应激性抑郁诱发情感神经环路神经元的树突棘和突触可塑性变化的机理

Depression is a severe mental disorder and the underlying mechanisms still remain largely unknown.。Currently, available antidepressant drugs show low efficacy, slowness of onset and serious side effects. Additionally, about 30 % of patients fail to respond and the recurrence of depression among responsive patients is very high. Therefore, it is necessary to study mechanisms underlying depression in order to develop new and efficient therapies. Several theories of depression exist, which involve monoamine, neurotrophic factors, glutamate and neuronalplasticity. However, none of these theories sufficiently explains the pathology and treatment of depression. Recent studies show that the neuroplasticity hypothesis may bridge these prevailing theories, which suggests that remodeling of dendritic arbors and alteration of excitatory synapse number and function in several brain areas in brain circuitry contribute to symptoms of depression in patients or depressive-like behaviors in animal models. Restoring spine loss or synaptic dysfunction could be a novel therapeutic target for depression. However, the mechanism through which depression or chronic stress remodels dendritic spines and synapses are poorly understood. Dysfunctions of glutamatergic and/or 5-HT systems in depression may be responsible for remodeling of dendritic spines and excitatory synapses in depression. Kalirin-7 plays an essential role in both formation and maintaining of dendritic spines and excitatory synapses. Chronic unpredictable mild stress (CUMS) is a well-established animal model for depression. Our results showed that CUMS decreased spine density and Kal7 expression in the rat hippocampus and PFC, accompanied by depressive-like behaviors, suggesting a role of Kalirin7 in CUMS-induced spine remodeling and depressive-like behaviors. Our aims are 1) determine the mechanisms of spines alterations in different neurons of brain circuitry induced by CUMS and the effects of antidepressants as well as the role of Kalirin7; 2) determine the role of both glutamate and 5-HT receptors in CUMS-induced depressive-like behaviors, alterations of dendritic spines and Kalirin7 expression as well as their relationships. The results of this study may enhance our understanding of depression and facilitate the development of efficient therapies for depression.

抑郁症是一种严重的精神疾病。对它的发病机理不完全清楚。神经环路的多个脑区神经元的树突棘发生形态和功能的变化可能导致了抑郁症状。恢复由抑郁引起的树突棘变化或兴奋性突触功能障碍可能是抑郁症治疗的新靶点。然而，对抑郁发生中树突棘变化的机制了解甚少。5-羟色胺和谷氨酸系统失调可能是抑郁症发生中树突棘可塑性变化的重要原因。Kal-7在树突棘和突触的形成和维持中发挥着必不可缺少的作用。慢性不可预见性应激是一个公认的抑郁症动物模型。应激诱发的抑郁行为降低海马和前额叶皮层神经元的树突棘密度和Kal-7表达。我们的目的是研究应激性抑郁发生中神经环路的相关脑区主要神经元树突棘变化的机理及抗抑郁治疗对这些树突棘和Kal-7的影响。确定5-羟色胺受体和谷氨酸受体在应激性抑郁发生中的作用及其对树突棘可塑性的影响及其Kal-7机制。研究结果可增强我们对抑郁症发病机制的理解，可望为发现治疗抑郁症的有效方法提供科学依据。

抑郁症是一种严重的精神疾病。对它的发病机理不完全清楚。大脑神经环路的多个脑区神经元的树突棘发生形态和功能的变化可能导致了抑郁症状。恢复由抑郁引起的树突棘和突触的变化可能是抑郁症治疗的新靶点。然而，对抑郁发生中树突棘及突触变化的机制了解甚少。Kalirin7在树突棘的形成和维持中发挥着必不可少的作用。慢性不可预见性温和应激（Chronic unpredictable mild stress, CUMS）是一个公认的研究抑郁症的动物模型。本项目结合行为学确定了CUMS慢性应激性抑郁发生中情感和记忆神经环路的相关脑区（前额叶, 海马, 伏隔核和杏仁核）主要神经元树突棘变化的机理及抗抑郁治疗药物和运动锻炼干预对抑郁样行为的逆转以及对神经元树突棘、谷氨酸受体和Kalirin7的影响。发现情感和记忆神经环路的相关脑区神经元可塑性变化参与了情绪行为和认知功能的调节。还发现Kalirin7在慢性应激性抑郁样行为发生中起重要作用。证实了5-羟色胺受体在CUMS性抑郁发生中通过调控树突棘可塑性和Kalirin7的表达而起重要作用。建立了研究抑郁症性别差异的动物模型并筛选出了和抑郁样行为性别差异相关的基因。明确了受雌激素和慢性应激调控并和应激性抑郁样行为以及学习记忆有关基因（Klotho和SOSTDC1）的作用。发现了雌激素调节神经元树突棘可塑性变化可能与Klotho表达有关。并证明了DPYSL2在慢性应激性抑郁样行为发生起重要作用以及机理。这些研究结果对于理解情感和记忆神经环路的相关脑区神经元树突棘在抑郁发生中的作用；对解释和理解雌激素对神经元可塑性的调节和对情绪行为、认知功能的影响；对应激性抑郁发生的5-HT学说及其单胺类学说、谷氨酸学说与神经可塑性学说的内在联系有了新的认识；有利于增强我们对抑郁症发生的性别差异和抑郁病人认知能力下降的理解。总之，研究结果可增强我们对抑郁症发病机制的理解，可望为发现治疗抑郁症的有效方法提供科学依据。