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Co-Regulation of Hormone Receptors, Neuropeptides, and Steroidogenic Enzymes 2 Across the Vertebrate Social Behavior Network 3 4 Brent M

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Co-Regulation of Hormone Receptors, Neuropeptides, and Steroidogenic Enzymes 2 Across the Vertebrate Social Behavior Network 3 4 Brent M bioRxiv preprint doi: https://doi.org/10.1101/435024; this version posted October 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Co-regulation of hormone receptors, neuropeptides, and steroidogenic enzymes 2 across the vertebrate social behavior network 3 4 Brent M. Horton1, T. Brandt Ryder2, Ignacio T. Moore3, Christopher N. 5 Balakrishnan4,* 6 1Millersville University, Department of Biology 7 2Smithsonian Conservation Biology Institute, Migratory Bird Center 8 3Virginia Tech, Department of Biological Sciences 9 4East Carolina University, Department of Biology 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 1 bioRxiv preprint doi: https://doi.org/10.1101/435024; this version posted October 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Running Title: Gene expression in the social behavior network 2 Keywords: dominance, systems biology, songbird, territoriality, genome 3 Corresponding Author: 4 Christopher Balakrishnan 5 East Carolina University 6 Department of Biology 7 Howell Science Complex 8 Greenville, NC, USA 27858 9 [email protected] 10 2 bioRxiv preprint doi: https://doi.org/10.1101/435024; this version posted October 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Abstract 2 The vertebrate basal forebrain and midbrain contain a set of interconnected nuclei 3 that control social behavior. Conserved anatomical structures and functions of these 4 nuclei have now been documented among fish, amphibians, reptiles, birds and mammals, 5 and these brain regions have come to be known as the vertebrate social behavior network 6 (SBN). While it is known that nuclei (nodes) of the SBN are rich in steroid and 7 neuropeptide activity linked to behavior, simultaneous variation in the expression of 8 neuroendocrine genes among several SBN nuclei has not yet been described in detail. 9 In this study, we use RNA-seq to profile gene expression across seven brain regions 10 representing five nodes of the vertebrate SBN in a passerine bird, the wire-tailed manakin 11 Pipra filicauda. Using weighted gene co-expression network analysis (WGCNA), we 12 reconstructed sets of coregulated genes, revealing striking patterns of variation in 13 neuroendocrine gene expression across the SBN. We describe regional expression 14 variation networks comprising a broad set of hormone receptors, neuropeptides, 15 steroidogenic enzymes, catecholamines, and other neuroendocrine signaling molecules. 16 Our findings highlight how heterogeneity of brain gene expression across the SBN can 17 provide functional insights into the neuroendocrine and genetic mechanisms that underlie 18 vertebrate social behavior. 19 20 21 INTRODUCTION 22 Over the last two decades, our understanding of the neuroendocrine and genetic 23 bases of vertebrate social behavior has progressed rapidly due to integrated studies of 24 how hormones and gene expression interact to modulate brain function and, ultimately, 25 behavior.1,2 Much of this research has focused on well-defined neural circuits that are 26 highly conserved across vertebrate taxa, such as the social behavior network (SBN). The 27 vertebrate SBN comprises six reciprocally connected brain regions, or nodes, located in 28 the basal (i.e., ‘limbic’) forebrain and midbrain.3,4 These nodes are: 1) the extended medial 29 amygdala, including the bed nucleus of the stria terminalis (BSTm) and, in birds, nucleus 30 taenia (TnA); 2) the lateral septum (LS); 3) the preoptic area (POA); 4) the anterior 31 hypothalamus (AH); 5) the ventromedial hypothalamus (VMH); and 6) the midbrain 3 bioRxiv preprint doi: https://doi.org/10.1101/435024; this version posted October 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 central grey (CG), including the intercollicular nucleus (ICo). Mounting evidence from 2 multiple vertebrate taxa suggests that these nodes are activated to varying degrees 3 during social interactions, and that collective neural activity across these nodes plays an 4 essential role in regulating various forms of social behavior (e.g., sexual behavior, 5 aggression, parental care, and social affiliation).3–7 Because the SBN represents a 6 fundamental element of the neural machinery underlying vertebrate social behavior, the 7 brain regions that make up this network are prime focal points for investigating how 8 changes in neuroendocrine activity and gene expression modulate intraspecific and 9 interspecific variation in behavior.8–10 10 11 The sex steroids and nonapeptide hormones (e.g., vasopressin, oxytocin) are potent 12 regulators of vertebrate social behavior. Accordingly, the brain regions of the SBN are 13 generally rich in sex steroid and nonapeptide receptors and thus responsive to these 14 hormones.3,4,6,11–14 The sex steroids and nonapeptides can have multiple receptors15–18 15 and the distribution of these receptors determines the sensitivity of the SBN nodes to 16 hormone action. In addition, regions of the SBN are, to varying degrees, sites of steroid 17 and nonapeptide hormone synthesis and metabolism. 