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/总结作为认知灵活性的一个功能上重要的方面，逆向学习会导致抑制/抑制先前建立的记忆。是信息更新的基础，也是适应变化的关键关于其对心理健康的影响、认知灵活性缺陷。逆向学习在心理和情绪障碍中普遍存在，并且被认为是一个新兴的治疗靶点，但人们的了解还有限。我们最近的实验数据揭示了认知灵活性的机制。与之前认识到的 cAMP 信号在广泛调节中的作用相反学习和记忆谱，特别是 8 型腺苷酸环化酶 (ADCY8) 调节逆转学习后旧记忆的活动依赖性抑制。利用我们最近开发的 Adcy8 条件敲除小鼠，我们将确定区域和细胞类型特异性 ADCY8 缺陷对突触和认知的影响灵活性：逆转/抑制先前建立的突触增强（即去势）和先前建立的记忆的逆转/抑制。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) 信号级联是 ADCY8 的分子底物。 ADCY8-PI3K/Akt-GSK3β信号级联的恢复是否可以因果纠正有缺陷的突触去潜能和旧记忆的逆转/抑制。我们将确定突触去潜能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 ADCY，结果该项目将描绘 ADCY8 在调节特定领域的独特作用我们还发现 cAMP 信号在功能上与认知和突触灵活性相关。预计从这项研究中学到的机制可能会建议靶向治疗减少某些患有改变的患者群体的逆转学习缺陷的策略 cAMP-PI3K/Akt-GSK3β 信号传导。