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.

项目摘要躁郁症是最常见的神经精神疾病之一，但生化改变是有助于疾病发作和进展仍然未知。循环抑郁和躁狂/躁狂情绪状态是躁郁症诊断所必需的，大多数躁郁症受试者也表现出认知和执行功能障碍的星座。认知障碍的大小是单个躁郁症患者日常功能障碍严重程度的最佳预测因素。研究一直鉴定出双相情感障碍病因的前额叶皮层（PFC）的功能障碍认知障碍和最近的工作表明，锥体上的树突状刺密度降低神经元有助于这种区域功能障碍。然而，潜在的生化机制导致双相情感障碍PFC破坏仍然未知。我们的初步数据确定了活动损失 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子集中。指导该提议的总体假设是PFC中的AKT信号降低阻碍了局部突触结构和功能可塑性，从而直接衰减其他大脑区域的正常募集在认知处理过程中由PFC支配。使用病毒介导的基因转移我们将过表达小鼠PFC中的主要阴性AKT（DN-AKT），以重现我们在双极的异常AKT活性疾病主题。然后，我们将确定这种参与PFC参与AKT的能力是否足以引起突触结构和功能可塑性的改变。此外，使用允许的转基因模型在行为任务期间暂时激活神经元的永久跟踪，我们将确定AKT是否破坏自由行为的小鼠认知过程中PFC神经元参与度减弱（AIM 1）。复杂的诸如认知之类的行为始终是动态法规在功能连通性中的产物多个大脑区域。使用病毒介导的基因转移和电路跟踪的组合，我们将操纵 DN-AKT在PFC和其他大脑区域之间的特定投影中的表达处理，并评估对区域参与和认知的影响。这种方法将有所帮助确定可能有助于破坏AKT活动的影响的可能的脑电路（而不是大脑区域）关于病理认知障碍（AIM 2）。如果我们的假设正确，这些研究将暗示异常 PFC中的AKT活性导致了四个核心临床和病理躁郁症的特征，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神经种群的参与/招募，以及4）PFC和PFC之间的功能连接改变其他前脑区域。

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。