Dopamine and D1 receptor in hippocampal dentate gyrus involved in chronic stress-induced alteration of spatial learning and memory in rats

IF 4.3 2区 医学 Q1 NEUROSCIENCES Neurobiology of Stress Pub Date : 2024-10-24 DOI:10.1016/j.ynstr.2024.100685
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Abstract

There is increasing evidence that chronic stress (CS), which occurs when the body is exposed to prolonged stressors, significantly impairs learning and memory. Dopamine (DA) plays a critical role in learning and memory in the hippocampus through the activation of D1-like receptors (D1R). However, the specific roles of DA and D1R in the hippocampal dentate gyrus (DG), particularly in CS-induced changes in spatial learning and memory, are not well understood. In this study, we established a CS rat model through the random application of various stressors. We assessed spatial learning and memory using the Morris water maze (MWM) and measured DA concentration and the amplitude of field excitatory postsynaptic potentials (fEPSP) in the DG during the MWM test in freely moving rats. We also examined the involvement of D1R in spatial learning and memory by microinjecting its antagonist (SCH23390) into the DG, and then analyzed the expressions of phosphorylated (p-) Ca2+/calmodulin-dependent protein kinase II (CaMKII), protein kinase A (PKA), and cAMP-response element binding protein (CREB) in the DG using Western blot. During the MWM test, compared with the control group, the escape latency was increased, and the percentage of distance in target quadrant and the number of platform crossings were decreased, in addition, the increase of fEPSP amplitude in the DG was significantly attenuated in CS group. In the control group, the DA concentration in the DG was significantly increased during the MWM test, and this response was enhanced in the CS group. Microinjection of SCH23390 into the DG significantly improved the spatial learning and memory impairments in CS rats, and reversed the inhibitory effect of CS on increase of fEPSP amplitude in the DG during the MWM test. Furthermore, SCH23390 partially reversed the inhibitory effects of CS on the expressions of p-CaMKII, p-PKA, and p-CREB in the DG. Our findings suggest that overactivation of the DA-D1R system in the hippocampal DG impairs spatial learning and memory and related synaptic plasticity in CS rats via downregulation of PKA-CREB signaling pathway.
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多巴胺和海马齿状回中的 D1 受体参与慢性应激诱导的大鼠空间学习和记忆改变
越来越多的证据表明,慢性应激(CS),即人体长期处于应激状态时发生的现象,会严重损害学习和记忆能力。多巴胺(DA)通过激活 D1 类受体(D1R)在海马的学习和记忆中发挥着关键作用。然而,DA和D1R在海马齿状回(DG)中的具体作用,尤其是在CS诱导的空间学习和记忆变化中的作用,还不是很清楚。在本研究中,我们通过随机施加各种应激源建立了 CS 大鼠模型。我们利用莫里斯水迷宫(MWM)评估了大鼠的空间学习和记忆能力,并测量了自由活动的大鼠在MWM测试中DG的DA浓度和场兴奋突触后电位(fEPSP)的振幅。我们还通过向DG显微注射D1R拮抗剂(SCH23390)研究了D1R参与空间学习和记忆的情况,然后用Western印迹分析了DG中磷酸化(p-)的Ca2+/钙调蛋白依赖性蛋白激酶II(CaMKII)、蛋白激酶A(PKA)和cAMP反应元件结合蛋白(CREB)的表达。在MWM试验中,与对照组相比,CS组的逃逸潜伏期增加,目标象限距离百分比和平台穿越次数减少,此外,DG中fEPSP振幅的增加在CS组明显减弱。在MWM测试中,对照组DG中的DA浓度明显增加,而在CS组中这一反应增强。向DG显微注射SCH23390可明显改善CS组大鼠的空间学习和记忆障碍,并逆转CS对MWM测试中DG中fEPSP振幅增加的抑制作用。此外,SCH23390还部分逆转了CS对DG中p-CaMKII、p-PKA和p-CREB表达的抑制作用。我们的研究结果表明,海马DG中DA-D1R系统的过度激活会通过下调PKA-CREB信号通路损害CS大鼠的空间学习和记忆以及相关的突触可塑性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Neurobiology of Stress
Neurobiology of Stress Biochemistry, Genetics and Molecular Biology-Biochemistry
CiteScore
9.40
自引率
4.00%
发文量
74
审稿时长
48 days
期刊介绍: Neurobiology of Stress is a multidisciplinary journal for the publication of original research and review articles on basic, translational and clinical research into stress and related disorders. It will focus on the impact of stress on the brain from cellular to behavioral functions and stress-related neuropsychiatric disorders (such as depression, trauma and anxiety). The translation of basic research findings into real-world applications will be a key aim of the journal. Basic, translational and clinical research on the following topics as they relate to stress will be covered: Molecular substrates and cell signaling, Genetics and epigenetics, Stress circuitry, Structural and physiological plasticity, Developmental Aspects, Laboratory models of stress, Neuroinflammation and pathology, Memory and Cognition, Motivational Processes, Fear and Anxiety, Stress-related neuropsychiatric disorders (including depression, PTSD, substance abuse), Neuropsychopharmacology.
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