Print Close

Cerebral expression and evolutionary annotation of oxytocin pathway genes

Poster No:

2115

Submission Type:

Abstract Submission

Authors:

Alina Marie Sartorius¹^,2, Jaroslav Rokicki¹^,3, Siri Birkeland⁴^,5, Francesco Bettella¹^,6, Claudia Barth¹^,7, Ann-Marie de Lange²^,8^,9, Marit Haram¹⁰^,11, Alexey Shadrin¹, Adriano Winterton¹², Nils Eiel Steen¹^,7, Emanuel Schwarz¹³, Dan Stein¹⁴, Ole Andreassen¹^,15, Dennis van der Meer¹^,16, Lars Westlye¹^,2^,15, Constantina Theofanopoulou¹⁷^,18, Daniel Santiago Quintana¹^,2^,15^,19

Institutions:

¹NORMENT, Division of Mental Health & Addiction, Oslo University Hospital & University of Oslo, Oslo, Norway, ²Department of Psychology, University of Oslo, Oslo, Norway, ³Centre of Research & Education in Forensic Psychiatry, Oslo University Hospital, Oslo, Norway, ⁴Faculty of Chemistry, Biotechnology & Food Science, Norwegian University of Life Sciences, Ås, Norway, ⁵Natural History Museum, University of Oslo, Oslo, Norway, ⁶Department of Medical Genetics, Division of Laboratory Medicine, Oslo University Hospital, Oslo, Norway, ⁷Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway, ⁸LREN, Department of Clinical Neurosciences, University of Lausanne, Lausanne, Switzerland, ⁹Department of Psychiatry, University of Oxford, Oxford, United Kingdom, ¹⁰Division of Mental Health & Addiction, Oslo University Hospital, Oslo, Norway, ¹¹Department of Mental Health & Suicide, Norwegian Institute of Public Health, Oslo, Norway, ¹²Department of Child Health & Development, Norwegian Institute of Public Health, Oslo, Norway, ¹³Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany, ¹⁴SA MRC Unit on Risk & Resilience in Mental Disorders, Universoty of Cape Town, Cape Town, South Africa, ¹⁵KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo & Oslo University Hospital, Oslo, Norway, ¹⁶School of Mental Health & Neuroscience, Faculty of Health, Medicine & Life Sciences, Maastricht University, Maastricht, Netherlands, ¹⁷Rockefeller University, New York, NY, ¹⁸New York University, New York, NY, ¹⁹NevSom, Department of Rare Disorders, Oslo University Hospital, Oslo, Norway

First Author:

Alina Marie Sartorius
NORMENT, Division of Mental Health & Addiction, Oslo University Hospital & University of Oslo|Department of Psychology, University of Oslo
Oslo, Norway|Oslo, Norway

Co-Author(s):

Jaroslav Rokicki
NORMENT, Division of Mental Health & Addiction, Oslo University Hospital & University of Oslo|Centre of Research & Education in Forensic Psychiatry, Oslo University Hospital
Oslo, Norway|Oslo, Norway

Siri Birkeland
Faculty of Chemistry, Biotechnology & Food Science, Norwegian University of Life Sciences|Natural History Museum, University of Oslo
Ås, Norway|Oslo, Norway

Francesco Bettella
NORMENT, Division of Mental Health & Addiction, Oslo University Hospital & University of Oslo|Department of Medical Genetics, Division of Laboratory Medicine, Oslo University Hospital
Oslo, Norway|Oslo, Norway

Claudia Barth
NORMENT, Division of Mental Health & Addiction, Oslo University Hospital & University of Oslo|Department of Psychiatric Research, Diakonhjemmet Hospital
Oslo, Norway|Oslo, Norway

Ann-Marie de Lange
Department of Psychology, University of Oslo|LREN, Department of Clinical Neurosciences, University of Lausanne|Department of Psychiatry, University of Oxford
Oslo, Norway|Lausanne, Switzerland|Oxford, United Kingdom

Marit Haram
Division of Mental Health & Addiction, Oslo University Hospital|Department of Mental Health & Suicide, Norwegian Institute of Public Health
Oslo, Norway|Oslo, Norway

