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Neural substrates of impaired behavioral inhibition in Williams syndrome, a disorder of social cognition


The evolution of the human brain has yielded advanced cognitive capacities supporting the development of language, technologically advanced material culture, and highly complex social behavior that has allowed for the development of the rich diversity of human cultures. Comparative neuroanatomy in evolutionary perspective continues to make great strides in characterizing and defining unique elements of the human neuroanatomical phenotype at the gross and microscopic level that underlie these key behavioral adaptations. In conjunction with these studies, an understanding of the functional implications of derived anatomical traits is gained through analyses of neurodevelopmental disorders, which help to define a spectrum of variation in the diversity of human brain phenotypes. Williams syndrome (WS) is a rare neurodevelopmental disorder caused by a hemideletion of ~1.6 Mb (25-28 genes) on human chromosome 7q11.23, a highly dynamic region associated with recent adaptive selection in hominoid lineages. Analyzing the neuroanatomical phenotype in WS provides the unique opportunity to study correlates of a distinctive cognitive and behavioral phenotype in a neurodevelopmental disorder of known genetic cause. Among the most notable behavioral phenotypes observed in WS is a generalized disinhibition of social behavior, likely rooted in the dysfunction of frontostriatal circuitry. We targeted the rostral territories of the striatum in that share important connectivity with the prefrontal cortex in reward circuitry. We provide new evidence for variation in neuroanatomy in WS underlying its unusual social and cognitive phenotype. Specifically, we found increased glial cell density in the caudate nucleus of the striatum, as well as a significant increase in the density of oligodendrocytes in the medial caudate nucleus, likely related to dysfunctional connectivity with the prefrontal cortex. We additionally found a decrease in the density of cholinergic interneurons in the medial caudate nucleus, which may serve important functions in the regulation of social interaction. These data suggest that deficits in behavioral control may be linked to dysfunction of local circuitry within the striatum in WS, mediated by imbalance between neuronal and glial cell density and interneuron function, which may underlie important differences in social behavior.

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