Department of Stereotactic and Functional Neurosurgery, Medical Center - University Freiburg, Faculty of Medicine, University of Freiburg, Breisacher Str. 64, 79106, Freiburg, Germany.
Functional Neuroconnectomics Group, Department of Experimental Epileptology and Cognition Research, Life and Brain Centre, University of Bonn, Medical School, 53105, Bonn, Germany.
Neuropharmacology. 2020 Jan 1;162:107834. doi: 10.1016/j.neuropharm.2019.107834. Epub 2019 Nov 1.
Resilience to stress is critical for the development of depression. Enhanced adenosine A receptor (AR) signaling mediates the antidepressant effects of acute sleep deprivation (SD). However, chronic SD causes long-lasting upregulation of brain AR and increases the risk of depression. To investigate the effects of AR on mood, we utilized two transgenic mouse lines with inducible AR overexpression in forebrain neurons. These two lines have identical levels of AR increase in the cortex, but differ in the transgenic AR expression in the hippocampus. Switching on the transgene promotes robust antidepressant and anxiolytic effects in both lines. The mice of the line without transgenic AR overexpression in the hippocampus (A1Hipp-) show very strong resistance towards development of stress-induced chronic depression-like behavior. In contrast, the mice of the line in which AR upregulation extends to the hippocampus (A1Hipp+), exhibit decreased resilience to depression as compared to A1Hipp-. Similarly, automatic analysis of reward behavior of the two lines reveals that depression resistant A1Hipp-transgenic mice exhibit high sucrose preference, while mice of the vulnerable A1Hipp + line developed stress-induced anhedonic phenotype. The A1Hipp + mice have increased Homer1a expression in hippocampus, correlating with impaired long-term potentiation in the CA1 region, mimicking the stressed mice. Furthermore, virus-mediated overexpression of Homer1a in the hippocampus decreases stress resilience. Taken together our data indicate for first time that increased expression of AR and Homer1a in the hippocampus modulates the resilience to stress-induced depression and thus might potentially mediate the detrimental effects of chronic sleep restriction on mood.
抗压能力对于抑郁症的发展至关重要。增强的腺苷 A 受体 (AR) 信号转导介导了急性睡眠剥夺 (SD) 的抗抑郁作用。然而，慢性 SD 会导致大脑 AR 的持久上调，并增加患抑郁症的风险。为了研究 AR 对情绪的影响，我们利用了两种在大脑前神经元中诱导性过表达 AR 的转基因小鼠系。这两种系的皮层中 AR 增加水平相同，但海马中的转基因 AR 表达不同。激活转基因在这两种系中都能促进强大的抗抑郁和抗焦虑作用。在没有海马中转基因 AR 过表达的系（A1Hipp-）的小鼠中，表现出对压力诱导的慢性抑郁样行为发展非常强的抵抗力。相比之下，AR 上调扩展到海马的系（A1Hipp+）的小鼠表现出对抑郁的抵抗力降低，与 A1Hipp-相比。同样，对两种系的奖励行为的自动分析表明，抗抑郁的 A1Hipp 转基因小鼠表现出高蔗糖偏好，而脆弱的 A1Hipp+系的小鼠则表现出压力诱导的快感缺失表型。A1Hipp+小鼠的海马中 Homer1a 表达增加，与 CA1 区的长时程增强受损相关，模拟应激小鼠。此外，海马中 Homer1a 的病毒介导过表达会降低应激抵抗力。总之，我们的数据首次表明，海马中 AR 和 Homer1a 的表达增加调节了应激诱导的抑郁的抵抗力，因此可能潜在地介导了慢性睡眠限制对情绪的不利影响。
