Neural computations occurring simultaneously in multiple cerebral cortical regions are critical for mediating behaviors. Progress has been made in understanding how neural activity in specific cortical regions contributes to behavior. However, there is a lack of tools that allow simultaneous monitoring and perturbing neural activity from multiple cortical regions. We have engineered a suite of technologies to enable easy, robust access to much of the dorsal cortex of mice for optical and electrophysiological recordings. First, I will describe microsurgery robots that can programmed to perform delicate microsurgical procedures such as large bilateral craniotomies across the cortex and skull thinning in a semi-automated fashion. Next, I will describe digitally designed, morphologically realistic, transparent polymer skulls that allow long-term (>300 days) optical access. These polymer skulls allow mesoscopic imaging, as well as cellular and subcellular resolution two-photon imaging of neural structures up to 600 µm deep. We next engineered a widefield, miniaturized, head-mounted fluorescence microscope that is compatible with transparent polymer skull preparations. With a field of view of 8 × 10 mm2 and weighing less than 4 g, the ‘mini-mScope’ can image most of the mouse dorsal cortex with resolutions ranging from 39 to 56 µm. We used the mini-mScope to record mesoscale calcium activity across the dorsal cortex during sensory-evoked stimuli, open field behaviors, social interactions and transitions from wakefulness to sleep.

The brain is remarkably flexible, and appears to instantly reconfigure its processing depending on what’s needed to solve a task at hand: fMRI studies indicate that distal brain areas appear to fluidly couple and decouple with one another depending on behavioral context. But the structural architecture of the brain is comprised of long-range axonal projections that are relatively fixed by adulthood. How does the global dynamism evident in fMRI recordings manifest at a cellular level? To bridge the gap between the activity of single neurons and cortex-wide networks, we correlated electrophysiological recordings of individual neurons in primary visual (V1) and retrosplenial (RSP) associational cortex with activity across dorsal cortex, recorded simultaneously using widefield calcium imaging. We found that individual neurons in both cortical areas independently engaged in different distributed cortical networks depending on the animal’s behavioral state, suggesting that locomotion puts cortex into a more sensory driven mode relevant for navigation.

Recent advancements in anatomical and functional imaging emphasize the presence of whole-brain networks organized according to functional and connectivity gradients, but how such structure shapes activity propagation and memory processes still lacks asatisfactory model. We analyse the fine-grained spatiotemporal dynamics of spontaneous activity in the entire dorsal cortex. through simultaneous recordings of wide-field voltage sensitive dye transients (VS), cortical ECoG, and hippocampal LFP in anesthetized mice. Both VS and ECoG show cortical avalanches. When measuring avalanches from the VS signal, we find a major deviation of the size scaling from the power-law distribution predicted by the criticality hypothesis and well approximated by the results from the ECoG. Breaking from scale-invariance, avalanches can thus be grouped in two regimes. Small avalanches consists of a limited number of co-activation modes involving a sub-set of cortical networks (related to the Default Mode Network), while larger avalanches involve a substantial portion of the cortical surface and can be clustered into two families: one immediately preceded by Retrosplenial Cortex activation and mostly involving medial-posterior networks, the other initiated by Somatosensory Cortex and extending preferentially along the lateral-anterior region. Rather than only differing in terms of size, these two set of events appear to be associated with markedly different brain-wide dynamical states: they are accompaniedby a shift in the hippocampal LFP, from the ripple band (smaller) to the gamma band (larger avalanches), and correspond to opposite directionality in the cortex-to-hippocampus causal relationship. These results provide a concrete description of global cortical dynamics, and shows how cortex in its entirety is involved in bi-directional communication in the hippocampus even in sleep-like states.