Cognitive impairment associated with androgen deprivation therapy for prostate cancer

认知障碍对前列腺癌幸存者的生活质量有严重的不利影响 雄激素剥夺治疗（ADT）。神经影像学研究显示， 内侧前额叶皮层（mPFC）和海马（Hipp）的缺陷，介导高级认知功能 过程，包括认知灵活性和空间认知，在ADT后受损。在这个项目中，我们将 研究雄激素诱导的认知障碍的机制 剥夺老鼠此外，由于目前还没有令人满意的ADT后认知障碍治疗方法，我们 将测试沃替西汀的疗效，沃替西汀是一种新型的多模式抗抑郁药，已被证明具有特异性 对抑郁症的认知障碍有独特的积极作用， ADT之后。与SSRIs类似，沃替西汀阻断血清素转运体，但它也对几种 突触前和突触后的5-羟色胺受体，使其对抑郁症状有额外的疗效， 通常对治疗有抵抗力，包括认知障碍。评估mPFC介导的认知功能 在大鼠中，我们将使用注意定势转换测试（AST）。并评估空间认知介导的 在海马体（Hipp）中，我们将使用新对象定位（NOL）测试。我们已经证明，ADT 会导致认知定势转换障碍因此，在目标1A中，我们将完成试点研究， 初步数据显示，在NOL测试中也存在空间认知缺陷。此外还有很多 在治疗前列腺癌的整个背景下要考虑的因素。因此，在目标1的其余部分中，与ADT一起， 和沃替西汀，我们将调查因素的相互影响，包括年龄相关的认知能力下降; 另一种诱导ADT的方法是使用GnRH拮抗剂地塞普利;以及使用多西他赛进行化疗。 事实上，由于最近标准治疗的变化，我们也将多西他赛纳入所有后续目标。 在目标2中，我们将研究与认知效应相关的功能可塑性神经过程 ADT和沃替西汀，测量刺激传入神经引起的mPFC电反应的变化 从内侧背丘脑（MDT）和腹侧海马，一个突触的功效和功能完整性的指示 大脑皮层回路在目标3中，我们将研究与结构可塑性相关的过程，测量 树突的复杂性和突触棘的密度和形态的锥体细胞，驱动的行为 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介导的。 因此，在目标4中，我们将通过微阵列分析评估mPFC和Hipp中基因表达的变化， 使用“候选因子”方法研究mRNA和蛋白质表达和磷酸化的变化 与可塑性相关的信号分子。该项目的结果可能会确定新的治疗目标， ADT后认知障碍，他们可能揭示沃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.