The role of Akt signaling in prefrontal circuit function and cognitive impairment

项目总结 双相情感障碍是最常见的神经精神障碍之一，然而 导致该病发生和发展的原因尚不清楚。而周期性抑郁和躁狂/低躁狂 情绪状态是诊断双相情感障碍的必要条件，大多数双相情感障碍受试者也表现出 认知和执行功能障碍的星座。认知障碍的程度是 个体双相情感障碍患者日常功能损害严重程度的最佳预测因子。 研究一直认为双相情感障碍的病因是前额叶皮质(PFC)功能障碍 认知障碍，最近的研究表明，锥体上树突棘密度的减少 神经元是这种局部功能减退的原因。然而，潜在的生化机制 导致双相情感障碍的PFC干扰仍不清楚。我们的初步数据显示， Akt激酶及其下游靶点mTOR激酶，在双相情感障碍受试者的特定子集中。 指导这一提议的最重要的假设是，PFC中Akt信号的减少阻碍了局部突触 结构和功能的可塑性，从而直接减弱其他脑区的正常招募 在认知加工过程中被PFC所支配。使用病毒介导的基因转移，我们将过度表达 小鼠PFC中显性-负性Akt(dN-Akt)以复制我们在双相中发现的异常Akt活性 无序受试者。然后，我们将确定这种在PFC中与Akt接触的能力受损是否足以导致 突触结构和功能可塑性的改变。此外，使用转基因模型，允许 对行为任务中短暂激活的神经元的永久跟踪，我们将确定Akt中断 在自由行为小鼠的认知过程中减弱PFC神经元的参与(目标1)。复合体 像认知这样的行为总是动态调节功能之间连通性的产物 多个脑区。使用病毒介导的基因转移和电路追踪的组合，我们将操纵 DN-Akt在PFC与其他经验性脑区的特定投射中的表达 处理，并评估由此对区域参与和认知产生的影响。这种方法会有所帮助。 确定可能导致Akt活动中断的大脑回路(而不仅仅是大脑区域) 关于病理性认知障碍(目标2)。如果我们的假设是正确的，这些研究将牵连异常 AKT在PFC中的活性有助于临床和病理性双相情感障碍的四个核心特征， 包括：1)认知功能障碍，2)神经元PFC突触可塑性受损，3)异常 参与/招募PFC神经群体，以及4)改变PFC和PFC之间的功能连接 其他前脑区域。

PROJECT SUMMARY Bipolar disorder is one of the most common neuropsychiatric disorders, yet the biochemical alterations that contribute to the disease onset and progression remain unknown. While cyclic depressive and manic/hypomanic mood states are requisite for bipolar disorder diagnosis, the majority of bipolar disorder subjects also exhibit a constellation of cognitive and executive function impairments. The magnitude of cognitive impairment is among the best predictors of the severity of day-to-day functional impairment in individual bipolar disorder patients. Studies have consistently identified dysfunction of the prefrontal cortex (PFC) in the etiology of bipolar disorder cognitive impairments, and recent work suggests that a reduction in the density of dendritic spines on pyramidal neurons contributes to this regional hypofunction. Nevertheless, the biochemical mechanisms that potentially contribute to bipolar disorder PFC disruption remain unknown. Our preliminary data identify a loss of activity in the Akt kinase and its downstream target, the mTOR kinase, in a specific subset of bipolar disorder subjects. The overarching hypothesis guiding this proposal is that reduced Akt signaling in the PFC impedes local synaptic structural and functional plasticity thereby attenuating the normal recruitment of other brain regions directly innervated by the PFC during cognitive processing. Using viral-mediated gene transfer we will overexpress dominant-negative Akt (DN-Akt) in the PFC of mice to reproduce the aberrant Akt activity we identified in bipolar disorder subjects. We will then determine if this impaired ability to engage Akt in the PFC is sufficient to cause alterations in synaptic structural and functional plasticity. Further, using a transgenic model that allows for the permanent tracking of neurons transiently activated during behavioral tasks, we will determine if Akt disruption attenuates PFC neuronal engagement during cognitive processing in freely behaving mice (Aim 1). Complex behaviors such as cognition are invariably the product of dynamic regulations in functional connectivity between multiple brain regions. Using a combination of viral-mediated gene transfer and circuit tracing, we will manipulate the expression of DN-Akt in specific projections between the PFC and other brain regions involved in experiential processing, and assess the resulting effects on regional engagement and cognition. This approach will help identify possible brain circuits (rather than just brain regions) that contribute to the effects of disrupted Akt activity on pathological cognitive impairment (Aim 2). If our hypothesis are correct, these studies will implicate aberrant Akt activity in the PFC in contributing to four core clinical and pathological bipolar disorder-relevant features, including: 1) cognitive dysfunction, 2) impaired neuronal PFC synaptic plasticity, 3) aberrant engagement/recruitment of PFC neural populations, and 4) altered functional connectivity between the PFC and other forebrain regions.