Rabelo Thallita K, Campos Ana Carolina P, Almeida Souza Thiago H, Mahmud Faiza, Popovic Milos R, Covolan Luciene, Betta Victor H C, DaCosta Leodante, Lipsman Nir, Diwan Mustansir, Hamani Clement
Sunnybrook Research Institute, Toronto, ON, Canada.
Sunnybrook Research Institute, Toronto, ON, Canada; Institute of Biomaterials and Biomedical Engineering University of Toronto, ON, Canada.
Brain Stimul. 2024 Nov-Dec;17(6):1186-1196. doi: 10.1016/j.brs.2024.10.006. Epub 2024 Oct 15.
Traumatic brain injury (TBI) is a major life-threatening event. In addition to neurological deficits, it can lead to long-term impairments in attention and memory. Deep brain stimulation (DBS) is an established therapy for movement disorders that has been recently investigated for memory improvement in various disorders. In models of TBI, stimulation delivered to different brain targets has been administered to rodents long after the injury with the objective of treating motor deficits, coordination and memory impairment.
To test the hypothesis that DBS administered soon after TBI may prevent the development of memory deficits and exert neuroprotective effects.
Male rats were implanted with DBS electrodes in the anterior nucleus of the thalamus (ANT) one week prior to lateral fluid percussion injury (FPI). Immediately after TBI, animals received active or sham stimulation for 6 h. Four days later, they were assessed in a novel object/novel location recognition test (NOR/NLR) and a Barnes maze paradigm. After the experiments, hippocampal cells were counted. Separate groups of animals were sacrificed at different timepoints after TBI to measure cytokines and brain derived neurotrophic factor (BDNF). In a second set of experiments, TBI-exposed animals receiving active or sham stimulation were injected with the tropomyosin receptor kinase B (TrkB) antagonist ANA-12, followed by behavioural testing.
Rats exposed to TBI given DBS had an improvement in several variables of the Barnes maze, but no significant improvements in NOR/NLR compared to Sham DBS TBI animals or non-implanted controls. Animals receiving stimulation had a significant increase in BDNF levels, as well as in hippocampal cell counts in the hilus, CA3 and CA1 regions. DBS failed to normalize the increased levels of TNFα and the proinflammatory cytokine IL1β in the perilesional cortex and the hippocampus of the TBI-exposed animals. Pharmacological experiments revealed that ANA-12 administered alongside DBS did not counter the memory improvement observed in ANT stimulated animals.
DBS delivered immediately after TBI mitigated memory deficits, increased the expression of BDNF and the number of hippocampal cells in rats. Mechanisms for these effects were not related to an anti-inflammatory effect or mediated via TrkB receptors.
创伤性脑损伤（TBI）是一种严重威胁生命的事件。除了神经功能缺损外，它还可导致注意力和记忆力的长期损害。深部脑刺激（DBS）是一种已确立的治疗运动障碍的方法，最近已被研究用于改善各种疾病的记忆力。在TBI模型中，在损伤很久之后才对啮齿动物进行不同脑靶点的刺激，目的是治疗运动功能缺损、协调能力和记忆障碍。
检验TBI后不久进行DBS可预防记忆缺陷的发展并发挥神经保护作用这一假设。
雄性大鼠在侧方流体冲击伤（FPI）前一周，于丘脑前核（ANT）植入DBS电极。TBI后立即对动物进行6小时的主动或假刺激。四天后，在新物体/新位置识别测试（NOR/NLR）和巴恩斯迷宫范式中对它们进行评估。实验结束后，对海马细胞进行计数。在TBI后的不同时间点处死单独的动物组，以测量细胞因子和脑源性神经营养因子（BDNF）。在第二组实验中，对接受主动或假刺激的TBI暴露动物注射原肌球蛋白受体激酶B（TrkB）拮抗剂ANA-12，随后进行行为测试。
与假刺激DBS TBI动物或未植入电极的对照组相比，接受DBS的TBI暴露大鼠在巴恩斯迷宫的几个变量上有所改善，但在NOR/NLR方面没有显著改善。接受刺激的动物BDNF水平以及海马齿状回、CA3和CA1区的细胞计数显著增加。DBS未能使TBI暴露动物的损伤周围皮质和海马中升高的肿瘤坏死因子α（TNFα）和促炎细胞因子白细胞介素1β（IL1β）水平恢复正常。药理学实验表明，与DBS一起给予的ANA-12并没有抵消在ANT刺激动物中观察到的记忆改善。
TBI后立即进行DBS可减轻大鼠的记忆缺陷，增加BDNF的表达和海马细胞数量。这些作用的机制与抗炎作用无关，也不是通过TrkB受体介导的。
