Section The R00 phase of this project will be conducted at the University of Illinois, Urbana-Champaign in the Department of Comparative Biosciences, College of Veterinary Medicine. Major psychiatric disorders, such as schizophrenia (SZ) and major depression, involve abnormal social behaviors and onset typically occurs after puberty. The genetic risk factors for SZ are frequently heterozygous in affected individuals and the clinical phenotypes can be highly variable. However, the factors that contribute to phenotypic variance and the timing of the onset of these disorders are poorly understood. Genomic imprinting is an epigenetic mechanism that causes preferential expression of the maternal or paternal allele for some genes. Imprinting causes parent-of-origin effects that influence the phenotype of inherited mutations. Canonical imprinting involves complete silencing of one parent?s allele and impacts a small number of genes. However, the author?s lab discovered that hundreds of genes in the mouse that exhibit a maternal or paternal allele expression bias. This phenomenon is called noncanonical imprinting. Noncanonical imprinting is highly enriched in the brain compared to the liver or muscle. Using a novel allele-specific in situ hybridization approach, the author found that noncanonical imprinted genes exhibit monoallelic expression in subpopulations of cells in the brain, suggesting a highly cell-type specific form of imprinting. Currently, it is not known whether noncanonical imprinting is a cell-type specific form of imprinting in the brain. Further, the field does not know whether noncanonical imprinting can change at puberty or whether social behaviors are impacted. The author found that tyrosine hydroxylase (Th) and dopa decarboxylase (Ddc) are noncanonical imprinted genes with a maternal allele bias in specific regions of the brain. TH and DDC synthesize monoamine neurotransmitters, which have important roles in social behavior and mental illness. Here, the author will test the hypothesis that noncanonical imprinting effects in monoaminergic circuits are a highly cell-type specific form of imprinting that can change in response to pubertal development and impact social behaviors with roles in mental illness.
Aim 1 will determine whether noncanonical imprinting is a cell-type specific form of imprinting in the monoamine system of the hypothalamus and uncover the hormone signaling mechanisms operational within each monoamine cell type using single-cell RNASeq.
Aim 2 will determine whether noncanonical imprinting in the preoptic area (POA) and arcuate nucleus (ARN) changes at puberty by profiling imprinting before and after puberty using RNASeq methods. The POA and ARN play important roles in puberty and social behaviors and preliminary data shows that noncanonical imprinting can change in these regions in response to hormonal signaling.
In Aim 3, Ddc heterozygous mutant mice will be used to determine whether noncanonical imprinting in monoamine circuits impacts offspring social behaviors. Social behaviors that are impacted in mental illness will be tested, including aggression, social recognition, social reward and reproductive behaviors.
This training program and study will advance our understanding of the expression of maternally and paternally inherited alleles in the brain and in neurons with important roles in social behavior and mental health. The proposed research is relevant to public health because it could lead to improvements in our ability to evaluate genetic risk factors for mental illness according to whether mutations are maternally or paternally derived.