Cognitive impairment associated with androgen deprivation therapy for prostate cancer

认知障碍严重影响前列腺癌幸存者的生活质量 采用雄激素剥夺疗法(ADT)治疗。神经成像研究表明，结构和功能 内侧前额叶皮质(MPFC)和海马区(Hipp)的缺陷，它们介导着更高级别的认知 ADT后受损的过程，包括认知灵活性和空间认知。在这个项目中，我们将 研究我们现在发现的雄激素引起认知障碍的机制 对大鼠的剥夺。此外，由于目前还没有令人满意的治疗ADT后认知障碍的方法，我们 将测试伏替西汀的疗效，这是一种新型多模式抗抑郁药物，已被证明具有特定的 对抑郁症患者的认知障碍有独特的积极作用，在潜在逆转认知障碍方面 ADT之后。与SSRI类似，伏替西汀阻断5-羟色胺转运体，但它也直接作用于几个 突触前和突触后的5-羟色胺受体，使其对抑郁症症状有额外的疗效， 往往对治疗有抵抗力，包括认知障碍。评估mPFC介导的认知功能 在大鼠身上，我们将使用注意定势转移测试(AST)。并评估在空间认知中调节的 海马区(HIPP)，我们将使用新颖的对象定位(NOL)测试。我们已经证明了ADT 会导致认知定势转换的障碍。因此，在目标1A中，我们将完成初步研究，在该研究中，我们 也有初步数据显示在NOL测试中存在空间认知缺陷。此外，还有许多 在治疗前列腺癌的整个背景下需要考虑的因素。因此，在AIM 1的其余部分中，连同ADT 和伏替西汀，我们将调查包括年龄相关性认知下降在内的因素的交互影响； 另一种方法是用促性腺激素释放激素拮抗剂dearelix诱导ADT，并用多西紫杉醇化疗。 事实上，由于最近护理标准的变化，我们也将在所有后续的目标中包括多西紫杉醇。 在目标2中，我们将研究与功能可塑性有关的神经过程，这可能会削弱认知效应。 ADT和伏替西汀，测量刺激传入神经元在mPFC中诱发的电反应的变化 来自丘脑内侧背核(MDT)和腹侧HIPP的突触有效性和功能完整性的指标 大脑皮层环路。在目标3中，我们将研究与结构塑性有关的过程，测量 驱动行为的锥体细胞上树突状细胞的复杂性和突触棘密度和形态 MPFC和HIPP的输出。雄激素的作用是通过基因转录和蛋白质表达来实现的。 因此，在目标4中，我们将通过微阵列分析来评估mPFC和HIPP中基因表达的变化，然后 使用“候选因子”方法研究mRNA和蛋白质表达及磷酸化的变化 特定的可塑性相关信号分子。该项目的结果可能确定治疗的新靶点。 ADT后的认知损害，它们可能揭示伏替西汀疗效的新机制。

Cognitive impairment has a serious detrimental impact on the quality of life for prostate cancer survivors treated by androgen deprivation therapy (ADT). Neuroimaging studies have shown structural and functional deficits in the medial prefrontal cortex (mPFC) and hippocampus (Hipp), which mediate higher order cognitive processes, including cognitive flexibility and spatial cognition, that are impaired after ADT. In this project, we will investigate mechanisms that underly the cognitive impairments we have now shown to be induced by androgen deprivation in rats. Also, as there is currently no satisfactory treatment for cognitive impairment after ADT, we will test the efficacy of vortioxetine, a novel multi-modal antidepressant drug that has been shown to have specific and unique positive effects on cognitive impairment in depression, in potentially reversing cognitive impairment after ADT. Similar to SSRIs, vortioxetine blocks the serotonin transporter, but it also has direct actions on several pre- and post-synaptic serotonin receptors that give it additional efficacy against symptoms of depression that are often resistant to treatment, including cognitive impairment. To assess mPFC-mediated cognitive function in rats, we will use the Attentional Set-shifting Test (AST). And to assess spatial cognition mediated in the hippocampus (Hipp), we will use the Novel Object Location (NOL) test. We have already shown that ADT induces an impairment in cognitive set-shifting. Thus in aim 1A, we will complete the pilot study in which we have preliminary data showing a spatial cognition deficit in the NOL test as well. In addition, there are many factors to consider in the full context of treating prostate cancer. Thus, in the rest of aim 1, together with ADT and vortioxetine, we will investigate the interacting influences of factors including age-related cognitive decline; an alternate method of inducing ADT with the GnRH antagonist degarelix; and chemotherapy with docetaxel. Indeed, because of recent changes to standard of care, we will also include docetaxel in all subsequent aims. In aim 2, we will then study neural processes related to functional plasticity that may underly the cognitive effects of ADT and vortioxetine, measuring changes in electrical response evoked in mPFC by stimulating afferents from the mediodorsal thalamus (MDT) and ventral Hipp, an indication of synaptic efficacy and functional integrity of cortical circuits. In aim 3, we will study processes related to structural plasticity, measuring changes in dendritic complexity and synaptic spine density and morphology on pyramidal cells that drive the behavioral output of the mPFC and Hipp. Effects of androgens are mediated by gene transcription and protein expression. Thus, in aim 4, we will assess changes in gene expression in the mPFC and Hipp by microarray analysis, then use a “candidate factor” approach to investigate changes in mRNA and protein expression and phosphorylation of specific plasticity-related signaling molecules. The results of this project may identify new targets for treating cognitive impairment after ADT, and they may reveal new mechanisms underlying the efficacy of vortioxetine.