Recent work has provided evidence for functional connections between the cerebellum and cerebral cortex, with the hemispheres and central zone of the vermis housing the main cerebro-cerebellar circuits. Cerebellar neuropathologies have been detected in cognitive disorders including autism spectrum disorder (ASD), schizophrenia and dementias, and modulation of Purkinje neurons in one lobule in the right lateral cerebellum results in altered social and cognitive behaviors. The excitatory neurons of the cerebellar nuclei (eCN) are the output neurons of the cerebellum that interconnect with the cerebral cortex via the pons and thalamus, but their development, electrophysiology and molecular genetics are poorly understood. In particular, functional relationships between the cerebellar nuclei and cerebral cortex have not been demonstrated. In order to understand how the cerebellum functions and modulates the activity of the cerebral cortex, it is necessary to define the molecular diversity of the eCN, understand how eCN subpopulations (subP) develop, map their circuitry and relate cerebro-cerebellar functions to specific eCN subP. A major problem for such studies is a lack of genetic tools for specifically marking and modulating eCN. This project will define molecular subP of the eCN and determine how and when the subP form during normal development and in developmental mutants in which a subset of eCN are lost (En1/2 mutants) using single cell RNA sequencing (scRNA-seq). Mouse lines will then be developed to manipulate eCN subP and applied to mapping the synaptic partners of subP of eCN and to optogenetics to inhibit/activate specific eCN. Electrophysiology and cognitive/social behavior assays will be used to determine the functional interactions between specific subP of the eCN and regions of the cerebral cortex. This project represents the first definition of the molecular subP of the cerebellar nuclei and determination of their functional impact on cerebral cortex functions.
The cerebellum, in addition to the cerebral cortex, is involved in cognitive and social disorders including autism and schizophrenia, however little is know of the neural circuits that connect the two brain structures. We will map how distinct subpopulations of neurons in the cerebellum project to the cerebral cortex during development and determine how they influence cerebro-cerebellar functions. Our results will provide insights into how cerebro-cerebellar circuits function and might be therapeutically modified in diseases.
|Bayin, N Sumru; Wojcinski, Alexandre; Mourton, Aurelien et al. (2018) Age-dependent dormant resident progenitors are stimulated by injury to regenerate Purkinje neurons. Elife 7:|
|Tan, I-Li; Wojcinski, Alexandre; Rallapalli, Harikrishna et al. (2018) Lateral cerebellum is preferentially sensitive to high sonic hedgehog signaling and medulloblastoma formation. Proc Natl Acad Sci U S A 115:3392-3397|
|Legué, Emilie; Gottshall, Jackie L; Jaumouillé, Edouard et al. (2016) Differential timing of granule cell production during cerebellum development underlies generation of the foliation pattern. Neural Dev 11:17|
|Joyner, Alexandra L (2016) From Cloning Neural Development Genes to Functional Studies in Mice, 30 Years of Advancements. Curr Top Dev Biol 116:501-15|
|Leto, Ketty; Arancillo, Marife; Becker, Esther B E et al. (2016) Consensus Paper: Cerebellar Development. Cerebellum 15:789-828|
|Leffler, Shoshana R; Legué, Emilie; Aristizábal, Orlando et al. (2016) A Mathematical Model of Granule Cell Generation During Mouse Cerebellum Development. Bull Math Biol 78:859-78|
|Szulc, Kamila U; Lerch, Jason P; Nieman, Brian J et al. (2015) 4D MEMRI atlas of neonatal FVB/N mouse brain development. Neuroimage 118:49-62|
|Legué, Emilie; Riedel, Elyn; Joyner, Alexandra L (2015) Clonal analysis reveals granule cell behaviors and compartmentalization that determine the folded morphology of the cerebellum. Development 142:1661-71|
|Sgadò, Paola; Genovesi, Sacha; Kalinovsky, Anna et al. (2013) Loss of GABAergic neurons in the hippocampus and cerebral cortex of Engrailed-2 null mutant mice: implications for autism spectrum disorders. Exp Neurol 247:496-505|
|Orvis, Grant D; Hartzell, Andrea L; Smith, Jenessa B et al. (2012) The engrailed homeobox genes are required in multiple cell lineages to coordinate sequential formation of fissures and growth of the cerebellum. Dev Biol 367:25-39|
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