Akt Signaling at the Crossroads of Depression and Addiction

描述（由申请人提供）：我们的项目建立在小鼠大脑中Akt1缺陷的多巴胺（DA）神经元特异性模型上。我们的目标是确定在不同的神经精神疾病，包括抑郁症和成瘾病理改变Akt信号的会聚结果是否在功能上相关。为了揭示可能影响抑郁样和成瘾行为的Akt信号转导受损的共同特征，我们将首先使用社会失败范式在Akt1突变小鼠和同类对照中诱导抑郁样行为。然后将应激小鼠暴露于精神兴奋剂可卡因。通过在Akt1突变小鼠中结合抑郁症和成瘾相关的行为范例，我们将测试由于遗传缺陷导致的Akt信号传导受损是否会通过应激进一步增强，以增强对可卡因的行为反应。我们的实验结果将确定可卡因和其他滥用药物操纵大脑回路的基本分子机制，并解释疾病相关的遗传变异和Akt信号传导中的后天损伤如何由于压力增加对其影响的易感性。DA神经元中这一关键信号通路的功能表征对于开发用于成瘾、抑郁和其他神经精神疾病的风险评估和治疗的生物标志物和方法具有重要潜力，并提高了对神经精神疾病中共有的常见风险因素的理解。

DESCRIPTION (provided by applicant): Our project builds on dopamine (DA) neuron-specific models of Akt1-deficiency in the mouse brain. Our goal is to determine if converging findings of pathologically altered Akt signaling in different neuropsychiatric disorders including depression and addiction are functionally related. To reveal common features of impaired Akt signaling that may impact on depression-like and addictive behaviors, we will first use the social defeat paradigm to induce depression-like behaviors in Akt1-mutant mice and congenic controls. Stressed mice will then be exposed to the psychostimulant cocaine. By combining depression- and addiction-related behavioral paradigms in Akt1-mutant mice, we will test whether impairment of Akt signaling due to genetic deficits is further enhanced by stress to augment behavioral responsiveness to cocaine. Results from our experiments will identify fundamental molecular mechanisms by which cocaine and other drugs of abuse manipulate brain circuitry, and explain how disease-related genetic variations and acquired impairments in Akt signaling due to stress increase susceptibility to their effects. The functional characterization of this pivotal signaling pathway in DA neurons holds significant potential for the development of biomarkers and approaches for risk assessment and treatment of addiction, depression and other neuropsychiatric disorders, and improves the understanding of common risk factors shared among neuropsychiatric disorders.