Aslan Julia, Reinhardt Patrick R, Koch Jennifer, Sonntag Kai-Christian, Freund Nadja
Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL-University Hospital, Ruhr-University Bochum.
Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL-University Hospital, Ruhr-University Bochum; International Graduate School of Neuroscience, Ruhr-University Bochum.
J Vis Exp. 2025 May 2(219). doi: 10.3791/68307.
Bipolar disorder is a mental health condition characterized by extreme mood swings, including periods of emotional highs (mania) and lows (depression). While the exact underlying neurobiology is not yet fully understood, imbalances in neurotransmitter systems, particularly dopamine, appear to play a central role. For this reason, manipulations of dopaminergic pathways have been used to model mania or depression in rodents. However, models that accurately represent the typical switch between these two episodes are rare, limiting face validity. In a unique model, modern techniques are used to temporarily increase dopamine D1 receptor expression, which has been implicated in the pathology of bipolar disorder. A tetracycline-inducible lentiviral construct that expresses the dopamine D1 receptor under the control of the calmodulin kinase II alpha promoter is stereotactically injected into the medial prefrontal cortex of adult rats. Dopamine D1 receptor overexpression is achieved by adding the tetracycline analog doxycycline to the animals' drinking water, leading to an increase in reward-related, impulsive, and risk-taking behaviors and a decrease in anxiety. These behaviors resemble a mania-like phenotype. By removing doxycycline from the drinking water, a depressive-like phenotype, characterized by increased helplessness and anhedonia, can be induced within the same animal. This article provides a step-by-step protocol for performing the surgery, as well as procedures for inducing the bipolar disorder-like phenotype. Additionally, considerations for assessing behavioral changes associated with mania-like and depressive-like behavior are described. This promising model, which demonstrates good construct and face validity, offers a valuable tool for further investigating the pathophysiological mechanisms of bipolar disorder.
双相情感障碍是一种心理健康状况，其特征是情绪极端波动，包括情绪高涨（躁狂）和低落（抑郁）期。虽然确切的潜在神经生物学机制尚未完全了解，但神经递质系统失衡，尤其是多巴胺失衡，似乎起着核心作用。因此，对多巴胺能通路的操纵已被用于在啮齿动物中模拟躁狂或抑郁。然而，能够准确呈现这两种发作之间典型转换的模型很少，限制了表面效度。在一个独特的模型中，现代技术被用于暂时增加多巴胺D1受体的表达，该受体与双相情感障碍的病理机制有关。一种在钙调蛋白激酶IIα启动子控制下表达多巴胺D1受体的四环素诱导慢病毒构建体被立体定向注射到成年大鼠的内侧前额叶皮质。通过在动物饮用水中添加四环素类似物强力霉素来实现多巴胺D1受体的过表达，这会导致与奖励相关、冲动和冒险行为增加，焦虑减少。这些行为类似于躁狂样表型。通过从饮用水中去除强力霉素，可以在同一只动物中诱导出以无助感和快感缺失增加为特征的抑郁样表型。本文提供了进行手术的分步方案，以及诱导双相情感障碍样表型的程序。此外，还描述了评估与躁狂样和抑郁样行为相关的行为变化的注意事项。这个有前景的模型具有良好的结构效度和表面效度，为进一步研究双相情感障碍的病理生理机制提供了一个有价值的工具。
