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Official websites use. Share sensitive information only on official, secure websites. Correspondence Brian Trainor: bctrainor ucdavis. Oxytocin is a neuropeptide that can produce anxiolytic effects and promote social approach. However, emerging evidence shows that under some conditions, oxytocin can instead induce anxiety-related behaviors. These diverse effects of oxytocin appear to be mediated by circuit-specific actions. Recent data showed that inhibition of oxytocin receptors OTRs in the bed nucleus of the stria terminalis BNST was sufficient to increase social approach and decrease social vigilance in female California mice Peromyscus californicus exposed to social defeat stress. As a member of the G-protein coupled receptor family, OTRs can induce distinct downstream pathways by coupling to different G-protein isoforms. In both females and males, carbetocin also increased social vigilance. In the anterior regions of BNST targeted in our carbetocin experiments, Cyp26b1 -expressing neurons had high average Oxtr expression. Oxytocin is traditionally considered to promote affiliative behaviors and has been put forth as a potential treatment for social deficits, such as those associated with autism spectrum disorder Ford and Young, ; MacDonald and MacDonald, ; Meyer-Lindenberg et al. Oxytocin can facilitate pair bonding, parental care, and social play across a wide range of species Bosch and Neumann, ; Bredewold et al. It is also implicated in human research to increase trust, empathy, and in-group cooperation De Dreu and Kret, ; Geng et al. However, emerging studies have reported that administration of oxytocin can generate avoidance of social contexts Beery, For example, intranasal oxytocin reduced social interaction in female California mice Steinman et al. In humans, intranasal oxytocin increased self-reported perceived social stress among male participants Eckstein et al. The mixed results suggest that oxytocin has a more complex role than promoting affiliative behaviors per se. The social salience hypothesis proposes that oxytocin enhances the salience of both positive or negative social contexts Shamay-Tsoory and Abu-Akel, It has been hypothesized that distinct neural circuits may mediate diverse behavioral effects of oxytocin Steinman et al. Oxytocin acting in the nucleus accumbens NAc and ventral tegmental area VTA has been found to promote social reward and enhance social approach Borland et al. In contrast, oxytocin has been found to produce anxiogenic effects in the bed nucleus of the stria terminalis BNST Duque-Wilckens et al. For instance, infusion of an OTR antagonist in the BNST impaired acquisition of cued fear in male rats Moaddab and Dabrowska, and attenuated the effects of social defeat stress in female California mice Duque-Wilckens et al. While there is a strong literature describing how oxytocin receptors modulate behaviors, less is known about the molecular pathways that mediate these effects. An important property of these receptors is that they are capable of modulating diverse signaling pathways and pathological processes. Although the molecular pathways of oxytocin receptor signaling are well-studied in vitro , it is less clear how the differential G-protein signaling translates into behavioral phenotypes Jurek and Neumann, A previous study from our group demonstrated that infusion of biased agonists for OTR-G q but not OTR-G i pathway in the NAc of stressed female California mice increased social approach and decreased social vigilance, a behavior in which an individual orients towards an unfamiliar conspecific while simultaneously avoiding it Williams et al. We also explored whether the oxytocin receptor gene Oxtr is expressed in different cell types in the BNST compared to the adjacent NAc. Differences in the cell-type expression of Oxtr across brain regions could contribute to variability in circuit-specific actions of oxytocin. To address these questions, we first microinjected the functionally selective OTR-G q agonist carbetocin into the anterior BNST and assessed social interaction behaviors. We used California mice, a species that is unique in that both males and females are aggressive. This has allowed for the study of social defeat stress in both sexes Kuske and Trainor, Sani-chip bedding, cotton nestlets, and enviro-dri Newco Distributors were provided in all cages. Drug infusion and behavioral tests were performed during the dark cycle. Previous studies have demonstrated that estrus cycle does not affect behaviors during the social interaction test Trainor et al. The mice were single housed and given a 7-day recovery period after surgery. The animals received daily subcutaneous injection of carprofen as anti-inflammatory from day 1 to 3 and handled daily for 1 minute to get used to scruffing. Twenty minutes following the infusion, mice were tested for social interaction. After behavior testing, mice were perfused, and brains were collected for Nissl stain to confirm successful cannula placement. The social interaction test consists of 3 phases, each lasting 3 minutes Greenberg et al. Mice were introduced into an empty arena 89 x 63 x 60cm and allowed to freely explore during the open field phase. During the acclimation phase, an empty wire cage was placed against one side of the arena for habituation. For the social interaction phase, a same-sex unfamiliar target mouse was placed into the wire cage. Distance traveled, time in the center zone located 14cm from the sides , and time that the focal mouse spent within the interaction zone within 8cm of the wire cage were recorded and analyzed using AnyMaze. Time that the focal mouse spent outside of the interaction zone while its head oriented towards the target mouse was defined