Akt Signaling at the Crossroads of Depression and Addiction

描述(申请人提供)：我们的项目建立在小鼠大脑中Akt1缺乏的多巴胺(DA)神经元特异性模型上。我们的目标是确定在包括抑郁症和成瘾在内的不同神经精神障碍中，Akt信号病理改变的趋同结果是否在功能上相关。为了揭示Akt信号受损可能影响抑郁样行为和成瘾行为的共同特征，我们将首先使用社会失败范式在Akt1突变小鼠和同源对照小鼠中诱导抑郁样行为。然后，应激小鼠将暴露在精神刺激剂可卡因中。通过结合Akt1突变小鼠中与抑郁和成瘾相关的行为范式，我们将测试由于遗传缺陷造成的Akt信号损害是否因应激而进一步增强，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电路的基本分子机制，并解释与疾病相关的遗传变异和因应激导致的Akt信号获得性损害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特征对于开发生物标记物和风险评估以及治疗成瘾、抑郁和其他神经精神障碍的方法具有重要的潜力，并提高了对神经精神疾病共同危险因素的理解。 与公共卫生相关：吸毒成瘾是一个重大但可预防的健康问题；然而，一旦成瘾过程启动，就很难扭转这种状况。因此，了解成瘾的生物学基础至关重要。这个项目是专注于 并建立在AKT1信号通路受损的生化和遗传学结果的基础上，这些AKT1信号受损的神经精神疾病与成瘾的高共患率有关。为了模拟Akt信号受损，我们将研究小鼠大脑中Akt1信号改变的转基因模型，重点检查Akt1缺乏作为确定行为对可卡因反应的可能风险和脆弱因素。

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.