Investigating the neurophysiological basis of circuit-specific laminar rs-fMRI

Resting-state fMRI has emerged as a potential method to identify diagnostic bio-imaging markers of a broad spectrum of neurological disorders by measuring the low-frequency fluctuation (LFF) correlation features of diseased brains. Due to the fMRI signal’s indirect coupling to neuronal activity, a fundamental challenge of rs- fMRI mapping is how to extract the true “functional connectivity” feature across cortices with circuit specificity. Both direct corticocortical connections, e.g. callosal projections, and subcortical neuromodulatory projections can modulate rs-fMRI connectivity with converging effects on neuro-glio-vascular (NGV) interactions. Also, au- tonomic regulation on gliovascular dynamics further confounds rs-fMRI LFF when interpreting the brain dam- age with vascular impairment in various cerebrovascular diseases. We propose to implement line-scanning and single-vessel fMRI methods in a multi-modal platform to dissect laminar and vascular-specific rs-fMRI LFF and decipher NGV signaling underlying rs-fMRI LFF. Here, we will focus on elucidating the transcallosal circuit- based interhemispheric rs-fMRI LFF correlation in the normal and diseased mouse model with hypoperfusion- induced cerebrovascular white matter injury in the corpus callosum. Three aims will be addressed: 1). We will investigate the causal linkage between laminar-specific bilateral LFF and transcallosal projection. Two hypoth- eses will be tested: i). Layer-specific transcallosal projections determine bilateral LFF laminar correlation pat- terns, and ii). Callosal-driven laminar LFF holds distinct oscillation features from brain state-dependent global LFF. 2). We will differentiate the NGV signaling of callosal-specific and global vascular LFF using multi-modal fMRI. Also, we will test two hypotheses: i). Callosal projection neuron-specific oscillation mediates circuit-spe- cific bilateral LFF, and ii). Distinct astrocytic Ca2+ signals coupled to either callosal projection neuronal activity or global neuromodulation contribute to different forms of LFF correlation. 3). We will specify callosal-specific and global vascular LFF in the hypoperfusion-induced white matter injury mouse model. We will test if hy- poperfusion-induced cerebral flow changes alter global vascular LFF and hypoperfusion-induced injury in the corpus callosum leads to altered bilateral rs-fMRI connectivity. This proposal aims to reveal the mechanistic NGV regulation of circuit-specific rs-fMRI LFF and apply novel rs-fMRI methods in the diseased mouse model to set the foundation to translate specific LFF correlation patterns as potential biomarkers of circuit dysfunction or vascular impairment in pathological brains.