Subsystem macroarchitecture of the intrinsic midbrain neural network and its tectal and tegmental subnetworks

Abstract

The midbrain is the smallest of three primary vertebrate brain divisions. Here we use network science tools to reveal the global organizing principles of intramidbrain axonal circuitry before adding extrinsic connections with the remaining nervous system. Curating the experimental neuroanatomical literature yielded 17,248 connection reports for 8,742 possible connections between the 94 gray matter regions forming the right and left midbrain. Evidence for the existence of 1,676 connections suggests a 19.2% connection density for this network, similar to that for the intraforebrain network [L. W. Swanson et al., Proc. Natl. Acad. Sci. U.S.A. 117, 31470–31481 (2020)]. Multiresolution consensus cluster analysis parceled this network into a hierarchy with 6 top-level and 30 bottom-level subsystems. A structure–function model of the hierarchy identifies midbrain subsystems that play specific functional roles in sensory–motor mechanisms, motivation and reward, regulating complex reproductive and agonistic behaviors, and behavioral state control. The intramidbrain network also contains four bilateral region pairs designated putative hubs. One pair contains the superior colliculi of the tectum, well known for participation in visual sensory–motor mechanisms, and the other three pairs form spatially compact right and left units (the ventral tegmental area, retrorubral area, and midbrain reticular nucleus) in the tegmentum that are implicated in motivation and reward mechanisms. Based on the core hypothesis that subsystems form functionally cohesive units, the results provide a theoretical framework for hypothesis-driven experimental analysis of neural circuit mechanisms underlying behavioral responses mediated in part by the midbrain.

Structure–function subsystem model and computational lesions of the central nervous system’s rostral sector (forebrain and midbrain)

“…1 B and D ) first principles. As in our preceding article ( 10 ), the database used for analysis was extracted from the results of axonal pathway tracing experiments indicating the presence (and weight) or absence of connections between all 560 gray matter regions (nodes) on the right (280 regions) and left (280 regions) sides of the ROS in our rat brain reference atlas ( 11 ) (see Dataset S1 for abbreviations), described with a defined vocabulary for axonal connections ( 12 , 13 ), and displayed on the atlas ( 11 ) or on a CNS flatmap ( 14 ). Connection reports (ranging from none to multiple) for each possible connection in the connection matrix ( Fig.…”

“…1 C ) were expertly collated from the primary structural neuroscience literature as described thoroughly elsewhere ( 9 ); for a comparison of collation results for the same connection matrix by two experts see reference ( 15 ). Our previously published subconnectomes for intraforebrain ( 9 ) and intramidbrain ( 10 ) connections were revised and updated here with new data (see SI Appendix , Materials and Methods ). The remaining eight subconnectomes connecting the two divisions ( Fig.…”

“…The collation identified 17,997 ipsilateral intra-ROS (ROS1) connections as existing and 56,439 as absent, a 24.2% connection density. As before ( 10 , 16 ), “unclear” values are binned with “absent” values, “axons-of-passage” are binned conservatively with “weak,” and “present” values are binned with “moderate.” In contrast, 6,316 contralateral intra-ROS connections from one side were identified as existing and 66,798 as absent (8.6% connection density). Thus, for each ROS side, 24,313 ipsilateral and contralateral connections were identified as existing, and 123,237 were identified as absent (16.5% connection density).…”

“…For the next step, network analysis, reported connection-weight values of “no data” were binned with “absent” and “unclear” values (see Dataset S3 ), and then all values were converted from the descriptive ordinal scale to a log 10 scale covering five orders of magnitude (see Dataset S4 , layer F) because this is the reported range of rat connectional data ( 9 , 10 ) ( Fig. 2 , Middle Column ).…”

“…1 B and D ) before adding the peripheral nervous system and its connections with the body, a grand connectome referred to as the neurome ( 7 ). Thus far, databases for the intrinsic macrocircuitry of the forebrain ( 9 ) and of the midbrain ( 10 ) have been constructed and analyzed. Here we add the set of macroconnections (hereafter referred to simply as connections) between the forebrain and midbrain ( Fig.…”