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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：
10515330
负责人：
Hongbing Wang
金额：
$ 46.22万
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/10515330
关键词：
Ablation 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 Homosynaptic Depression Impaired cognition Impairment Knockout Mice Knowledge Label Learning Light Link Long-Term Depression Long-Term Potentiation LoxP-flanked allele Maps Mediating Memory 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 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.

抽象/总结