Cerebellar output neurons can impair non-motor behaviors by altering development of extracerebellar connectivity Journal Article
| Authors: | Lee, A. S.; Arefin, T. M.; Gubanova, A.; Stephen, D. N.; Liu, Y.; Lao, Z.; Krishnamurthy, A.; De Marco García, N. V.; Heck, D. H.; Zhang, J.; Rajadhyaksha, A. M.; Joyner, A. L. |
| Article Title: | Cerebellar output neurons can impair non-motor behaviors by altering development of extracerebellar connectivity |
| Abstract: | 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. © The Author(s) 2025. |
| Keywords: | immunohistochemistry; adult; controlled study; unclassified drug; gene mutation; genetics; microscopy; nonhuman; animal cell; mouse; animal; metabolism; animals; mice; mice, knockout; animal tissue; cerebellum; gene; purkinje cell; cell survival; embryo; animal experiment; brain cortex; brain injury; nerve tissue proteins; transcription factor; embryo development; homeodomain proteins; neurons; data base; mice, inbred c57bl; histology; physiology; c57bl mouse; in situ hybridization; brain; brain development; interneuron; granule cell; transgene; homeodomain protein; motor dysfunction; motor performance; image processing; nerve protein; nerve cell; diffusion weighted imaging; stereotactic procedure; diphtheria toxin; knockout mouse; learning; social behavior; behavior, animal; cerebellum nucleus; vestibular nucleus; neural pathways; working memory; adulthood; biological development; primary somatosensory cortex; hippocampus; connectivity; cell; motor coordination; learning disorder; grip strength; animal behavior; parvalbumin; nerve ending; functional connectivity; spatial memory; memory, short-term; short term memory; cell loss; engrailed 2 protein; primary motor cortex; nerve tract; nerve cell excitability; male; female; article; engrailed 1; stereotypy; gene knockout; golgi stain; chemogenetics; en1 protein, mouse; engrailed 2; molecular layer; behavioral outcome; motor learning; reversal learning; sepw1 cre gene; swimming speed; thalamus intralaminar nucleus; total distance traveled |
| Journal Title: | Nature Communications |
| Volume: | 16 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-02-21 |
| Start Page: | 1858 |
| Language: | English |
| DOI: | 10.1038/s41467-025-57080-6 |
| PUBMED: | 39984491 |
| PROVIDER: | scopus |
| PMCID: | PMC11845701 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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