Oxytocin and vasopressin neural networks: Implications for social behavioral diversity and translational neuroscience

Abstract

Oxytocin- and vasopressin-related systems are present in invertebrate and vertebrate bilaterian animals, including humans, and exhibit conserved neuroanatomical and functional properties. In vertebrates, these systems innervate conserved neural networks that regulate social learning and behavior, including conspecific recognition, social attachment, and parental behavior. Individual and species-level variation in central organization of oxytocin and vasopressin systems has been linked to individual and species variation in social learning and behavior. In humans, genetic polymorphisms in the genes encoding oxytocin and vasopressin peptides and/or their respective target receptors have been associated with individual variation in social recognition, social attachment phenotypes, parental behavior, and psychiatric phenotypes such as autism. Here we describe both conserved and variable features of central oxytocin and vasopressin systems in the context of social behavioral diversity, with a particular focus on neural networks that modulate social learning, behavior, and salience of sociosensory stimuli during species-typical social contexts.

Keywords: Autism spectrum disorders; Avpr1a; Functional connectivity; Functional coupling; Neuropeptides; Oxtr; Pair bonding; Salience; Social attachment; Social behavior; Social behavior network; Social cognition; Social decision-making network; Valence.

Figure 1. Morphology, neuroanatomical projections, and release mechanisms of OT neurons

This schematic represents current views of OT neuronal structure and function. Magnocellular and parvocellular OT neurons project to distinct targets. In addition to projections to the posterior pituitary, magnocellular OT axons can innervate extrahypothalamic forebrain and midbrain regions, and dendrites can contact the third ventricle. In contrast, parvocellular OT neurons are thought to project predominantly to hindbrain and brainstem regions. Glutamatergic networks link magnocellular OT neurons and are thought to synchronize pulsatile release into the periphery. Though not pictured, axon collaterals from some parvocellular OT neurons can synapse onto, excite, and trigger OT release from magnocellular OT neurons in the SON. OT is stored in LDCVs that populate the soma, dendrites, and axons but are typically absent in terminals; thus en passant release is thought to be the primary form of axonal OT release. Axonal and somatodendritic OT release can be triggered without depolarization via activation of MC4Rs or the activity of transmembrane proteins such as CD38. Following somatodendritic release, OT can bind to autoreceptors and prime OT neurons for firing, and may also volume diffuse to other central targets. Abbreviations: BBB=blood brain barrier; 3V=3^rd ventricle.

Figure 2. Diversity in region-specific OTR expression is associated with diversity in social behavior

Representative autoradiograms illustrate accumbal OTR binding density (indicated by black labeling) in rodent and primate species exhibiting divergent social behaviors and mating strategies: (A) mouse, (B) montane vole, (C) rhesus macaque, (D) “low” OTR-expressing prairie vole, (E) “high” OTR-expressing prairie vole, and (F) marmoset. Black arrowheads indicate position of the NAc in each section. In contrast to mice, montane voles, and rhesus macaques, prairie voles and marmosets exhibit alloparental behavior, socially monogamous mating strategies, and dense OTR binding in the NAc (D-F versus A-C). This same pattern is observed across individual prairie voles, which vary in region-specific OTR densities (e.g. D versus E) and social behavior: OTR density in the NAc is positively correlated with individual variation in both alloparental care and socially monogamous behavior. Thus, region-specific OTR expression is associated with individual and species diversity in social behavior, although it is not sufficient to predict social behavioral phenotype in all mammals. OTR expression in the NAc represents one of several examples linking region-specific OT/AVP-like receptor expression to social behavioral phenotype in birds and mammals, a topic that is discussed in more depth in under “OT/AVP-like receptors contribute to social behavioral diversity.” Autoradiograms were adapted from (Burbach et al., 2006) and (Freeman and Young, 2016) with permission.

Figure 3. Oxytocin and vasopressin modulate distributed neural networks during social contexts

(A) Schematic highlighting brain regions in which OTR (red) and/or V1aR (blue; purple indicates both systems are important) activation is thought to modulate social information processing and/or behavior in prairie voles and other species. For example, regions outlined in black represent a simplified neural network model of OTR-expressing brain regions that are thought to distributively encode both valence and incentive salience of social stimuli (e.g. individual sociosensory profiles). Select dopamine (green), OT (maroon), and other (black) axonal projections are thought to be critical for these processes. AVP axonal projections are not depicted for clarity; however, V1aR activation in the LS and VP are also thought to modulate these processes. Additional systems that are not depicted (e.g. corticotrophin releasing factor, µ- and κ-opioid, etc.) are also important. Regions that are thought to modulate additional dimensions of social learning and behavior in prairie voles are included. For example, V1aRs in the retrosplenial cortex (RSC) are thought to modulate sociospatial memory, while OTRs in the anterior cingulate cortex (ACC) are critical for consoling behavior. Abbreviations: ACC=anterior cingulate cortex; AON=anterior olfactory nucleus; BLA=basolateral amygdala; LS=lateral septum; MeA=medial amygdala; MOB=main olfactory bulb; NAc=nucleus accumbens; PFC=prefrontal cortex; PVN=paraventricular nucleus of the hypothalamus; RSC=retrosplenial cortex; VP=ventral pallidum; VTA=ventral tegmental area. (B) Central OTRs modulate correlated Fos expression across a hypothesized “social salience network” during sociosexual interaction and mating in male prairie voles. Heatmaps represent pairwise correlation coefficients of Fos expression between nodes of the network in three experimental treatment groups. Following central administration of artificial cerebral spinal fluid (aCSF), social isolation is associated with weakly correlated Fos expression across the network. In contrast, aCSF-treatment followed by sociosexual interaction and mating with a female is associated with strongly and positively correlated Fos expression across the network as a whole. This effect is disrupted by central administration of a selective OTR antagonist (OTA) prior to sociosexual interaction and mating, which is associated with a significant decrease in correlated Fos expression across nodes of the network. These and other data are consistent with hypotheses that central OT/AVP-like signaling modulates distributed network states during social contexts in vertebrates, and are reviewed under “OT/AVP-like neuromodulation of social information processing networks.” Heatmaps were adapted from (Johnson et al., 2016a) with permission. Abbreviations (see above): NAcc=nucleus accumbens core; NAcs=nucleus accumbens shell.