Feehan S M, Kritzer M F
Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY, United States.
Front Behav Neurosci. 2025 Sep 2;19:1646733. doi: 10.3389/fnbeh.2025.1646733. eCollection 2025.
Parkinson's disease (PD) is characterized by non-motor impairments including symptoms anxiety. These disturbances manifest in up to 40% of patients, most often early in the course of disease. While disruptive to all patients' lives, signs of anxiety are also more prevalent and/or more severe in female PD patients. Unfortunately, anxiolytic drugs are rarely used to manage these signs, as these medications can increase PD patients' risks for worsening of cognitive deficits and falls. The treatments commonly used in PD to improve patients' motor function or lessen signs of depression are often without positive effect on measures of anxiety. Thus, clinical needs for successful treatment of anxiety symptoms in PD are frequently unmet.
The work presented here used longitudinal Elevated Plus Maze (EPM) testing in male and female wild type rats and in male and female rats with knockout of the PTEN-induced putative kinase 1 gene ( ) to determine whether these are suitable models for translational studies examining the neural substrates that underpin the sex-specific expression of anxiety symptoms in PD.
Behavioral testing in male and female wild type and rats showed that rats of both biological sex initially displayed hyperlocomotion and broad, possibly impulsive exploration of all portions of the elevated plus maze, including its open, unprotected spaces. While these behaviors persisted in males, by 7 months of age, EPM performance in female rats changed dramatically and included convergent behavioral measures indicative of significantly heightened anxiety, e.g., reduced open arm entries, slower speeds of ambulation in open arms, avoidance of distal ends of open arms. These and other signs of an anxiety remained through final testing of the female cohort at 12 months of age.
Unlike a surprising number of other rodent models of PD that fail to emulate clinically observed anxiety and/or male/female differences in these signs, the data presented here identify rats as strongly suited to lead translational efforts to better understand the neurobiological and neuroendocrine bases for anxiety symptoms in PD, their sex differences and their sex-specific sensitivities to therapeutic interventions.
帕金森病（PD）的特征包括非运动障碍，其中焦虑症状较为常见。这些干扰在高达40%的患者中出现，最常出现在疾病进程的早期。虽然这些症状会对所有患者的生活造成影响，但焦虑症状在女性PD患者中更为普遍和/或更为严重。不幸的是，抗焦虑药物很少用于控制这些症状，因为这些药物会增加PD患者认知功能恶化和跌倒的风险。PD中常用的改善患者运动功能或减轻抑郁症状的治疗方法，通常对焦虑症状没有积极影响。因此，PD中成功治疗焦虑症状的临床需求常常得不到满足。
本研究采用纵向高架十字迷宫（EPM）测试，对雄性和雌性野生型大鼠以及雄性和雌性PTEN诱导的假定激酶1基因敲除大鼠进行测试，以确定这些模型是否适合用于转化研究，以探究帕金森病中焦虑症状性别特异性表达的神经基础。
对雄性和雌性野生型大鼠以及敲除大鼠的行为测试表明，两种性别的敲除大鼠最初均表现出运动亢进，对高架十字迷宫的所有部分，包括开放、无保护的空间进行广泛、可能是冲动性的探索。虽然这些行为在雄性敲除大鼠中持续存在，但到7个月大时，雌性敲除大鼠的EPM表现发生了显著变化，包括一些行为指标表明焦虑显著增加，例如进入开放臂的次数减少、在开放臂中的行走速度减慢、避开开放臂的远端。这些以及其他焦虑迹象在12个月大时对雌性敲除大鼠的最终测试中仍然存在。
与许多其他未能模拟临床上观察到的焦虑和/或这些症状的性别差异的PD啮齿动物模型不同，本文所呈现的数据表明敲除大鼠非常适合引领转化研究，以更好地理解PD中焦虑症状的神经生物学和神经内分泌基础、它们的性别差异以及它们对治疗干预的性别特异性敏感性。
