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

Akt 信号传导在前额叶回路功能和认知障碍中的作用

• 批准号: 10320445
• 负责人: MICHAEL Edward CAHILL
• 金额: $ 22.66万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-18 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320445
• 关键词: AKT1 gene; AKT3 gene; Attenuated; Behavior; Behavioral; Behavioral Symptoms; Biochemical; Bipolar Disorder; Brain; Brain region; Clinical; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Complex; Data; Delusions; Dendritic Spines; Diagnosis; Disease; Disease Progression; Dominant-Negative Mutation; Etiology; Exhibits; FRAP1 gene; Functional disorder; Gene Transfer; Genetic Predisposition to Disease; Hallucinations; Haplotypes; Impaired cognition; Impairment; Individual; Manic; Mediating; Mediator of activation protein; Memory; Mental Depression; Moods; Mus; Neurobehavioral Manifestations; Neuronal Plasticity; Neurons; Neuropsychology; Onset of illness; PDPK1 gene; Pathologic; Pathway interactions; Patients; Periodicity; Phenotype; Phosphotransferases; Population; Prefrontal Cortex; Prosencephalon; Proteins; Psychoses; Recording of previous events; Regulation; Reporting; Role; Severities; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Structure; Synapses; Synaptic plasticity; Testing; Time; Transcript; Transgenic Model; Treatment Protocols; Viral; Visuospatial; Work; cognitive control; cognitive function; cohort; comparative; density; depressive symptoms; executive function; functional disability; functional plasticity; genetic variant; hippocampal pyramidal neuron; hypomania; in vivo; interest; mTOR Signaling Pathway; neuropsychiatric disorder; neuropsychiatry; novel; overexpression; protein expression; recruit; relating to nervous system; risk variant

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.

项目概要 双相情感障碍是最常见的神经精神疾病之一，但其生化改变 导致疾病发生和进展的因素仍不清楚。当周期性抑郁和躁狂/轻躁狂时 情绪状态是双相情感障碍诊断的必要条件，大多数双相情感障碍受试者也表现出 一系列认知和执行功能障碍。认知障碍的严重程度介于 个体双相情感障碍患者日常功能障碍严重程度的最佳预测因子。 研究一致发现前额皮质（PFC）功能障碍是双相情感障碍的病因 认知障碍，最近的研究表明锥体上树突棘密度的减少 神经元导致这种区域功能减退。然而，潜在的生化机制 导致双相情感障碍 PFC 破坏的因素仍然未知。我们的初步数据表明， Akt 激酶及其下游靶标 mTOR 激酶在双相情感障碍受试者的特定亚群中。 指导该提议的首要假设是 PFC 中 Akt 信号传导的减少会阻碍局部突触 结构和功能可塑性，从而直接削弱其他大脑区域的正常募集 在认知处理过程中受 PFC 的支配。使用病毒介导的基因转移，我们将过度表达 小鼠 PFC 中的显性失活 Akt (DN-Akt) 可重现我们在双相情感障碍中发现的异常 Akt 活性 紊乱科目。然后我们将确定这种在 PFC 中参与 Akt 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，使用转基因模型可以 对行为任务期间短暂激活的神经元进行永久跟踪，我们将确定 Akt 是否受到干扰 减弱自由行为小鼠认知处理过程中 PFC 神经元的参与（目标 1）。复杂的 诸如认知之类的行为始终是功能连接动态调节的产物 多个大脑区域。结合使用病毒介导的基因转移和电路追踪，我们将操纵 DN-Akt 在 PFC 和参与体验的其他大脑区域之间的特定投影中的表达 处理，并评估由此产生的对区域参与和认知的影响。这种方法将有助于 识别可能导致 Akt 活动中断的影响的大脑回路（而不仅仅是大脑区域） 病理性认知障碍（目标 2）。如果我们的假设是正确的，这些研究将暗示异常现象 PFC 中的 Akt 活性有助于四个核心临床和病理双相情感障碍相关特征， 包括：1) 认知功能障碍，2) 神经元 PFC 突触可塑性受损，3) 异常 PFC 神经群的参与/招募，以及 4) 改变 PFC 和 其他前脑区域。

项目成果

Biochemical Mechanisms that Control the Effects of RhoA Small GTPase Signaling on Synaptic Stability and Cognition.

控制 RhoA 小 GTP 酶信号传导对突触稳定性和认知影响的生化机制。

• 发表时间: 2022-05
• 作者: Bjornson, Kathryn;Cahill, Michael
• 通讯作者: Cahill, Michael

Assessing protein distribution and dendritic spine morphology relationships using structured illumination microscopy in cultured neurons.

使用结构化照明显微镜评估培养神经元中的蛋白质分布和树突棘形态关系。

• 发表时间: 2024-03-15
• 作者: Bjornson, Kathryn J;Cahill, Michael E
• 通讯作者: Cahill, Michael E

Stress-mediated dysregulation of the Rap1 small GTPase impairs hippocampal structure and function.

压力介导的 Rap1 小 GTP 酶失调会损害海马结构和功能。

• 发表时间: 2023-09-15
• 影响因子: 5.8
• 作者: Bjornson, Kathryn J;Vanderplow, Amanda M;Yang, Yezi;Anderson, Danielle R;Kermath, Bailey A;Cahill, Michael E
• 通讯作者: Cahill, Michael E