Mapping the corticoreticular pathway from cortex-wide anterograde axonal tracing in the mouse

Abstract

The corticoreticular pathway (CRP) has been implicated as an important mediator of motor recovery and rehabilitation after central nervous system damage. However, its origins, trajectory and laterality are not well understood. This study mapped the mouse CRP in comparison with the corticospinal tract (CST). We systematically searched the Allen Mouse Brain Connectivity Atlas (© 2011 Allen Institute for Brain Science) for experiments that used anterograde tracer injections into the right isocortex in mice. For each eligible experiment (N = 607), CRP and CST projection strength were quantified by the tracer volume reaching the reticular formation motor nuclei (RF_motor ) and pyramids, respectively. Tracer density in each brain voxel was also correlated with RF_motor versus pyramids projection strength to explore the relative trajectories of the CRP and CST. We found significant CRP projections originating from the primary and secondary motor cortices, anterior cingulate, primary somatosensory cortex, and medial prefrontal cortex. Compared with the CST, the CRP had stronger projections from each region except the primary somatosensory cortex. Ipsilateral projections were stronger than contralateral for both tracts (above the pyramidal decussation), but the CRP projected more bilaterally than the CST. The estimated CRP trajectory was anteromedial to the CST in the internal capsule and dorsal to the CST in the brainstem. Our findings reveal a widespread distribution of CRP origins and confirm strong bilateral CRP projections, theoretically increasing the potential for partial sparing after brain lesions and contralesional compensation after unilateral injury.

Keywords: brain mapping; extrapyramidal tracts; locomotion; motor activity; postural balance; pyramidal tracts.

Figure 1.

Experiment selection flow diagram.

Figure 2.. Locations of cortical anterograde tracer injections and brainstem targets of interest.

Top panel. Each eligible injection experiment (N=607) is marked with a 0.1 mm diameter black sphere within the translucent brain surface rendering. Cortical regions of interest are outlined on the surface and annotated. In the middle and right images, the left hemi-brain and olfactory bulb have been removed from the surface rendering to better visualize the anterior cingulate and medial prefrontal areas. Bottom panel. From left to right, slices are x=0.4 mm, y=−5.2 mm and y=−7.3 mm, relative to the midpoint of the anterior commissure. RF_motor, reticular formation motor nuclei involved with limb movement.

Figure 3.. Anterograde tracer projections from cortical injection sites to the reticular formation motor nuclei (RF_motor) or medullary pyramids.

Projection strength is the volume of tracer-labelled pixels in the target of interest (RF_motor or pyramids) divided by the injection site volume. Results from each eligible injection experiment (N=607) are mapped onto the nearest surface vertex with a 0.1 mm radius circle, color-coded with the projection strength from that cortical site to each brainstem target of interest. These results are mapped onto an opaque surface rendering of the right hemi-brain with the olfactory bulb removed for better visualization. Cortical regions of interest are outlined and annotated.

Figure 4.. Projection strength to the brainstem targets by cortical injection site and target laterality.

Projection strength is the volume of tracer-labelled pixels in the target divided by the injection site volume. Panels A and B. Each eligible injection experiment (N=607) is shown as a ‘+’ symbol, with projection strength truncated at 1.0 for visualization. Horizontal bars indicate the 75^th percentile. Panel C. Distribution of tracer laterality across injection experiments for each target. Vertical bars indicate median laterality indices.

Figure 5.. Exploratory trajectory analysis of the corticoreticular pathway (CRP) versus the corticospinal tract (CST).

Mapped results are T statistics from a general linear model of projection density at each voxel, testing its association with the projection strength to the reticular formation motor nuclei (RF_motor) versus the medullary pyramids, while controlling for whole-brain projection strength (N=607). These results are from non-parametric permutation testing using threshold-free cluster enhancement, and are thresholded at a two-sided, false discovery rate corrected p<0.05. Blue T statistics indicate a significantly greater association with RF_motor (CRP) projection strength, while red/yellow T statistics indicate a significantly greater association with pyramids (CST) projection strength. The analysis was done in volume space (rows 2–6) and these volumetric images are in neurologic orientation. Coordinate labels are in mm, relative to the midpoint of the anterior commissure. For visualization, results were also projected onto the surface model of the right hemibrain without the olfactory bulb (row 1). This surface visualization includes black outlines of the cortical regions of interest shown in other figures.

Figure 6.. Schematic diagram of the corticoreticular-reticulospinal pathway and corticospinal tract.

Line thickness is roughly proportional to estimated projection density, based on the current findings and prior research. Dark blue circles represent reticular formation motor nuclei. Pathways originating from the left cortex are omitted to show contralateral projections. For clarity, only singular decussation points are shown for the corticoreticular and reticulospinal tracts.