Conner Meagan R, Jang Doyeon, Anderson Brenda J, Kritzer Mary F
Graduate Program in Neuroscience, Stony Brook University, Stony Brook, NY, United States.
Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY, United States.
Front Neurol. 2020 Sep 17;11:942. doi: 10.3389/fneur.2020.00942. eCollection 2020.
Episodic memory deficits are among the earliest appearing and most commonly occurring examples of cognitive impairment in Parkinson's disease (PD). These enduring features can also predict a clinical course of rapid motor decline, significant cognitive deterioration, and the development of PD-related dementia. The lack of effective means to treat these deficits underscores the need to better understand their neurobiological bases. The prominent sex differences that characterize episodic memory in health, aging and in schizophrenia and Alzheimer's disease suggest that neuroendocrine factors may also influence episodic memory dysfunction in PD. However, while sex differences have been well-documented for many facets of PD, sex differences in, and sex hormone influences on associated episodic memory impairments have been less extensively studied and have never been examined in preclinical PD models. Accordingly, we paired bilateral neostriatal 6-hydroxydopamine (6-OHDA) lesions with behavioral testing using the What-Where-When Episodic-Like Memory (ELM) Task in adult rats to first determine whether episodic-like memory is impaired in this model. We further compared outcomes in gonadally intact female and male subjects, and in male rats that had undergone gonadectomy-with and without hormone replacement, to determine whether biological sex and/or sex hormones influenced the expression of dopamine lesioned-induced memory deficits. These studies showed that 6-OHDA lesions profoundly impaired recall for all memory domains in male and female rats. They also showed that in males, circulating gonadal hormones powerfully modulated the negative impacts of 6-OHDA lesions on What, Where, and When discriminations in domain-specific ways. Specifically, the absence of androgens was shown to fully attenuate 6-OHDA lesion-induced deficits in ELM for "Where" and to partially protect against lesion-induced deficits in ELM for "What." In sum, these findings show that 6-OHDA lesions in rats recapitulate the vulnerability of episodic memory seen in early PD. Together with similar evidence recently obtained for spatial working memory, the present findings also showed that diminished androgen levels provide powerful, highly selective protections against the harmful effects that 6-OHDA lesions have on memory functions in male rats.
情景记忆缺陷是帕金森病（PD）中最早出现且最常见的认知障碍例子之一。这些持久的特征还可预测快速的运动功能衰退、显著的认知恶化以及与PD相关的痴呆症的发展临床进程。缺乏治疗这些缺陷的有效方法凸显了更好地了解其神经生物学基础的必要性。健康、衰老、精神分裂症和阿尔茨海默病中情景记忆所具有的显著性别差异表明，神经内分泌因素可能也会影响PD中的情景记忆功能障碍。然而，虽然PD的许多方面都有充分记录的性别差异，但相关情景记忆损伤方面的性别差异以及性激素对其的影响研究较少，且从未在临床前PD模型中进行过研究。因此，我们将双侧新纹状体6-羟基多巴胺（6-OHDA）损伤与成年大鼠使用“什么-哪里-何时”类情景记忆（ELM）任务的行为测试相结合，首先确定该模型中是否存在类情景记忆损伤。我们进一步比较了性腺完整的雌性和雄性受试者以及接受去势手术（有无激素替代）的雄性大鼠的结果，以确定生物性别和/或性激素是否会影响多巴胺损伤诱导的记忆缺陷的表达。这些研究表明，6-OHDA损伤严重损害了雄性和雌性大鼠所有记忆领域的回忆。研究还表明，在雄性大鼠中，循环性腺激素以特定领域的方式有力地调节了6-OHDA损伤对“什么”“哪里”和“何时”辨别能力的负面影响。具体而言，雄激素缺乏被证明可完全减轻6-OHDA损伤诱导的ELM中“哪里”辨别能力的缺陷，并部分预防“什么”辨别能力的损伤。总之，这些发现表明大鼠中的6-OHDA损伤重现了早期PD中情景记忆的易损性。与最近在空间工作记忆方面获得的类似证据一起，目前的研究结果还表明雄激素水平降低为6-OHDA损伤对雄性大鼠记忆功能的有害影响提供了强大、高度选择性的保护。
