Department of Pharmacology, Medical University of Innsbruck, Peter Mayr Strasse 1A, 6020 Innsbruck, Austria.
Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, National Institutes of Health, MD, USA.
Neurobiol Dis. 2019 May;125:55-66. doi: 10.1016/j.nbd.2019.01.009. Epub 2019 Jan 21.
Parkinson's disease (PD) presents with a constellation of non-motor symptoms, notably increased anxiety, which are currently poorly treated and underrepresented in animal models of the disease. Human post-mortem studies report loss of catecholaminergic neurons in the pre-symptomatic phases of PD when anxiety symptoms emerge, and a large literature from rodent and human studies indicate that catecholamines are important mediators of anxiety via their modulatory effects on limbic regions such as the amygdala. On the basis of these observations, we hypothesized that anxiety in PD could result from an early loss of catecholaminergic inputs to the amygdala and/or other limbic structures. To interrogate this hypothesis, we bilaterally injected the neurotoxin 6-OHDA in the mouse basolateral amygdala (BL). This produced a restricted pattern of catecholaminergic (tyrosine-hydroxylase-labeled) denervation in the BL, intercalated cell masses and ventral hippocampus, but not the central amygdala or prefrontal cortex. We found that this circuit-specific lesion did not compromise performance on multiple measures of motor function (home cage, accelerating rotarod, beam balance, pole climbing), but did increase anxiety-like behavior in the elevated plus-maze and light-dark exploration tests. Fear behavior in the pavlovian cued conditioning and passive avoidance assays was, by contrast, unaffected; possibly due to preservation of catecholamine innervation of the central amygdala from the periaqueductal gray. These data provide some of the first evidence implicating loss of catecholaminergic neurotransmission in midbrain-amygdala circuits to increased anxiety-like behavior. Our findings offer an initial step towards identifying the neural substrates for pre-motor anxiety symptoms in PD.
帕金森病（PD）表现出一系列非运动症状，尤其是焦虑增加，目前这些症状治疗效果不佳，并且在疾病的动物模型中代表性不足。人类尸检研究报告称，在 PD 的症状出现前的无症状阶段，儿茶酚胺能神经元丧失，并且来自啮齿动物和人类研究的大量文献表明，儿茶酚胺通过对杏仁核等边缘区域的调制作用是焦虑的重要介质。基于这些观察结果，我们假设 PD 中的焦虑可能是由于蓝斑核中儿茶酚胺传入的早期丧失以及对其他边缘结构的影响。为了探究这一假设，我们在小鼠蓝斑核的双侧注射神经毒素 6-OHDA。这导致蓝斑核、中间细胞群和腹侧海马中的儿茶酚胺（酪氨酸羟化酶标记）去神经支配呈现出受限的模式，但不包括中央杏仁核或前额叶皮层。我们发现，这种特定于回路的损伤不会影响多项运动功能测量（笼内、加速旋转棒、平衡棒、杆攀爬）的表现，但会增加高架十字迷宫和明暗探索测试中的焦虑样行为。相比之下，在条件性恐惧和被动回避测试中，恐惧行为没有受到影响；这可能是由于中脑-杏仁核回路中的儿茶酚胺传入保留了来自导水管周围灰质的支配。这些数据提供了一些初步证据，表明中脑-杏仁核回路中儿茶酚胺神经传递的丧失与焦虑样行为增加有关。我们的发现为确定 PD 中运动前焦虑症状的神经基础提供了初步步骤。
