Wide-Field Calcium Imaging of Dynamic Cortical Networks during Locomotion.

Motor behavior results in complex exchanges of motor and sensory information across cortical regions. Therefore, fully understanding the cerebral cortex's role in motor behavior requires a mesoscopic-level description of the cortical regions engaged, their functional interactions, and how these functional interactions change with behavioral state. Mesoscopic Ca2+ imaging through transparent polymer skulls in mice reveals elevated activation of the dorsal cerebral cortex during locomotion. Using the correlations between the time series of Ca2+ fluorescence from 28 regions (nodes) obtained using spatial independent component analysis (sICA), we examined the changes in functional connectivity of the cortex from rest to locomotion with a goal of understanding the changes to the cortical functional state that facilitate locomotion. Both the transitions from rest to locomotion and from locomotion to rest show marked increases in correlation among most nodes. However, once a steady state of continued locomotion is reached, many nodes, including primary motor and somatosensory nodes, show decreases in correlations, while retrosplenial and the most anterior nodes of the secondary motor cortex show increases. These results highlight the changes in functional connectivity in the cerebral cortex, representing a series of changes in the cortical state from rest to locomotion and on return to rest.

Wide-field calcium imaging of cortical activation and functional connectivity in externally- and internally-driven locomotion.

The role of the cerebral cortex in self-initiated versus sensory-driven movements is central to understanding volitional action. Whether the differences in these two movement classes are due to specific cortical areas versus more cortex-wide engagement is debated. Using wide-field Ca2+ imaging, we compared neural dynamics during spontaneous and motorized treadmill locomotion, determining the similarities and differences in cortex-wide activation and functional connectivity (FC). During motorized locomotion, the cortex exhibits greater activation globally prior to and during locomotion starting compared to spontaneous and less during steady-state walking, during stopping, and after termination. Both conditions are characterized by FC increases in anterior secondary motor cortex (M2) nodes and decreases in all other regions. There are also cortex-wide differences; most notably, M2 decreases in FC with all other nodes during motorized stopping and after termination. Therefore, both internally- and externally-generated movements widely engage the cortex, with differences represented in cortex-wide activation and FC patterns.

Cerebral cortical functional hyperconnectivity in a mouse model of spinocerebellar ataxia type 8 (SCA8).

Spinocerebellar Ataxia Type 8 (SCA8) is an inherited neurodegenerative disease caused by a bidirectionally expressed CTG●CAG expansion mutation in the ATXN-8 and ATXN8-OS genes. While primarily a motor disorder, psychiatric and cognitive symptoms have been reported. It is difficult to elucidate how the disease alters brain function in areas with little or no degeneration producing both motor and cognitive symptoms. Using transparent polymer skulls and CNS-wide GCaMP6f expression, we studied neocortical networks throughout SCA8 progression using wide-field Ca2+ imaging in a transgenic mouse model of SCA8. We observed that neocortical networks in SCA8+ mice were hyperconnected globally which led to network configurations with increased global efficiency and centrality. At the regional level, significant network changes occurred in nearly all cortical regions, however mainly involved sensory and association cortices. Changes in functional connectivity in anterior motor regions worsened later in the disease. Near perfect decoding of animal genotype was obtained using a generalized linear model based on canonical correlation strengths between activity in cortical regions. The major contributors to decoding were concentrated in the somatosensory, higher visual and retrosplenial cortices and occasionally extended into the motor regions, demonstrating that the areas with the largest network changes are predictive of disease state.

Wide-field calcium imaging of cortical activation and functional connectivity in externally- and internally-driven locomotion.

The neural dynamics underlying self-initiated versus sensory driven movements is central to understanding volitional action. Upstream motor cortices are associated with the generation of internally-driven movements over externally-driven. Here we directly compare cortical dynamics during internally- versus externally-driven locomotion using wide-field Ca2+ imaging. We find that secondary motor cortex (M2) plays a larger role in internally-driven spontaneous locomotion transitions, with increased M2 functional connectivity during starting and stopping than in the externally-driven, motorized treadmill locomotion. This is not the case in steady-state walk. In addition, motorized treadmill and spontaneous locomotion are characterized by markedly different patterns of cortical activation and functional connectivity at the different behavior periods. Furthermore, the patterns of fluorescence activation and connectivity are uncorrelated. These experiments reveal widespread and striking differences in the cortical control of internally- and externally-driven locomotion, with M2 playing a major role in the preparation and execution of the self-initiated state.

Wide-field calcium imaging of cortical activation and functional connectivity in externally- and internally-driven locomotion.

The neural dynamics underlying self-initiated versus sensory driven movements is central to understanding volitional action. Upstream motor cortices are associated with the generation of internally-driven movements over externally-driven. Here we directly compare cortical dynamics during internally- versus externally-driven locomotion using wide-field Ca2+ imaging. We find that secondary motor cortex (M2) plays a larger role in internally-driven spontaneous locomotion transitions, with increased M2 functional connectivity during starting and stopping than in the externally-driven, motorized treadmill locomotion. This is not the case in steady-state walk. In addition, motorized treadmill and spontaneous locomotion are characterized by markedly different patterns of cortical activation and functional connectivity at the different behavior periods. Furthermore, the patterns of fluorescence activation and connectivity are uncorrelated. These experiments reveal widespread and striking differences in the cortical control of internally- and externally-driven locomotion, with M2 playing a major role in the preparation and execution of the self-initiated state.