Alexey Shadrin
NORMENT, Division of Mental Health & Addiction, Oslo University Hospital & University of Oslo
Oslo, Norway

Adriano Winterton
Department of Child Health & Development, Norwegian Institute of Public Health
Oslo, Norway

Nils Eiel Steen
NORMENT, Division of Mental Health & Addiction, Oslo University Hospital & University of Oslo|Department of Psychiatric Research, Diakonhjemmet Hospital
Oslo, Norway|Oslo, Norway

Emanuel Schwarz
Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University
Mannheim, Germany

Dan Stein
SA MRC Unit on Risk & Resilience in Mental Disorders, Universoty of Cape Town
Cape Town, South Africa

Ole Andreassen
NORMENT, Division of Mental Health & Addiction, Oslo University Hospital & University of Oslo|KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo & Oslo University Hospital
Oslo, Norway|Oslo, Norway

Dennis van der Meer
NORMENT, Division of Mental Health & Addiction, Oslo University Hospital & University of Oslo|School of Mental Health & Neuroscience, Faculty of Health, Medicine & Life Sciences, Maastricht University
Oslo, Norway|Maastricht, Netherlands

Lars Westlye
NORMENT, Division of Mental Health & Addiction, Oslo University Hospital & University of Oslo|Department of Psychology, University of Oslo|KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo & Oslo University Hospital
Oslo, Norway|Oslo, Norway|Oslo, Norway

Constantina Theofanopoulou
Rockefeller University|New York University
New York, NY|New York, NY

Daniel Santiago Quintana
NORMENT, Division of Mental Health & Addiction, Oslo University Hospital & University of Oslo|Department of Psychology, University of Oslo|KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo & Oslo University Hospital|NevSom, Department of Rare Disorders, Oslo University Hospital
Oslo, Norway|Oslo, Norway|Oslo, Norway|Oslo, Norway

Introduction:

Oxytocin (OT) is a neuropeptide involved in a range of functions across vertebrate species, from parturition and lactation (e.g., 1, 2, 3) to energy regulation (4, 5) in different vertebrates. In humans, OT has been investigated as a treatment for mental disorders and conditions due to its link to social cognition (6), albeit with inconclusive results thus far (7). The extent of OT's functions suggests its evolutionary conservation. Genetic and imaging studies on selected OT genes have aided in unraveling the role of the OT system, however, more than 150 genes are involved in OT signaling. An evolutionary timeline for all genes in the pathway remains incomplete, as does their cerebral expression. A characterization of the evolutionary history and cerebral expression of genes in the OT signaling pathway might help in better understanding the system's current function and purpose.

Methods:

To assign the 154 genes in the OT pathway to different phylostrata in evolution, we deployed BLASTp and phylostratigraphy across 39 species (26 invertebrates, 13 vertebrates), ranging from bacteria to modern humans. In addition, microsynteny was used in vertebrates. The genes were categorized as 'ancient', 'medium-aged' and 'modern' based on the resulting genes ages. We also tested for positive selection signatures in a subset of 'modern' OT pathway genes. Subsequently, the differential expression of the three gene age subsets across the human body, including the brain, was assessed with FUMA. Given the results, the cerebral expression specificity of the modern OT gene set was explored using the Allen Human Brain Atlas (AHBA; preprocessed with the abagen toolbox (8) and summarized using the included Desikan-Killiany atlas). We compared the expression of the modern OT gene set in each donor in a given brain region against the whole-brain across-donor population mean of the same gene set.

