Parent-of-origin dependent allelic regulation of social behaviors in mice by noncanonically imprinted monoamine synthesis genes

Monoamine neurotransmitters are central regulators of social behavior, yet it is unknown whether genomic imprinting of genes within their signaling pathways modulate these behaviors. The monoamine synthesis genes tyrosine hydroxylase (Th) and dopa decarboxylase (Ddc) exhibit tissue-specific, noncanonical imprinting in mice, with preferential maternal allele expression in the brain and paternal biased Ddc expression in peripheral tissues. Prior work indicated that imprinting of these genes causes parent-of-origin dependent allelic influences on mood-related and foraging behaviors. Here, we test whether alleles in this pathway also shape social behavior in a parent-of-origin-dependent manner. We identify strong maternal allele-biased expression of Th and Ddc in the anteroventral and preoptic periventricular (AVPV/PVpo) area of the hypothalamus using reciprocal CAST/EiJ x C57Bl/6J F1 hybrids and pyrosequencing-based allelic quantification. This region contains a sexually dimorphic dopaminergic cell population that is implicated in regulating social behaviors with prominent sex differences, though we did not detect sex differences in allelic bias in either tissue for Th or Ddc. To determine whether the parent-of-origin of Th and Ddc alleles influences social behavior we use reciprocal heterozygous null-allele mice. In males, maternally inherited Th null alleles reduce sociability, whereas paternally inherited Ddc null alleles increase aggression and impair social recognition. These behavioral outcomes align with the tissue-specific maternal Th and paternal Ddc expression biases. Together, these findings provide the first evidence that noncanonical imprinting of monoamine synthesis genes modulates social behavior in a mammalian organism. Parent-of-origin effects in the monoamine pathway may therefore contribute to natural variation in social behavior.