The Neural Mechanism Of Olfaction Effect On Learning And Memory

Alzheimer’s disease(AD)is a common senile neurodegenerative disease characterized by extracellular AP plaque deposition and intracellular phosphorylated Tau tangles,and progressive learning and cognitive impairment.However,so far to now,the etiology,pathogenesis and therapy of AD are still unclear.So,it is important to understand the early onset of AD and intervene.An abnormality in olfactory function was found in the early stages of AD,before cognitive impairment.Multiple studies have demonstrated that the olfaction impairment can affect the learning and memory,but the mechanism is elusive.Thus,this thesis mainly focuses on exploring how olfaction effects learning and memory on molecular and circuit levels as following two aspects1)Genetic studies have suggested that AD is a complex heterogeneous disease and involved multiple genes,instead of a single gene,as well as age-related factors and environmental factors.Screening genetic risk factors,and identification hub genes,their genetic networks and signaling pathways in early-stage AD will provide more potential diagnostic markers and therapeutic targets.Based on the reasons,the large-scale RNA sequencing was used to confirm the key genes and networks were searched in AD patients’postmortem samples.Ppp2r5a was chose as candidate gene to test the availability as early therapeutic targets,and provide a useful research basis for the early prevention and treatment of AD.Firstly,PPP2R5A protein alternation was tested in AD mice and wild type mice by immunofluorescent staining.Secondly,quantitative olfactory bulb proteomics analysis was done for searching the protein network change by upregulating Ppp2r5a in AD and age-matched wild type mice.Thirdly,resting state MRI and anterograde transsynaptic labeling were used to test the neural network change by upregulating Ppp2r5a in AD and age-matched wild type mice.Lastly,testing the behavioral phenotypes in AD and age-matched wild type mice by disturbance of Ppp2r5a.Our results had shown:(1)PPP2R5A located in synapse.(2)PPP2R5A accumulation in cytoplasm along with age,especially in old AD mice.(3)Ppp2r5a induced the synapse abnormality.(4)Multiple brain areas connections were abnormal,especially limbic system by upregulating Ppp2r5a.(5)The olfaction function and spatial memory were impaired in wild type mice by upregulating Ppp2r5a.And the spatial memory impairment was worsen in AD mice.(6)The multiple behavior in wild type and AD mice by knockdown Ppp2r5a.So,these data indicated that Ppp2r5a modulated learning and memory in AD mice via two different mechanisms.2)To attain the neural circuit basis of olfaction effect on learning and memory,we combined viral trans-synaptic tracing systems and ChAT-cre transgenic mice to systematically reveal the relationship between the olfactory system and the different subsets of BFCNs.The retrograde AAV-RV tracing was used to test different subregional BFCNs received diverse inputs from multiple olfactory cortices.And c-fos immunoflescent staining was utilized to test the neurons activated in the BF during olfaction related tasks.These data revealed the different inputs of different subpopulation of basal forebrain cholinergic neurons from the olfaction system.The cholinergic neurons in HDB,SI and MCPO may have the strongest relation with the olfaction system,both structurally and functionally.Based on two aspects as above,we preliminarily explored molecular and neural circuit mechanism of olfaction effect learning and memory,and hoped to provide more effective studying basis for early prevence and therapy of AD.