Results:

Of the 154 genes in the OT pathway, we classified 28 as evolutionary 'ancient', as they have homologs dating to 3500 – 1100 million years ago (mya). Another 28 genes had homologs dating to 1000 – 550 mya, which we classified as 'medium-aged'. The majority of the OT pathway genes (n = 98) were 'modern', having evolved between vertebrate (540 mya) and homini evolution. Of those modern genes, most emerged around jawless or jawed vertebrates (540 - 530 mya), including OXTR (encoding the OT receptor), OXT (encoding the OT ligand) and CD38 (regulating OT secretion). 44% of those were under positive selection during vertebrate evolution. The medium-aged genes were up-regulated in blood vessel and the bladder, while the modern genes were up-regulated in muscle tissue and the brain. In the human brain, those modern OT pathway genes displayed significantly up-regulated expression in four cortical regions (e.g., precentral gyrus), and they were significantly down-regulated in five sub-cortical regions (e.g., hippocampus; fig. 1). Of note, OXTR and CD38 were still above-average expressed in all subcortical regions.

Supporting Image: abagen_analysis_ScC_combined_cropped_italics_brainstem.png

·Fig. 1. Expression of modern OT pathway genes in the human brain. (a) Subcortical mRNA values. Vertical black line shows the whole-brain mean. * = pFDR < 0.05. (b) Cortical t-values (unilateral left).

Conclusions:

In this study we found that the vast majority (64%) of homologs in the OT signaling pathway emerged with and after vertebrate evolution and can thus be considered 'modern'. We further show that approximately 36% of homologs of genes supporting the OT signaling pathway date further back, that is 3500 to 550 million years. OXT, OXTR, and CD38 have their earliest homolog around 540 – 530 mya. Accordingly, we suggest that the evolution of the OT signaling pathway was a gradual process in which evolutionary ancient genes first started interacting with and supporting OT signaling around the evolution of vertebrates, but other genes joined the OT signaling system afterwards. Finding that only modern genes in the OT pathway were up-regulated in the brain, specifically the cortical regions, might indicate that cognition and social behavior were not an initial function but only have evolved later when new environmental demands required it.

Genetics:

Genetics Other ²

Neuroanatomy, Physiology, Metabolism and Neurotransmission:

Cortical Anatomy and Brain Mapping ¹

Subcortical Structures

Neuroinformatics and Data Sharing:

Brain Atlases

Databasing and Data Sharing

Keywords:

Atlasing

Cross-Species Homologues

Open Data

Preprint

Structures

Sub-Cortical

Other - Cerebral gene expression

^1|2Indicates the priority used for review

Provide references using author date format

(1) Vargas-Pinilla, P. (2015). Evolutionary pattern in the OXT-OXTR system in primates: Coevolution and positive selection footprints. Proceedings of the National Academy of Sciences, 112(1), 88-93. https://doi.org/10.1073/pnas.1419399112. (2) Howarth, G. (2001). Amniotomy plus intravenous oxytocin for induction of labour. The Cochrane Database of Systematic Reviews, 3: CD003250. https://doi.org/10.1002/14651858.CD003250. (3) Ruis, H. (1981). Oxytocin enhances onset of lactation among mothers delivering prematurely. BMJ, 283(6287), 340-342. https://doi.org/10.1136/bmj.283.6287.340. (4) Blevins, J. E. (2015). Translational and therapeutic potential of oxytocin as an anti-obesity strategy: Insights from rodents, nonhuman primates and humans. Physiology & Behavior, 152, B, 438-449. https://doi.org/10.1016/j.physbeh.2015.05.023. (5) Jurek, B. (2018). The oxytocin receptor: From intracellular signaling to behavior. Physiological Reviews, 98(3), 1805-1908. https://doi.org/10.1152/physrev.00031.2017. (6) Quintana, D. S. (2015). Low dose oxytocin delivered intranasally with Breath Powered device affects social-cognitive behavior: a randomized 4-way crossover trial with nasal cavity dimension assessment. Translational Psychiatry, 5(7), e602. https://doi.org/10.1038/tp.2015.93. (7) Bradley, E. R. (2017). Oxytocin effects in schizophrenia: Reconciling mixed findings and moving forward. Neuroscience & Biobehavioral Reviews, 80, 35-56. https://doi.org/10.1016/j.neubiorev.2017.05.007. (8) Markello, R. D. (2021). Standardizing workflows in imaging transcriptomics with the abagen toolbox. eLife, 10:e72129. https://doi.org/10.7554/eLife.72129.