14,19 Our understanding of how 18 these hormones act to modulate social behavior requires a holistic approach that can 19 quantify the patterns of neuroendocrine gene expression that dictate hormone action in 20 the SBN, including genes for hormone receptors, steroidogenic enzymes, and 21 nonapeptides. Moreover, steroids can act through both genomic and non-genomic 22 pathways to affect gene expression and subsequent behavior.15,16,20 As such, identifying 23 the molecular products of steroid actions that influence neuron activity in the SBN can 24 shed much needed light on the mechanistic underpinnings of steroid-mediated behavior. 25 26 The accessibility of RNA sequencing (RNA-seq) technology to researchers studying 27 non-traditional model organisms provides new and exciting opportunities to deepen our 28 understanding of the molecular pathways through which hormones influence the brain 29 and behavior.9,21–23 Functional genomics provides an ideal tool for beginning to 30 understand how suites or networks of co-expressed genes modulate behavior. To date, 31 a number of studies have leveraged whole-brain transcriptomic data to identify the gene 4 bioRxiv preprint doi: https://doi.org/10.1101/435024; this version posted October 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 modules (i.e., sets of co-regulated genes) underlying among-individual variation due to 2 sex, social status, ecotype, and reproductive strategy22,24–26 as well as interspecific 3 differences in reproductive and social behaviors across species.27–29 Mounting evidence 4 suggests, however, that patterns of gene co-expression vary among subdivisions of the 5 vertebrate brain.30–33 For example, studies of birds and mammals have revealed 6 distinctive gene co-expression profiles in the amygdala and hypothalamus34–36, 7 suggesting that suites of behaviorally relevant genes are differentially expressed among 8 nodes of the SBN. Indeed, results from candidate gene studies have demonstrated that 9 expression levels of key neuroendocrine genes can vary widely across regions of the 10 SBN, and that relationships between neuroendocrine gene expression and behavior are 11 region-dependent.14,36–38 Moving forward, it is therefore necessary to examine individual 12 nuclei (or cell groups) as opposed to whole brains to learn how patterns of gene co- 13 expression across nodes of the SBN and other behavioral circuits underlie variation in 14 social behavior.9 To our knowledge, no study has yet employed whole-transcriptome 15 sequencing to compare gene co-expression profiles across several nuclei of the avian 16 SBN. 17 18 To continue probing the neuroendocrine and genomic architecture of complex social 19 behaviors, we used RNA-seq and weighted gene co-expression network analyses 20 (WGCNA) to describe region-specific patterns of gene expression across multiple nodes 21 of the SBN in the male wire-tailed manakin (Pipra filicauda). This South American lek- 22 breeding bird exhibits a rare form of cooperation, whereby males form coalitions to 23 perform elaborate cooperative courtship displays. These males establish long-term 24 display partnerships that form the basis of complex social networks, and which have clear 25 fitness benefits for both territorial (i.e., increased reproductive success)39 and non- 26 territorial males (i.e., increased probability of territory acquisition).40 Territorial and non- 27 territorial males show substantial variation in behavioral phenotype, yet the hormonal and 28 genetic bases for these differences remain largely unknown. Here, we sequenced total 29 RNA extracted from six distinct brain nuclei (BSTm, TnA, LS, POM, VMH, and ICo) 30 representing five of the six nodes of the vertebrate SBN, and an additional brain region 31 (arcopallium intermedium, AI) hypothesized to be involved in androgen-dependent 5 bioRxiv preprint doi: https://doi.org/10.1101/435024; this version posted October 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
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