Ultrasonic disruption of the blood–brain barrier enables in vivo functional mapping of the mouse barrel field cortex with manganese-enhanced MRI

Abstract

Though mice are the dominant model system for studying the genetic and molecular underpinnings of neuroscience, functional neuroimaging in mice remains technically challenging. One approach, Activation-Induced Manganese-enhanced MRI (AIM MRI), has been used successfully to map neuronal activity in rodents. In AIM MRI, manganese2+ acts a calcium analog and accumulates in depolarized neurons. Because manganese2+ shortens T1, regions of elevated neuronal activity enhance in MRI. However, because manganese does not cross the blood–brain barrier (BBB), the need to osmotically disrupt the BBB has limited the use of AIM MRI, particularly in mice. In this work, the BBB was opened in mice using unfocused, transcranial ultrasound in combination with gas-filled microbubbles. Using this noninvasive technique to open the BBB bilaterally, manganese could be quickly administered to the whole mouse brain. With this approach, AIM MRI was used to map the neuronal response to unilateral mechanical stimulation of the vibrissae in lightly sedated mice. The resultant 3D activation map agreed well with published representations of the vibrissae regions of the barrel field cortex. The anterior portions of the barrel field cortex corresponding to the more rostral vibrissae showed greater activation, consistent with previous literature. Because the ultrasonic opening of the BBB is simple, fast, and noninvasive, this approach is suitable for high-throughput and longitudinal studies in awake mice. This approach enables a new way to map neuronal activity in mice with manganese.