Imaging of Functional Connectivity in the Mouse Brain

Abstract

Functional neuroimaging (e.g., with fMRI) has been difficult to perform in mice, making it challenging to translate between human fMRI studies and molecular and genetic mechanisms. A method to easily perform large-scale functional neuroimaging in mice would enable the discovery of functional correlates of genetic manipulations and bridge with mouse models of disease. To satisfy this need, we combined resting-state functional connectivity mapping with optical intrinsic signal imaging (fcOIS). We demonstrate functional connectivity in mice through highly detailed fcOIS mapping of resting-state networks across most of the cerebral cortex. Synthesis of multiple network connectivity patterns through iterative parcellation and clustering provides a comprehensive map of the functional neuroarchitecture and demonstrates identification of the major functional regions of the mouse cerebral cortex. The method relies on simple and relatively inexpensive camera-based equipment, does not require exogenous contrast agents and involves only reflection of the scalp (the skull remains intact) making it minimally invasive. In principle, fcOIS allows new paradigms linking human neuroscience with the power of molecular/genetic manipulations in mouse models.

Mesoscale infraslow spontaneous membrane potential fluctuations recapitulate high-frequency activity cortical motifs

“…In particular, prefrontal cortex and retrosplenial cortex were identified as hubs, comprising two distinct modules of the rat default network 6 . These results are also broadly similar to functional resting-state connectivity exhibited using intrinsic signal optical imaging, which reflects inherently infraslow processes in mice 7 and suggests common consistent features of infraslow, resting-state, bilateral connectivity across imaging modalities.…”

“…To assess the spatiotemporal structure of specifically infraslow spontaneous activity, we down-sampled our acquired imaging data by integrating video frames to a sampling rate of 1 Hz and then applied a zero-phase lag Chebyshev bandpass (0.02-0.08 Hz) filter. This frequency band was selected on the basis of previous reports of infraslow activity in rodents and our own measurements of VSD signal power and functional structure 6,7,38,39 . We observed fluctuations in the resultant VSD signal ( Supplementary Fig.…”

“…Given the susceptibility of infraslow frequency fluctuations to be potentially confounded by non-neuronal phenomenon, we examined the mechanistic basis underlying our observed infraslow fluctuations 7,[42][43][44] . Topical treatment of the cortical surface with TTX (10 mM), a voltage-gated sodium channel antagonist, completely abolished whisker sensory stimulation-evoked VSD responses from primary barrel somatosensory cortex associated with the C2 whisker (BCS1), secondary barrel somatosensory cortex associated with the C2 whisker (BCS2) and from motor cortex associated with C2 whisker (mBC) indicating complete and spatially widespread inhibition of sensory-evoked activity in the cortex ( Supplementary Fig.…”

“…6). These latter potential sources of signal contamination are thought to contribute to a global signal confound that accompanies imaging of infraslow activity in both fc-fMRI and intrinsic optical signal imaging 7,35,42,49 . Frequently, postacquisition data processing to remove the global signal is implemented to reveal underlying functional connectivity, but remains controversial due to questions about the strictly artifactual nature of the global signal and the dependence of observed resting-state anti-correlations on its removal 35,50 .…”

“…From its early description as 'infraslow' 4 , spontaneous or resting-state activity at this very low-frequency domain (o0.1 Hz) has been observed as a consistent feature of ongoing brain activity across different species [4][5][6][7] and across different brain states 5,[8][9][10] , though its precise function and mechanistic underpinnings remain unclear. In the developing brain, electrophysiological infraslow activity in the form of neuronal activity transients or bursting activity has been linked with the development of neuronal networks 11,12 , whereas in the adult brain, infraslow activity has been demonstrated to synchronize with higher-frequency brain activity 13,14 and to correlate to variability in behavioural performance 15,16 .…”