The brain is a highly dynamic organ in which neural activity, vascular regulation, and molecular signaling are intricately intertwined. Understanding these relationships is essential for uncovering the mechanisms that underlie both cognitive function and dysfunction. In vivo imaging enables the direct measurement of neural activity and cerebral blood flow in living animals with cellular resolution, providing a powerful window into brain function in both health and disease (chapter 1). This dissertation leverages a range of optical imaging tools to examine how cerebral blood flow and neural dynamics, and the relationship between them, are impacted in two distinct contexts: Alzheimer’s disease (AD) (chapter 4) and psychedelic drug action (chapter 5). Alzheimer’s disease is characterized by disruptions in both neural activity and blood flow, yet the precise mechanisms through which these impairments arise—and whether they can be reversed—remain unclear. In the first focus of this thesis, I review our understanding of these impairments, as well as current research examining therapeutic targets to eliminate such dysfunction (chapter 2). Next, using in vivo two-photon microscopy, I demonstrate how a specific impaired activity pattern can be improved after the restoration of cerebral blood flow (CBF) deficits. Increasing CBF in AD model mice leads to enhanced orientation tuning in visual cortex neurons, providing a potential therapeutic mechanism for restoring cortical function (chapter 4). For the second focus of this thesis, I leverage in vivo imaging techniques to evaluate cerebral blood flow and neural activity changes in the context of psychedelics, specifically psilocybin. Psychedelics are known to profoundly alter consciousness and have promising therapeutic potential for treating mood disorders such as anxiety, depression, and addiction (chapter 3). However, their effects on the coordination between neural and vascular activity in the brain, a relationship known as neurovascular coupling (NVC), are less well understood. Clinical fMRI studies investigating psychedelic drug action rely on NVC to examine blood flow changes as a proxy for neural activity. Using micro- and mesoscale in vivo imaging techniques, I show that psilocybin alters stimulus-evoked neurovascular coupling in mouse visual cortex and discuss potential mechanisms underlying these changes, and how these alterations may influence the interpretation of fMRI imaging with psychedelics (chapter 5). Together, these studies highlight the power of in vivo imaging to uncover complex, dynamic interactions between neural activity and cerebral blood flow across multiple spatial and temporal scales. This dissertation not only demonstrates the utility of these imaging techniques in identifying neural and vascular impairments in AD and psychedelic drug action but also provides a framework for how these tools can be used to guide future therapeutic strategies. By combining cellular-resolution imaging with systems-level analysis, this work contributes to a deeper understanding of brain function in both pathological and pharmacologically altered states (chapter 6).