Stress Diminishes BDNF-stimulated TrkB Signaling, TrkB-NMDA Receptor Linkage and Neuronal Activity in the Rat Brain.
Stress Diminishes BDNF-stimulated TrkB Signaling, TrkB-NMDA Receptor Linkage and Neuronal Activity in the Rat Brain.
复制标题
DOI：
10.1016/j.neuroscience.2021.07.011
复制
发表时间：
2021-10-01
期刊：
影响因子：
3.3
通讯作者：
Wang HY
中科院分区：
文献类型：
--
作者：
Robinson S;Mogul AS;Taylor-Yeremeeva EM;Khan A;Tirabassi AD;Wang HY
暴露在强烈或反复的压力源下会导致抑郁或创伤后应激障碍。应激引起的神经系统改变包括神经营养素信号的受损，这被认为会影响突触的完整性和可塑性。本研究采用体外实验的方法，研究了急性或重复应激对海马区(HIPPO)和前额叶皮质(PFC)中BDNF刺激的TrkB信号的影响。急性复合应激组的大鼠在一天内经历了5个应激源，而重复的不可预测应激源组的大鼠在10天内经历了20个应激源。应激暴露后，将切片与Vehicle或BDNF孵育，然后进行免疫沉淀和免疫印迹分析，以评估与BDNF-TrkB信号相关的蛋白水平、激活状态和蛋白-蛋白质连接。三个关键发现是：1)暴露于应激源显著减少了BDNF刺激的河马和PFC中的TrkB信号，从而减少了TrkB的激活，减少了接头蛋白对TrkB的募集，减少了下游信号分子的激活，中断了TrkB-NMDAR的连接，并改变了基础和BDNF刺激的Arc表达。2)应激后，刺激BDNF增强了PFC内TrkB-NMDAR的连接，提示了该区域的代偿机制。3)我们发现在PFC和河马中，TrkB信号、TrkB-NMDAR连锁和Arc表达之间存在解偶联。此外，在反复暴露于应激源后，在这两个区域都观察到促炎症细胞因子的强劲激增。总之，这些数据为未来的研究提供了治疗靶点，这些研究将研究如何逆转应激诱导的BDNF-TrkB信号下调，并强调需要进行功能研究，检查PFC中与应激相关的TrkB-NMDAR活动。
Exposure to intense or repeated stressors can lead to depression or PTSD. Neurological changes induced by stress include impaired neurotrophin signaling, which is known to influence synaptic integrity and plasticity. The present study used an ex vivo approach to examine the impact of acute or repeated stress on BDNF-stimulated TrkB signaling in hippocampus (HIPPO) and prefrontal cortex (PFC). Rats in an acute multiple stressor group experienced five stressors in one day whereas rats in a repeated unpredictable stressor group experienced 20 stressors across 10 days. After stress exposure, slices were incubated with vehicle or BDNF, followed by immunoprecipitation and immunoblot assays to assess protein levels, activation states and protein-protein linkage associated with BDNF-TrkB signaling. Three key findings are 1) exposure to stressors significantly diminished BDNF-stimulated TrkB signaling in HIPPO and PFC such that reductions in TrkB activation, diminished recruitment of adaptor proteins to TrkB, reduced activation of downstream signaling molecules, disruption of TrkB-NMDAr linkage, and changes in basal and BDNF-stimulated Arc expression were observed. 2) After stress, BDNF stimulation enhanced TrkB-NMDAr linkage in PFC, suggestive of compensatory mechanisms in this region. 3) We discovered an uncoupling between TrkB signaling, TrkB-NMDAr linkage and Arc expression in PFC and HIPPO. In addition, a robust surge in pro-inflammatory cytokines was observed in both regions after repeated exposure to stressors. Collectively, these data provide therapeutic targets for future studies that investigate how to reverse stress-induced downregulation of BDNF-TrkB signaling and underscore the need for functional studies that examine stress-related TrkB-NMDAr activities in PFC.
登录
查看更多内容
影响因子：
2.9
作者：
Bloomer, Wendy A. C.;VanDongen, Hendrika M. A.;VanDongen, Antonius M. J.
通讯作者：
VanDongen, Antonius M. J.
DOI：
10.1017/s1461145712000168
发表时间：
2013-03-01
影响因子：
4.8
作者：
Benekareddy, Madhurima;Nair, Amrita R.;Vaidya, Vidita A.
通讯作者：
Vaidya, Vidita A.
DOI：
10.1093/ijnp/pyw089
发表时间：
2017-03-01
期刊：
The international journal of neuropsychopharmacology
影响因子：
--
作者：
Dong C;Zhang JC;Yao W;Ren Q;Ma M;Yang C;Chaki S;Hashimoto K
通讯作者：
Hashimoto K
影响因子：
2.7
作者：
Bhakta, Ami;Gavini, Kartheek;Parameshwaran, Kodeeswaran
通讯作者：
Parameshwaran, Kodeeswaran
影响因子：
3.3
作者：
Coogan, AN;O'Neill, LAJ;O'Connor, JJ
通讯作者：
O'Connor, JJ