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akt1缺乏症的多巴胺（DA）神经元特异性模型上。我们的目标是确定不同神经精神疾病（包括抑郁症和成瘾）中病理改变的Akt信号的趋同发现是否与功能相关。为了揭示可能影响抑郁样行为和成瘾行为的Akt信号受损的共同特征，我们将首先在akt1突变小鼠和基因对照中使用社会失败范式诱导抑郁样行为。然后，应激小鼠将被暴露在精神兴奋剂可卡因中。通过结合akt1突变小鼠的抑郁和成瘾相关行为范式，我们将测试应激是否会进一步增强由于遗传缺陷导致的Akt信号损伤，从而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药物滥用操纵大脑回路的基本分子机制，并解释由于压力导致的疾病相关遗传变异和Akt信号的获得性损伤如何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共同危险因素的理解。

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. PUBLIC HEALTH RELEVANCE: Drug addiction is a significant but preventable health concern; however, once the addiction process has been initiated, reversing it is difficult. Understanding the biological substrates of addiction is therefore of critical importance. This project is focused on the Akt kinase intracellular signaling pathway and builds on biochemical and genetic findings of impaired AKT1 signaling in neuropsychiatric disorders with high comorbidity for addiction. To model impaired Akt signaling, we will study genetically-modified models of altered Akt1 signaling in the mouse brain with an emphasis on examining Akt1 deficiency as a possible risk and vulnerability factor in determining behavioral responsiveness to cocaine.