Integrating TPM and PAM to examine the metabolic underpinning of neurovascular repair after stroke - PROJECT SUMMARY
Each year, over 800,000 people in the United States suffer from a stroke. Although the vast majority survive the
acute event, over half of survivors suffer moderate to severe impairment in motor, sensory, or cognitive function.
As a consequence, stroke remains the leading cause of long-term disability, costing over $34 billion annually in
direct medical costs and indirect costs (lost productivity) in the United States. In the face of this enormous disease
burden, there are few therapies to improve stroke recovery. The brain has some intrinsic capacity for repair, but
our understanding of the underlying mechanisms remains very limited. Recent studies suggest that a successful
recovery from stroke injury requires neurovascular remodeling to reorganize the damaged brain network. Indeed,
circuit repair and the resultant remapping is essential for stroke recovery. Moreover, cerebrovascular remodeling
and changes in cerebral oxygen metabolism are observed in animals and patients after stroke and are associated
with improved outcomes. Tight coordination of neural repair and cerebrovascular remodeling is likely required to
meet energy requirements of brain repair. However, the spatiotemporal coordination of neurovascular repair and
the attendant changes in oxygen metabolism after stroke remain incompletely understood. We seek to answer
these important questions by developing a new dual-modal intravital imaging technique that integrates 2-photon
fluorescence microscopy (TPM) and multi-parametric photoacoustic microscopy (PAM) for high-resolution, time-
lapse and comprehensive imaging of neurovascular repair and metabolic changes after stroke. To this end, we
have developed a prototype TPM-PAM system and a new cranial window with dual transparency (i.e., light and
ultrasound), long lifetime, and compatibility for awake-brain imaging. Building on the strong scientific basis, this
proposed project will focus on the development of a high-sensitivity TPM-PAM system for longitudinal imaging
of the spatiotemporal interplay of post-stroke neural repair and cerebrovascular remodeling, as well as dynamic
imaging of the coupling between neuronal activity, blood flow, and blood oxygen supply, at single-neuron single-
capillary level in the awake mouse brain. The proposed research has three specific aims: (1) develop an optically
transparent and acoustically sensitive microresonator for integration of TPM and PAM with high sensitivity, (2)
develop and validate the microresonator-based TPM-PAM for neurovascular imaging in GCaMP mice, and (3)
determine the spatiotemporal relationship between functional vascular repair and neuronal circuit repair after
stroke. Advancing our understanding of stroke repair through the development and application of TPM-PAM may
reveal promising new therapeutic targets to enhance functional recovery.
