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. Haploinsufficency of PTCH 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.
Footnotes
Email address: Thomas Jackson: twjacks2{at}ncsu.edu, Gabriel Bendfeldt: gabendfe{at}ncsu.edu, Kelby Beam: kabeam2{at}ncsu.edu, Kylie Rock: kdrock{at}ncsu.edu, Scott Belcher: smbelch2{at}ncsu.edu
Funding: This work was supported in part by NIEHS training grant 5T32ES007046-38 and NIEHS grant P30ES025128.
Conflicts: The authors declare no conflicts of interest.
Abbreviations: ASD, Autism Spectrum Disorder; BCNS, Basal cell nevus syndrome; EGL, External germinal layer; ERβ, Estrogen receptor beta; GCPs, Granule cell precursors; HPE, holoprosencephaly; IGL, Internal granular layer; MB, medulloblastoma; ML, Molecular layer; mPFC, Medial prefrontal cortex; PL, Purkinje cell layer; Shh, Sonic hedgehog; ThN md and ThN vl, Thalamic mediodorsal and ventrolateral nuclei; VTA, Ventral tegmental area