Project Summary This supplement is requested in response to NOT-AG-20-008 “Notice of Special Interest: Alzheimer's-focused administrative supplements for NIH grants that are not focused on Alzheimer's disease”. The PI's parent grant investigates the synaptic mechanisms, especially excitatory and inhibitory synaptic circuit mechanisms underlying visual cortical processing in the mouse primary visual cortex (V1), using challenging techniques such as in vivo whole-cell patch clamp recording and two-photon imaging guided patch recording, in normal healthy mice. In the proposed extended research, we will apply the same techniques to disease models related to Alzheimer's disease (AD). Malfunctioning of the blood-brain barrier (BBB) has been strongly implicated in contributing to the onset and progression of AD. Since BBB is important for maintaining normal functioning of neural circuits in the brain, pericyte diseases that cause BBB malfunction may result in abnormal neural circuit computation and information processing even before neuronal degeneration, which is a hallmark of AD. Using awake mouse visual cortex as a model system, we will test a central hypothesis that pericyte degeneration initiates disruption of cortical information processing by selectively injuring some specific types of cortical inhibitory neurons, resulting in alterations of the balance between excitatory (E) and inhibitory (I) synaptic circuits and weakening of coordinated control of brain activity prior to neurodegenerative changes. In collaboration with Dr. Berislav Zlokovic who is a renowned scientist in the field of pericyte biology, BBB and AD, we will test this hypothesis in two BBB deficiency mouse models: inducible pericyte-ablation model, and pericyte deficiency and rescue model. We will examine functional spiking responses of excitatory and inhibitory neurons in V1 of these mouse models, as well as visually evoked excitatory and inhibitory synaptic inputs to individual cortical neurons, at different disease progression stages. Through the propose studies, we hope to generate an understanding of how changes in the E/I balance contribute to the disruption of neural circuit computation in AD disease progression.