Singewald Nicolas
Department of Pharmacology & Toxicology, Institute of Pharmacy and Center of Molecular Biosciences, University of Innsbruck, A-6020 Innsbruck, Austria.
Neurosci Biobehav Rev. 2007;31(1):18-40. doi: 10.1016/j.neubiorev.2006.02.003. Epub 2006 Apr 18.
Pathological anxiety involves aberrant processing of emotional information that is hypothesized to reflect perturbations in fear/anxiety pathways. The affected neurobiological substrates in patients with different anxiety disorders are just beginning to be revealed. Important leads for this research can be derived from findings obtained in psychopathologically relevant rodent models of enhanced anxiety, by revealing where in the brain neuronal processing in response to diverse challenges is different to that in animals with lower anxiety levels. Different functional mapping methods in various rodent models, including psychogenetically selected lines or genetically modified animals, have been used for this purpose. These studies show that the divergent anxiety-related behavioral response of high-anxiety- vs. normal and/or low-anxiety rodents to emotional challenges is associated with differential neuronal activation in restricted parts of proposed fear/anxiety circuitries including brain areas thought to be important in stress, emotion and memory. The identification of neuronal populations showing differential activation depends in part on the applied emotional challenge, indicating that specific facets of elicited fear or anxiety preferentially engage particular parts of the fear/anxiety circuitry. Hence, only the use of an array of different challenges will reveal most affected brain areas. A number of the neuronal substrates identified are suggested as candidate mediators of dysfunctional brain activation in pathological anxiety. Indeed, key findings revealed in these rodent models show parallels to observations in human symptom provocation studies comparing anxiety disorder patients with healthy volunteers. Work to investigate exactly which of the changed neuronal activation patterns in high-anxiety rodents has to be modulated by therapeutic drugs to achieve effective anxiolysis and via which neurochemical pathways this can be accomplished is at its early stages but has identified a small number of promising candidates. Extending these approaches should help to provide further insight into these mechanisms, revealing new leads for therapeutic targets and strategies.
病理性焦虑涉及情绪信息的异常处理，据推测这反映了恐惧/焦虑通路的紊乱。不同焦虑症患者受影响的神经生物学底物才刚刚开始被揭示。这项研究的重要线索可以从在焦虑增强的心理病理学相关啮齿动物模型中获得的发现中得出，通过揭示大脑中对各种挑战的神经元处理在何处与焦虑水平较低的动物不同。为此，在各种啮齿动物模型中使用了不同的功能映射方法，包括心理遗传学选择的品系或基因改造动物。这些研究表明，高焦虑与正常和/或低焦虑啮齿动物对情绪挑战的不同焦虑相关行为反应与拟议的恐惧/焦虑回路受限部分的不同神经元激活有关，这些回路包括被认为在压力、情绪和记忆中很重要的脑区。显示不同激活的神经元群体的识别部分取决于所应用的情绪挑战，这表明引发的恐惧或焦虑的特定方面优先涉及恐惧/焦虑回路的特定部分。因此，只有使用一系列不同的挑战才能揭示受影响最大的脑区。一些被确定的神经元底物被认为是病理性焦虑中大脑激活功能失调的候选介质。事实上，这些啮齿动物模型中揭示的关键发现与比较焦虑症患者和健康志愿者的人类症状激发研究中的观察结果相似。研究哪些高焦虑啮齿动物中改变的神经元激活模式必须通过治疗药物进行调节才能实现有效的抗焦虑作用以及通过哪些神经化学途径可以实现这一目标的工作尚处于早期阶段，但已经确定了少数有希望的候选者。扩展这些方法应该有助于进一步深入了解这些机制，揭示治疗靶点和策略的新线索。
