Mechanism underlying cognitive and synaptic flexibility

认知和突触灵活性的潜在机制

基本信息

批准号：
10305632
负责人：
Hongbing Wang
金额：
$ 48.79万
依托单位：
MICHIGAN STATE UNIVERSITY
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：
2020-12-01 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10305632
关键词：
Address Adenylate Cyclase Adult Affect Attenuated Automobile Driving Behavioral Brain Cells Chemosensitization Cognition Cognitive Cognitive deficits Computer Analysis Cues Cyclic AMP Data Dependence Frequencies Gene Expression Profile Genetic Glycogen Synthase Kinase 3 Hippocampus (Brain)Homosynaptic Depression Hyperactivity Impaired cognition Impairment Knockout Mice Knowledge Label Learning Light Link Long-Term Depression Long-Term Potentiation LoxP-flanked allele Maps Mediating Memory Memory impairment Mental Health Mental disorders Molecular Molecular Target Mood Disorders Mouse Strains Mus Neuronal Plasticity Neurons Neurophysiology - biologic function Optics Outcome Outcome Study Phosphotransferases Proto-Oncogene Proteins c-akt Reversal Learning Role Signal Transduction Synapses Synaptic plasticity System Therapeutic Transgenic Mice Update base cell type cognitive function conditional knockout conditioned fear daily functioning environmental change fear memory flexibility glycogen synthase kinase 3 beta hippocampal pyramidal neuron insight mouse model neurotransmission optogenetics patient population patient subsets restoration spatial memory spatiotemporal synaptic depression targeted treatment therapeutic target tool trait transcriptome whole genome

项目摘要

Abstract/Summary As a functionally important aspect of cognitive flexibility, reversal learning leads to inhibition/suppression of the previously established memory. Effective reversal learning is fundamental for information updating and essential for adaptation to changing environmental cues. Regarding its impact on mental health, deficits in cognitive flexibility and reversal learning are prevalent in psychological and mood disorders, and are considered as an emerging therapeutic target. However, there is limited understanding of mechanisms underlying cognitive flexibility. Our recent experimental data revealed that, contrary to the previously recognized role of cAMP signaling in regulating broad spectrum of learning and memory, type 8 adenylyl cyclase (ADCY8) specifically regulates the activity-dependent suppression of old memory following reversal learning. With our recently developed Adcy8 conditional knockout mice, we will determine the effects of region- and cell type-specific ADCY8 deficiency on synaptic and cognitive flexibility: reversal/suppression of the previously established synaptic potentiation (i.e. depotentiation) and reversal/suppression of the previously established memory. Further, computational analysis with transcriptome landscape predicts that the PI3K (phosphatidylinositide 3-kinase)/Akt (protein kinase B)-GSK3β (glycogen synthase kinase 3β) signaling cascade is the molecular substrate of ADCY8. We will determine whether restoration of the ADCY8-PI3K/Akt-GSK3β signaling cascade causally corrects the defective synaptic depotentiation and reversal/suppression of old memory. Finally, we will determine the causal effect of synaptic depotentiation on old memory suppression and its dependency on the ADCY8-PI3K/Akt-GSK3b signaling cascade. Considering that there are 10 different ADCYs in mammalian system, the outcome of this project will delineate a unique of role of ADCY8 in regulating a specific domain of cAMP signaling that is functionally linked to cognitive and synaptic flexibility. We also expect that the mechanisms learned from this study may suggest targeted therapeutic strategies to attenuate reversal learning deficits in certain patient population with altered cAMP-PI3K/Akt-GSK3β signaling.

摘要/摘要作为认知灵活性在功能上重要的方面，反向学习导致抑制/抑制先前建立的记忆。有效的逆转学习对于信息更新至关重要，对于适应更改至关重要环境提示。将其对心理健康的影响，认知灵活性缺陷反向学习在心理和情绪障碍中很普遍，并且是被认为是新兴的治疗靶标。但是，理解有限认知灵活性的基础机制。我们最近发现的实验数据这与以前认可的cAMP信号在调节广泛中的作用形成鲜明对比学习和记忆的范围，类型8 adenylyl环化酶（ADCY8）反向学习后，调节了对旧记忆的活动依赖性抑制。通过我们最近开发的ADCY8条件敲除小鼠，我们将确定区域和细胞类型特异性ADCY8缺乏对突触和认知的影响灵活性：逆转/抑制先前建立的突触电位（即电源）和对先前建立的内存的反转/抑制。更远，带有转录组景观的计算分析预测PI3K （磷脂酰肌醇3-激酶）/Akt（蛋白激酶B）-GSK3β（糖原合酶激酶3β）信号传导级联反应是ADCY8的分子底物。我们将确定是否恢复ADCY8-PI3K/AKT-GSK3β信号传导级联因果纠正突触沉积和反转/抑制旧记忆的缺陷。最后，我们将确定突触沉积对旧记忆的因果影响抑制及其对ADCY8-PI3K/AKT-GSK3B信号级联的依赖性。考虑到哺乳动物系统中有10种不同的adcys，结果该项目将描述ADCY8在调节中的独特角色与认知和突触灵活性有关的cAMP信号传导。我们也是期望从这项研究中学到的机制可能表明有针对性的治疗性减轻某些患者群体的逆转学习缺陷的策略 CAMP-PI3K/AKT-GSK3β信号传导。