Cerebellar output neurons can impair non-motor behaviors by altering development of extracerebellar connectivity
The capacity of the brain to compensate for insults during development depends on the type of cell loss, whereas the consequences of genetic mutations in the same neurons are difficult to predict. We reveal powerful compensation from outside the mouse cerebellum when the excitatory cerebellar output neurons are ablated embryonically and demonstrate that the main requirement for these neurons is for motor coordination and not basic learning and social behaviors. In contrast, loss of the homeobox transcription factors Engrailed1/2 (EN1/2) in the cerebellar excitatory lineage leads to additional deficits in adult learning and spatial working memory, despite half of the excitatory output neurons being intact. Diffusion MRI indicates increased thalamo-cortico-striatal connectivity in En1/2 mutants, showing that the remaining excitatory neurons lacking En1/2 exert adverse effects on extracerebellar circuits regulating motor learning and select non-motor behaviors. Thus, an absence of cerebellar output neurons is less disruptive than having cerebellar genetic mutations.
Authors
- Detlef Heck (ORCID: https://orcid.org/0000-0003-2438-4064)
- Zhimin Lao
- Alexandra L. Joyner (ORCID: https://orcid.org/0000-0001-7090-9605)
- Anjana Krishnamurthy (ORCID: https://orcid.org/0000-0002-4584-1722)
- Tanzil Mahmud Arefin (ORCID: https://orcid.org/0000-0002-4876-7548)
- Andrew S. Lee (ORCID: https://orcid.org/0000-0002-1791-375X)
- Natalia V. De Marco García (ORCID: https://orcid.org/0000-0002-5540-258X)
- Jiangyang Zhang (ORCID: https://orcid.org/0000-0003-0740-2662)
- Anjali M. Rajadhyaksha (ORCID: https://orcid.org/0000-0002-8399-5466)
- Alina Gubanova
- Yu Liu (ORCID: https://orcid.org/0000-0002-7384-6176)
- Daniel N. Stephen
Institutions
- Cornell University (US)
- University of Rochester Medical Center (US)
- Kettering University (US)
- MIND Research Institute (US)
- University of Minnesota, Duluth (US)
- Weill Cornell Medicine (US)
- New York University (US)
- Temple University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-21
- DOI
- https://doi.org/10.1038/s41467-025-57080-6
- Citations
- 5
- Primary Topic
- Vestibular and auditory disorders
- Type
- article
- Field-Weighted Citation Impact
- 4.21
Funders
- University of Texas Southwestern Medical Center
- Fordham University
- Cycle for Survival
- National Institutes of Health
- Weill Cornell Medical College
- University of California, Davis
- National Institute of Mental Health
- National Institute on Drug Abuse
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development