The Unipolar Brush Cells (UBCs) are interneurons situated in the cerebellar granular layer and in granule cell containing regions of the cochlear nuclear complex. In the cerebellar cortex, UBCs and granule cells share mossy fiber inputs and represent the only two excitatory glutamatergic neuron classes. In rodents, UBCs have a more restricted distribution than in other mammals and abound in vestibulo-cerebellar lobules, with minor contingents in other lobules of the midline vermis. Across mammalian species, UBCs are preferentially associated with sensory input systems, while they appear to eschew regions targeted primarily by the cortico-ponto-cerebellar pathway. The UBC has typically only one dendrite that terminates with a brush of dendrioles;these establish a giant excitatory synapse with the rosette-like terminal of a mossy fiber;UBC axons ramify among granule cells and form a strikingly unique, cortex-intrinsic system of mossy fiber-like branches. The UBC, with its one-to-one giant synapse, is thought to amplify the input of an individual fiber and synchronize the activity of hundreds of target granule cells, thus influencing the firing pattern of subsets of overlying Purkinje cells. While in cerebellum UBCs are highly enriched in the caudal vermal and lateral lobules densely innervated by primary and secondary vestibular fibers, in the cochlear nuclear complex their density is highest in the polysensory innervated dorsal nucleus. Consequently, the notion has been put forward that these unique neurons are important for regulating head position in space, influencing posture and eye movements and improving auditory performance. Previous evidence indicates the UBC population is chemically heterogeneous and consists of two main chemotypes, a subset expressing the calcium binding protein calretinin, and a calretinin-negative subset expressing the metabotropic glutamate receptor mGluR1a. In this competitive renewal, the P.I. and his collaborators propose to test individual facets of the hypotheses that the properties of UBCs subclasses are related to specific types of inputs, that additional subclass specific chemotypes exist, and that input qualities transmitted by the UBC axon affect the cerebellar network.
Specific aims will analyze possible sublineage specific inputs of UBCs, investigate their developmental plasticity and electrophysiologic properties, search for novel UBC chemotypes and study the network impact of UBC excitation. The proposed research is based on multidisciplinary approaches and will be primarily centered on mice to take advantage of the availability of strains of mutant animals with genetically transmitted neurological defects as well as of bacterial artificial chromosome (BAC)-transgenic mice expressing enhanced green fluorescent protein (eGFP) under the control of a specific promoter.

Public Health Relevance

Unipolar brush cells are a heterogeneous class of neurons that are part of the hindbrain's microcircuits regulating body posture, head position in space, eye movements and orienting to sounds. This research proposal will identify differential properties of the two major subclasses of these cells and conduct experiments designed to understand the cells' functions utilizing anatomical, biochemical, electrical and gene discovery techniques.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Auditory System Study Section (AUD)
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Chen, Daofen
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Northwestern University at Chicago
Anatomy/Cell Biology
Schools of Medicine
United States
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Sekerkova, Gabriella; Watanabe, Masahiko; Martina, Marco et al. (2014) Differential distribution of phospholipase C beta isoforms and diaglycerol kinase-beta in rodents cerebella corroborates the division of unipolar brush cells into two major subtypes. Brain Struct Funct 219:719-49
Perge, Janos A; Niven, Jeremy E; Mugnaini, Enrico et al. (2012) Why do axons differ in caliber? J Neurosci 32:626-38
Kim, Jin-Ah; Sekerkova, Gabriella; Mugnaini, Enrico et al. (2012) Electrophysiological, morphological, and topological properties of two histochemically distinct subpopulations of cerebellar unipolar brush cells. Cerebellum 11:1012-25
Mugnaini, Enrico; Sekerkova, Gabriella; Martina, Marco (2011) The unipolar brush cell: a remarkable neuron finally receiving deserved attention. Brain Res Rev 66:220-45
Birnstiel, S; Slater, N T; McCrimmon, D R et al. (2009) Voltage-dependent calcium signaling in rat cerebellar unipolar brush cells. Neuroscience 162:702-12
Nunzi, M G; Mugnaini, E (2009) Aspects of the neuroendocrine cerebellum: expression of secretogranin II, chromogranin A and chromogranin B in mouse cerebellar unipolar brush cells. Neuroscience 162:673-87
Dino, M R; Mugnaini, E (2008) Distribution and phenotypes of unipolar brush cells in relation to the granule cell system of the rat cochlear nucleus. Neuroscience 154:29-50
Russo, Marco J; Yau, Hau-Jie; Nunzi, Maria-Grazia et al. (2008) Dynamic metabotropic control of intrinsic firing in cerebellar unipolar brush cells. J Neurophysiol 100:3351-60
Sekerkova, G; Dino, M R; Ilijic, E et al. (2007) Postsynaptic enrichment of Eps8 at dendritic shaft synapses of unipolar brush cells in rat cerebellum. Neuroscience 145:116-29
Morin, F; Dino, M R; Mugnaini, E (2001) Postnatal differentiation of unipolar brush cells and mossy fiber-unipolar brush cell synapses in rat cerebellum. Neuroscience 104:1127-39

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