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IN VIVO IMAGING OF CEREBRAL BLOOD FLOW AND NEURAL ACTIVITY CHANGES IN THE CONTEXTS OF ALZHEIMER’S DISEASE AND PSYCHEDELICS

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dc.contributor.authorZirkel, Rick
dc.contributor.chairSchaffer, Chrisen_US
dc.contributor.committeeMemberEllwood, Ianen_US
dc.contributor.committeeMemberKwan, Chun Hay Alexen_US
dc.contributor.committeeMemberZipfel, Warrenen_US
dc.date.accessioned2025-08-21T14:14:42Z
dc.date.available2025-08-21T14:14:42Z
dc.date.issued2025-05
dc.description199 pagesen_US
dc.description.abstractThe 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).en_US
dc.identifier.doihttps://doi.org/10.7298/x8kg-0f69
dc.identifier.otherZirkel_cornellgrad_0058F_14945
dc.identifier.otherhttps://www.proquest.com/LegacyDocView/DISSNUM/31999762
dc.identifier.otherbibid: 16938334
dc.identifier.urihttps://hdl.handle.net/1813/117676
dc.language.isoen
dc.relation.localurihttps://newcatalog.library.cornell.edu/catalog/16938334
dc.rightsAttribution 4.0 International*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subjectAlzheimer's diseaseen_US
dc.subjectcerebral blood flowen_US
dc.subjectmouseen_US
dc.subjectneuronal calcium imagingen_US
dc.subjectpsychedelicsen_US
dc.subjecttwo-photon imagingen_US
dc.titleIN VIVO IMAGING OF CEREBRAL BLOOD FLOW AND NEURAL ACTIVITY CHANGES IN THE CONTEXTS OF ALZHEIMER’S DISEASE AND PSYCHEDELICSen_US
dc.typedissertation or thesisen_US
dcterms.licensehttps://hdl.handle.net/1813/59810.2
thesis.degree.disciplineBiomedical Engineering
thesis.degree.grantorCornell University
thesis.degree.levelDoctor of Philosophy
thesis.degree.namePh. D., Biomedical Engineering

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