar disorder, depression, and autism. Our preliminary studies showed that COP1 is localized to principal neurons of the mouse prefrontal cortex; COP1 deletion in the principal neurons of the forebrain cortex and hippocampal CA1 in COP1 conditional knockout (Cop1CKO) mice caused an increase in spine density and an enhancement in excitatory synaptic functions in these neurons; these Cop1CKO mice show enhanced cognitive functions and resilience to chronic stress. These preliminary results raise our hypothesis that COP1 plays an important role in dendritic spines, cognition and stress resilience. Our aims are to test this hypothesis: Determine the role of COP1 in spine formation and synaptic functions using Cop1cko mice and WT littermate controls, determine the role of COP1 in cognition and stress resilience, and identify significant substrates through which COP1 affects dendritic spines, cognition and stress resilience. Spatial memory and recognition memory are related to stress and stress-related disorders, and align with declarative memory construct in cognitive system domain of the Research Domain Criteria (RDoC). The results from this study may enhance our understanding of spine formation, cognition, stress resilience and lead to the development of novel interventions for reversing cognitive impairments, enhancing stress resilience, and for treating stress-related disorders. The outcomes of this study are associated with mental health.

维持健康的树突棘和突触功能对于正常的大脑功能是必不可少的。树突棘的数量由突触活动精确控制和协调，以确保功能性脑网络的完整性。树突棘的密度、形状和大小的破坏与精神障碍有关，这是公认的。内侧前额叶皮层（mPFC）是信息处理中心，与海马形成脑回路。海马体被公认为是认知的重要脑区。这种在精神疾病中发现的认知功能障碍可能是由于大脑皮层-前额叶皮层回路中断造成的。海马体和mPFC对压力很敏感。压力是抑郁症等精神疾病的危险因素。慢性应激诱导的认知功能障碍伴随着啮齿动物mPFC和海马CA1区锥体神经元的棘密度降低和突触可塑性受损。但其潜在机制却知之甚少。蛋白质降解的严格调节对于正常的大脑功能至关重要。维持正常的泛素-蛋白酶体系统（UPS），调节蛋白质降解，是大脑正常发育，突触形成和可塑性所必需的。UPS的失调会导致疾病，例如E3连接酶的突变会导致精神疾病。组成型光形态发生蛋白1（COP1）是一种E3泛素连接酶，是其多种底物的重要负调控因子。COP1在小鼠脑发育中起重要作用，但COP1在成人脑中的功能尚不清楚。全基因组关联研究表明，COP1是焦虑、双相情感障碍、抑郁和自闭症的危险因素。我们的初步研究表明，COP1定位于小鼠前额叶皮层的主要神经元; COP1条件性敲除（Cop1CKO）小鼠前脑皮层和海马CA1区的主要神经元中的COP1缺失导致这些神经元中的棘密度增加和兴奋性突触功能增强;这些Cop1CKO小鼠表现出增强的认知功能和对慢性应激的恢复力。这些初步结果提出了我们的假设，即COP1在树突棘，认知和压力恢复中起着重要作用。我们的目的是验证这一假设：确定COP 1在棘形成和突触功能中的作用，使用Cop1cko小鼠和WT同窝对照，确定COP 1在认知和应激恢复中的作用，并确定COP 1影响树突棘，认知和应激恢复的重要底物。空间记忆和再认记忆与应激和应激相关障碍有关，与研究领域标准（RDoC）认知系统领域的陈述性记忆结构一致。这项研究的结果可能会增强我们对脊柱形成、认知、压力恢复力的了解，并导致开发新型干预措施来逆转认知障碍、增强压力恢复力和治疗压力相关疾病。这项研究的结果与心理健康有关。