From the Department of Biology, Faculty of Science, Universitat de Girona, Girona, Spain (Riberas-Sánchez, Puig-Parnau, Huguet, Kádár); and the Psychobiology Unit, Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain (Vila-Solés, García-Brito, Aldavert-Vera, Segura-Torres).
From the Department of Biology, Faculty of Science, Universitat de Girona, Girona, Spain (Riberas-Sánchez, Puig-Parnau, Huguet, Kádár); and the Psychobiology Unit, Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain (Vila-Solés, García-Brito, Aldavert-Vera, Segura-Torres)
J Psychiatry Neurosci. 2024 Mar 15;49(2):E96-E108. doi: 10.1503/jpn.230066. Print 2024 Jan-Feb.
The assessment of deep brain stimulation (DBS) as a therapeutic alternative for treating Alzheimer disease (AD) is ongoing. We aimed to determine the effects of intracranial self-stimulation at the medial forebrain bundle (MFB-ICSS) on spatial memory, neurodegeneration, and serum expression of microRNAs (miRNAs) in a rat model of sporadic AD created by injection of streptozotocin. We hypothesized that MFB-ICSS would reverse the behavioural effects of streptozotocin and modulate hippocampal neuronal density and serum levels of the miRNAs.
We performed Morris water maze and light-dark transition tests. Levels of various proteins, specifically amyloid-β precurser protein (APP), phosphorylated tau protein (pTAU), and sirtuin 1 (SIRT1), and neurodegeneration were analyzed by Western blot and Nissl staining, respectively. Serum miRNA expression was measured by reverse transcription polymerase chain reaction.
Male rats that received streptozotocin had increased hippocampal levels of pTAU S202/T205, APP, and SIRT1 proteins; increased neurodegeneration in the CA1, dentate gyrus (DG), and dorsal tenia tecta; and worse performance in the Morris water maze task. No differences were observed in miRNAs, except for miR-181c and miR-let-7b. After MFB-ICSS, neuronal density in the CA1 and DG regions and levels of miR-181c in streptozotocin-treated and control rats were similar. Rats that received streptozotocin and underwent MFB-ICSS also showed lower levels of miR-let-7b and better spatial learning than rats that received streptozotocin without MFB-ICSS.
The reversal by MFB-ICSS of deficits induced by streptozotocin was fairly modest.
Spatial memory performance, hippocampal neurodegeneration, and serum levels of miR-let-7b and miR-181c were affected by MFB-ICSS under AD-like conditions. Our results validate the MFB as a potential target for DBS and lend support to the use of specific miRNAs as promising biomarkers of the effectiveness of DBS in combatting AD-associated cognitive deficits.
深部脑刺激（DBS）作为治疗阿尔茨海默病（AD）的治疗选择正在进行评估。我们旨在通过向链脲佐菌素（STZ）注射的散发性 AD 大鼠模型中，确定内侧前额束（MFB-ICSS）的颅内自我刺激对空间记忆、神经退行性变和血清 microRNAs（miRNAs）表达的影响。我们假设 MFB-ICSS 将逆转 STZ 的行为影响，并调节海马神经元密度和血清中 miRNAs 的水平。
我们进行了 Morris 水迷宫和明暗过渡测试。通过 Western blot 和尼氏染色分别分析了各种蛋白质，特别是淀粉样前体蛋白（APP）、磷酸化 tau 蛋白（pTAU）和 SIRT1 水平以及神经退行性变。通过逆转录聚合酶链反应测量血清 miRNA 表达。
接受 STZ 的雄性大鼠海马 pTAU S202/T205、APP 和 SIRT1 蛋白水平升高；CA1、齿状回（DG）和背侧被盖 tecta 中的神经退行性变增加；Morris 水迷宫任务的表现更差。miRNA 无差异，除了 miR-181c 和 miR-let-7b。在 MFB-ICSS 后，CA1 和 DG 区的神经元密度和 STZ 处理和对照大鼠中 miR-181c 的水平相似。接受 STZ 并接受 MFB-ICSS 的大鼠也表现出较低水平的 miR-let-7b 和更好的空间学习，而未接受 MFB-ICSS 的 STZ 大鼠则较差。
MFB-ICSS 对 STZ 诱导的缺陷的逆转相当温和。
在 AD 样条件下，MFB-ICSS 影响空间记忆表现、海马神经退行性变以及血清 miR-let-7b 和 miR-181c 的水平。我们的结果验证了 MFB 作为 DBS 的潜在靶点，并支持使用特定的 miRNAs 作为 DBS 对抗 AD 相关认知缺陷有效性的有希望的生物标志物。