as social vigilance and scored manually. Behavioral data analyses were performed in RStudio. Pairwise comparisons with Bonferroni correction were used for post-hoc analyses. For data that did not meet the assumptions of normal distribution or homogeneity of variance i. Single-cell sequencing data were analyzed in RStudio using Seurat v4. We used the Welch et al. Cells with unique features under and over were filtered out. To visualize Oxtr expressing neurons, gene counts were normalized and scaled from the main Seurat object. Linear dimensionality reduction was performed by principal component analysis PCA. The expression level of Oxtr across different neuron clusters was quantified and visualized using the DotPlot function. We also visualized the expression of other transcripts including thyrotropin-releasing hormone receptor Trhr , dopamine receptors Drd1, Drd2, Drd3 , serotonin receptors Htr1a, Htr1b , Htr2a , Htr2c , neuropeptide Y receptors Npy1r , Npy2r , opioid receptors Oprk1 , Oprd1 , Oprm1 , and tachykinin precursor Tac1 in a Dotplot to compare with Oxtr. The same approach was used for the NAc analysis. We accessed published data Chen et al. In addition, the expression level of Oxtr across different NAc cell types and interneuron types Sst, Pvalb, Chat was visualized using the DotPlot function. Representative heat maps demonstrated the location of one mouse per treatment group during the interaction phase Fig. Histology was used to confirm successful placement of cannula guides and location of the needle tracts Fig. Representative heatmaps showed that during the interaction phase, a mouse that received the higher dose of carbetocin spent less time in the interaction zone compared with the other treatment groups c. There were no significant differences across all treatment groups during the open field or the acclimation phases d,e,f. Brain slices were Nissl stained to confirm successful injection sites red shading. Similar results were observed in males. Representative heatmaps showed that during the interaction phase, a mouse that received the drug spent less time in the interaction zone compared with the other treatment groups c. There were no significant differences across all treatment groups during the open field or the acclimation phase d,e,f. In females, 5. Similarly, in males, 5. Oxtr was expressed across various neuron types and had similar expression patterns between males and females Fig. In both sexes, Oxtr had the highest average expression 2. Oxtr was also highly expressed over 1. Percentage expression of gene markers for inhibitory neurons Gad1 and Gad2 , excitatory neurons Slac17a6 or Slc17a8 and glial cells Gfap in female left and male right Oxtr -expressing cells. Male and female animals showed similar expression patterns of Oxtr a, b. The expression of Cyp26b1 in the anterior region overlaps with our carbetocin microinjection sites d. Image credit: Allen Institute. Adult male Mus NAc cells were grouped into 8 different clusters: astrocytes, oligodendrocytes, endothelial cells, interneurons, dopamine receptor 1-expressing cells, dopamine receptor 2-expressing cells, and oligodendrocyte progenitor cells Fig. These results contrast with cell types in the BNST, where only The remaining NAc Oxtr cell types were expressed in D2 medium spiny neurons 5. We also visualized the expression of Oxtr across different interneuron subtypes Fig. Oxtr expression overlapped with somatostatin Sst -expressing interneurons and was generally absent from parvalbumin Pvalb and cholingeric Chat interneurons Fig 5D. Calbindin1 Calb1 and Calb2 were expressed in all interneurons. Oxtr is expressed primarily in the dopamine D1 receptor medium spiny neurons and interneurons A. A Dotplot across all cell types B shows Oxtr has the highest average and percent expression in the interneurons IN. When examining interneuron subtypes C , a Dotplot was shows that Oxtr expression occurs primarily in somatostatin Sst expressing interneurons. Comparatively few Oxtr transcripts were expressed in Pvalb or Chat neurons. Dots for Sst appear gray due to its high abundance relative to other transcripts. These behavioral responses mirror behavior patterns observed in mice exposed to social defeat Duque-Wilckens et al. Although the mechanism of action for carbetocin has never been demonstrated in vivo , prior work in the NAc, suggests that OTR-Gq signaling is most likely the mechanism of action. Meanwhile in the NAc, Oxtr is mainly expressed in both D1 dopamine receptor neurons and interneurons. Anatomical variation in Oxtr cell-type expression may be an important factor contributing to circuit-specific effects of Oxtr on behavior. In vitro , carbetocin can activate V1a receptors at high concentrations Passoni et al. However, it is unlikely that decreases in social approach and increases in social vigilance were driven by V1a receptors. Infusion of a highly selective V1a receptor antagonist into the BNST reduced social approach in unstressed males and females Duque-Wilckens et al. On the contrary, infusion of a selective oxytocin receptor antagonist into the BNST increased social approach and reduced social vigilance in stressed females Duque-Wilckens et al. If carbetocin infusions activated V1a receptors, we would expect to see enhanced social approach, which is the opposite of what we observed. Together, these results suggest that the anxiogenic behavioral effects of carbetocin in the anterior BNST are mediated by oxytocin receptors. Similarly, in a non-social context, OTR neurotransmission in the dorsolateral BNST facilitated acquisition of cued fear response in male rats Martinon et al. We also observed that intra-BNST administration of carbetocin induced similar behavioral phenotypes in both sexes. Sex differences have been reported