Abnormal spatial memory processing in tau pathology and neurodegeneration

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Abstract Tau pathology, including tau protein hyperphosphorylation, neurofibrillary tangles and subsequent neurodegeneration, plays a key role in cognitive symptoms of tauopathies including Alzheimer’s disease. Recent studies using animal models have made rapid progress in understanding tau pathogenesis and its involvement in cognitive deficits. However, behavioral deficits are ultimately mediated by functional changes in neural circuits in vivo. An important question that has rarely been studied is how neural circuit functions are altered in the living brain with ongoing tau pathology and neurodegeneration. Here we propose to determine in vivo functional abnormalities caused by tau pathology and neurodegeneration in the neural circuits of hippocampus (HP) and entorhinal cortex, areas that are crucial for memory loss in tauopathies. Primarily using the tetrode recording technique, in combination with behavioral and pharmacological manipulations, we will simultaneously record a large number of neurons in freely moving animals of tauopathy mouse models, including the transgenic rTg4510 mouse and htau mouse. We will focus on a specific “internal-external imbalance” hypothesis: The memory circuits in these mice cannot form normal memories because they are dominated by internal activities generated within the hippocampus and thus fail to respond to external sensory input. To test the hypothesis, we will aim to determine whether activities of HP neurons in tauopathy models are preferentially driven by internal activities more than those in control mice, how this abnormality is generated by the memory neural circuits, what computational process it alters, and how it is linked to behavioral memory deficits.