title: Alterations in the expression of a neurodevelopmental gene exert long-lasting effects on cognitive-emotional phenotypes and functional brain networks: translational evidence from the stress-resilient Ahi1 knockout mouse.
abstract: Many psychiatric disorders are highly heritable and may represent the clinical outcome of early aberrations in the formation of neural networks. The placement of brain connectivity as an 'intermediate phenotype' renders it an attractive target for exploring its interaction with genomics and behavior. Given the complexity of genetic make up and phenotypic heterogeneity in humans, translational studies are indicated. Recently, we demonstrated that a mouse model with heterozygous knockout of the key neurodevelopmental gene Ahi1 displays a consistent stress-resilient phenotype. Extending these data, the current research describes our multi-faceted effort to link early variations in Ahi1 expression with long-term consequences for functional brain networks and cognitive-emotional phenotypes. By combining behavioral paradigms with graph-based analysis of whole-brain functional networks, and then cross-validating the data with robust neuroinformatic data sets, our research suggests that physiological variation in gene expression during neurodevelopment is eventually translated into a continuum of global network metrics that serve as intermediate phenotypes. Within this framework, we suggest that organization of functional brain networks may result, in part, from an adaptive trade-off between efficiency and resilience, ultimately culminating in a phenotypic diversity that encompasses dimensions such as emotional regulation and cognitive function.
authors.affiliation: Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Lotan
authors.affiliation: Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Lifschytz
authors.affiliation: Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: B
authors.initials: B
authors.lastname: Mernick
authors.affiliation: MRI Laboratory, Human Biology Research Center, Department of Nuclear Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Lory
authors.affiliation: The Rachel and Selim Benin School of Computer Science and Engineering, Hebrew University, Jerusalem, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Levi
authors.affiliation: MRI Laboratory, Human Biology Research Center, Department of Nuclear Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Ben-Shimol
authors.affiliation: MRI Laboratory, Human Biology Research Center, Department of Nuclear Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: G
authors.initials: G
authors.lastname: Goelman
authors.affiliation: Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: B
authors.initials: B
authors.lastname: Lerer
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001921:Brain / Q000503:physiopathology; D001931:Brain Mapping; D003071:Cognition / Q000502:physiology; D004644:Emotions / Q000502:physiology; D005260:Female; D015870:Gene Expression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009415:Nerve Net / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C465818:Ahi1 protein, mouse; D011518:Proto-Oncogene Proteins