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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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘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，导致疾病的发生和进展仍然未知。而周期性抑郁和躁狂/轻躁狂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认知和执行功能障碍的集合。认知障碍的程度是是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。研究已经一致确定功能障碍的前额叶皮层（PFC）的病因双相情感障碍认知障碍，最近的工作表明，在锥体细胞上树突棘密度的减少，神经元导致了这种区域性功能减退。然而，潜在的生化机制，导致双相情感障碍PFC破坏的原因尚不清楚。我们的初步数据表明， 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亚群中的作用。指导这一提议的主要假设是PFC中Akt信号的减少阻碍了局部突触的形成。结构和功能的可塑性，从而直接减弱其他脑区的正常募集在认知过程中受到前额叶皮层的支配使用病毒介导的基因转移，显性负性Akt（DN-Akt）在小鼠PFC重现异常Akt活性，我们确定在双相情感障碍，紊乱的主题然后，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，使用允许在小鼠体内表达的转基因模型，永久跟踪行为任务期间短暂激活的神经元，我们将确定Akt是否中断在自由行为小鼠的认知过程中减弱PFC神经元的参与（Aim 1）。复杂行为，如认知，总是功能连接的动态调节的产物，多个大脑区域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和其他参与经验性认知的脑区之间的特定投射中的表达，处理，并评估对区域参与和认知的影响。这种方法将有助于确定可能的大脑回路（而不仅仅是大脑区域），这些回路有助于破坏Akt活动的影响病理性认知障碍（Aim 2）。如果我们的假设是正确的，这些研究将表明 PFC中的Akt活性促成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）PFC和其他前脑区域。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

DOI：
10.1016/j.xpro.2023.102829
发表时间：
2024-03-15
期刊：
STAR PROTOCOLS
影响因子：
0
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.

DOI：
10.1016/j.isci.2023.107566
发表时间：
2023-09-15
期刊：
ISCIENCE
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.

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。