Long-range Circuit Dysfunction Of Pyramidal Neurons In Alzheimer's Disease Mouse Model

Pyramidal neurons form neural circuits with other neurons through axons,which are the center-stage for many important cognitive processes,such as learning and memory.On the basis of clinical trials and animal experiments for Alzheimer's disease(AD),it has been shown that the dysregulation of pyramidal neurons in the medial prefrontal cortex,such as decreased synaptic plasticity,were directly related to memory impairment.However,how the long-range circuit dysfunction of pyramidal neurons leads to memory impairment,remains unclear.To identify the mechanism of the long-range circuit dysfunction of pyramidal neurons,I investigated the axonopathy of pyramidal neurons in the whole-brain in the AD mouse model.The main results are as follows:First,the neural circuitry mechanism on how the pyramidal tract neurons in the medial prefrontal cortex involved in the retrieval of object recognition memory in the AD mouse model was studied.Combining with transgenic mouse,chemical genetics,optogenetics,and the fiber photometry in vivo calcium imaging,the role of pyramidal tract neurons in object recognition memory was confirmed.Inhibition of pyramidal tract neurons in the medial prefrontal cortex of wild type mice impaired the retrieval of object recognition memory.Using virus tracing and fluorescence Micro-Optical Sectioning Tomography(f MOST),the upstream input and downstream output circuits of pyramidal tract neurons were analyzed.Furthermore,during the retrieval of memory,optogenetic activation of pyramidal tract neurons and their axon terminals that projected to the supramammillary nucleus can rescue the object recognition memory impairment in mouse model of AD.The anatomical results of retrograde tracing and f MOST whole brain fine imaging showed that compared with the control group,pyramidal tract neurons in the medial prefrontal cortex received fewer cholinergic inputs from the basal forebrain at 6-month AD mouse.The in vivo transmitter test results also verified the reduction of acetylcholine transmitter release.These changes in the input circuit altered the response patterns of pyramidal tract neurons in the medial prefrontal cortex to novel and familiar objects.Inhibition of cholinergic fibers in the medial prefrontal cortex impaired the retrieval of object recognition memory in wild type mice,while activation of this circuit can rescue the object recognition memory impairment in AD mouse.Secondly,the temporal and regional progression of axonopathy was investigated during AD mouse development.The whole-brain imaging was performed at subcellular resolution(0.32×0.32×2?m³)to obtain continuous three-dimensional datasets of 5×FAD_Thy-GFP mice.By comparing the axon morphology of 6,7,8,and 16-week-old AD mouse,the axonopathy were firstly found in the lateral septal nucleus,subiculum,and medial mammillary nucleus.Specially,the axonopathy in the medial mammillary nucleus displayed distinct progression patterns that increased firstly and then decreased.With transsynaptic tracer,I confirmed that these pathological axons were mainly from the subiculum.Optogenetical activation of fibers in the medial mammillary nucleus from pyramidal neurons in the subiculum could rescue the spatial memory in AD mouse,indicating that axonopathy in the circuit was related to spatial memory impairement.In conclusion,this study revealed how the long-range input and output circuits of pyramidal tract neurons in the prefrontal cortex regulate the object recognition memory.In addition,this work investigated an early-stage spatiotemporal axonopathy pattern of pyramidal neurons.These findings underlined the importance to study the mechanism of neurodegenerative diseases at the level of neural circuits,promote the understanding of related molecules,cells,circuit damage and memory disorders,and provide new clues for further research on therapeutic targets and drug development.