Abstract
Emerging research in non-human animals implicates cerebellar projections to the ventral tegmental area (VTA) in appetitive behaviors, but these circuits have not been characterized in humans. Here, we mapped cerebello-VTA white-matter connectivity in a cohort of men and women using probabilistic tractography on diffusion imaging data from the Human Connectome Project. We uncovered the topographical organization of these connections by separately tracking from parcels of cerebellar lobule VI, crus I/II, vermis, paravermis, and cerebrocerebellum. Results revealed that connections between the cerebellum and VTA predominantly originate in the right cerebellar hemisphere, interposed nucleus, and paravermal cortex, and terminate mostly ipsilaterally. Paravermal crus I sends the most connections to the VTA compared to other lobules. We discovered a medial-to-lateral gradient of connectivity, such that the medial cerebellum has the highest connectivity with the VTA. Individual differences in microstructure were associated with measures of negative affect and social functioning. By splitting the tracts into quarters, we found that the socio-affective effects were driven by the third quarter of the tract, corresponding to the point at which the fibers leave the deep nuclei. Taken together, we produced detailed maps of cerebello-VTA structural connectivity for the first time in humans and established their relevance for trait differences in socio-affective regulation.
Significance Statement This is the first study in humans to identify the white matter connections between each deep cerebellar nucleus and the VTA in an anatomically detailed manner. Our findings are highly consistent with the rodent literature, showing strong conservation across species. This provides a foundation for direct translational research using chemogenetic and optogenetic methods in rodents to study neuropsychiatric disorders associated with this pathway. We identify a double dissociation of socio-affective functioning and cerebellar deep nuclei and sagittal segments, hinting at a medial-to-lateral hierarchy of cerebellar function based on cerebellar phylogeny.
Footnotes
This research includes calculations carried out on HPC resources supported in part by the National Science Foundation through major research instrumentation grant number 1625061 and by the US Army Research Laboratory under contract number W911NF-16-2-0189. This work was supported by a National Institute of Health grants to I. Olson (R01 NICHD R01HD099165; R01 MH118545-01A1) and to H. Sullivan-Toole (F32 MH127948-01A1). The content is solely the responsibility of the authors and does not represent the official views of the National Institute of Mental Health or the National Institutes of Health. Data were provided by the Human Connectome Project, WU-Minn Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University. We thank Drs. Volker Coenen, Marco Reisert, and Sascha du Lac for their insights into cerebello-midbrain connectivity and comments on the cerebellar connections to each DCN, respectively. We also thank Katie Jobson, Haroon Popal, and Vishnu Murty for contributing their knowledge of cerebellar and reward circuitry.
Authors report no conflict of interest.
