Abstract
Sonic hedgehog (SHH) signaling is essential for the differentiation and migration of early stem cell populations during cerebellar development. Dysregulation of SHH-signaling can result in cerebellar overgrowth and the formation of the brain tumor medulloblastoma. Treatment for medulloblastoma is extremely aggressive and patients suffer life-long side effects including behavioral deficits. Considering that other behavioral disorders including autism spectrum disorders, holoprosencephaly, and basal cell nevus syndrome are known to present with cerebellar abnormalities, it is proposed that some behavioral abnormalities could be inherent to the medulloblastoma sequalae rather than treatment. Using a haploinsufficient SHH receptor knockout mouse model (Ptch1+/−), a partner preference task was used to explore activity, social behavior and neuroanatomical changes resulting from dysregulated SHH signaling. Compared to wild-type, Ptch1+/− females displayed increased activity by traveling a greater distance in both open-field and partner preference tasks. Social behavior was also sex-specifically modified in Ptch1+/− females that interacted more with both novel and familiar animals in the partner preference task compared to same-sex wild-type controls. Haploinsufficiency of PTCH1 resulted in cerebellar overgrowth in lobules IV/V and IX of both sexes, and female-specific decreases in hippocampal size and isocortical layer thickness. Taken together, neuroanatomical changes related to deficient SHH signaling may alter social behavior.
Highlights
The cerebellum is a brain region important for coordinating control of voluntary motor movement, muscle tone, and balance (Altman and Bayer, 1997)
Normal cerebellar function depends on properly integrated actions of neurons residing in the three distinctive layers of the mature cerebellum: the molecular layer (ML), Purkinje cell layer (PL), and the internal granular layer (IGL)
Granule cell precursors (GCPs) arise from a population of rhombic lip progenitors that migrate to the cerebellum and form the external germinal layer (EGL) where GCP proliferation continues until post-natal day 15 in mouse (Altman and Bayer, 1997)
Summary
The cerebellum is a brain region important for coordinating control of voluntary motor movement, muscle tone, and balance (Altman and Bayer, 1997). Emerging evidence supports the existence of behavioral circuits integrating the cerebellum, prefrontal cortex, and thalamus through dopaminergic signaling (Rogers et al., 2013a). Normal cerebellar function depends on properly integrated actions of neurons residing in the three distinctive layers of the mature cerebellum: the molecular layer (ML), Purkinje cell layer (PL), and the internal granular layer (IGL). Granule cell precursors (GCPs) arise from a population of rhombic lip progenitors that migrate to the cerebellum and form the external germinal layer (EGL) where GCP proliferation continues until post-natal day 15 in mouse (Altman and Bayer, 1997). During the postnatal period of cerebellar development, the GCPs mitotically arrest, differentiate, and migrate through the ML and PL, and reach their final destination in the IGL as mature granule cells. Development of the stereotypic structure of the cerebellum is a tightly regulated process that requires specific gradients of key morphogens (Martinez et al, 2013)
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