Understanding the relationships between FUS-BBB opening, neuroinflammation and the neurovascular response

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Project Summary: The blood-brain barrier (BBB) is a critical protective structure that tightly controls which biologics are able to pass from the blood stream into the brain parenchyma, excluding toxins but also preventing the delivery of almost all neurotherapeutics. Focused ultrasound (FUS) is an emerging technology that allows the possibility of non- invasive and controlled opening of the BBB for delivery of therapeutics that would not otherwise reach the brain. Using conservative protocols, FUS-BBB opening procedures are being done today in clinical trials, safely and successfully, for treatment of several neurological diseases. Expansion to a wider range of clinical applications will require treatment parameters to be pushed into a regime where the safety concerns related to secondary effects of BBB disruption are not fully understood. These concerns include the initiation of inflammatory and immune responses and, recently demonstrated by our group, alteration of cerebral blood flow regulation. In this project we aim to understand the relationships between FUS-BBB opening, neuroinflammation, and alteration of cerebral blood flow regulation so that the field of FUS-BBB opening can be moved forward safely into new applications. We will use state of the art optical imaging techniques to directly measure the neuronal, astrocytic, and blood flow components of the neurovascular response following FUS-BBB opening. Markers of the inflammatory response will be assessed in brain samples collected immediately after imaging. The data will be acquired over a range of intensities, time points, and drug effects in order to elucidate the key mechanisms that link FUS-BBB opening, neuroinflammation, and the suppression of the neurovascular response. In Aim 1 we will focus on the role of neuronal and astrocytic activity following FUS-BBB opening and how changes in their signaling can affect the blood flow component of the neurovascular response. In Aim 2 we will define the relationships between markers of acute neuroinflammation and the attenuation of the neurovascular response, including the effects of an anti-inflammatory drug given at the time of FUS-BBB opening. In Aim 3 we will investigate the effects of repeated FUS-BBB opening on these fundamental processes, including testing the hypothesis that pre-conditioning the inflammatory process will allow subsequent BBB openings to be achieved with a muted response. This project will deliver significant new knowledge regarding the relationship between FUS-BBB opening, the inflammatory response, and attenuation of the neurovascular response. Gaining this knowledge is critical for safely driving the field of FUS-BBB opening into new clinical applications.