in neural and behavioral responses to intranasal oxytocin in human Domes et al. However, sex differences were not observed in OTR expression across a wide range of brain regions and oxytocin infusions into anterior BNST of California mice had similar behavioral effects in both sexes Duque-Wilckens et al. These results suggest that sex differences in oxytocin release may be a key driver for sex differences in stress responses. Previous studies have demonstrated that systemic and central administration of carbetocin could reverse stress-induced depression and anxiety-related behaviors Chaviaras et al. In one study, two weeks of intraperitoneal i. In another study, either acute intravenous, intraperitoneal or intracerebroventricular injection of carbetocin reduced immobility during forced swim tests in male rats Chaviaras et al. These studies indicated that both chronic and acute administration of carbetocin could induce anti-depressant or anxiolytic effects. Instead, our results showed that intra-BNST infusion of carbetocin decreased social approach and increased social vigilance. There is growing evidence that the behavioral effects of OTR are circuit-specific Steinman et al. For example, microinjection of carbetocin in the NAc, which is adjacent to the anterior BNST, induced an opposite behavioral phenotype by increasing social approach and decreasing vigilance in stressed female California mice Williams et al. Similarly, oxytocin infusion into the dorsal lateral septum blocked social fear responses after conditioning Zoicas et al. Taken together, our results support the hypothesis that the behavioral effects of OTR signaling are brain region-specific. Although many mechanisms, likely contribute to circuit specific actions of OTR, one contributing factor could be Oxtr expression in different cell types across the brain. In the Welch et al. Over 40 cell types were identified in Welch et al. One cell type that had the most abundant Oxtr expression was Cyp26b1 -expressing neurons. Cyp26b1 encodes a type of retinoic acid degradation enzyme White et al. A recent sequencing study of BNST observed increased expression of Cyp26b1 in male mice that exhibited increased social approach after chronic social defeat resilient compared to mice that exhibited reduced social approach susceptible Gururajan et al. Although clinical and preclinical research suggests that retinoic acid signaling can modulate depression and anxiety-related behaviors Bremner and McCaffery, , no studies have manipulated Cyp26b-1 function in the extended amygdala. This transcript could be an interesting target for functional studies, especially given that Cyp26b1 is part of a group of transcripts that distinguish the anterior basolateral amygdala BLA from the posterior BLA Hintiryan and Dong, Intriguingly, retrograde tracing studies show a strong connection between the caudal anterior BLA and the anteromedial BNST, the primary target of the carbetocin experiments. The Welch et al. Oxtr had similar expression patterns across different neuron clusters in males and females. It is possible that RNA transcript expression level may not be linearly correlated with the protein expression level. In the NAc, Oxtr was primarily observed in D1 medium spiny neurons and interneurons. This result provides new insights into previous behavioral pharmacology experiments that identified coordination between oxytocin and dopamine signaling in the NAc. For example, in female prairie voles the formation of pair bonds requires activation of both OTR and D2 receptors Liu and Wang, The fact that almost no D2 neurons express Oxtr suggests that pair bond formation in voles could be mediated by the coordinated action of D2 neurons and either D1 neurons or interneurons. Although there are many fewer interneurons than medium spiny neurons, interneurons have significant effects on behavior Castro and Bruchas, ; Robison and Nestler, Increased activity of somatostatin interneurons enhances the rewarding effects of cocaine in a place preference assay Ribeiro et al. Interestingly, optogenetic manipulations of somatostatin interneurons in the absence of cocaine or another salient context had no effects on place preference or locomotor behavior. Behavioral effects of oxytocin are also generally stronger in social contexts e. Also notable is that in male mice Oxtr positive somatostatin interneurons in the medial prefrontal cortex promote interest in females during estrus Nakajima et al. Oxytocin can promote diverse behavioral effects by acting in different neural circuits. The availability of single cell RNA-seq methods allows for the ability to determine how Oxtr is expressed in different cell types in different brain regions. While some BNST neurons have electrophysiological properties inward rectification in response to current injection that are similar to medium spiny neurons, they have different input resistances and resting membrane potentials Egli and Winder, Our analyses of Oxtr mRNA have important implications for interpreting mechanisms of oxytocin action. For example, in male rats, oxytocin excites Type I interneurons within the dorsolateral BNST through a post-synaptic mechanism Francesconi et al. Excitation of these interneurons suppresses the activity of adjacent Type II neurons that project to the central nucleus of the amygdala. This observation is especially interesting as optical excitation of different populations of BNST projection neurons can produce different behavioral effects Kim et al. The complexities of how oxytocin modulates different brain circuits likely contribute to the mixed results observed in clinical studies using intranasal oxytocin as a therapeutic treatment for anxiety Leppanen et al. Future studies should explore potential interaction between region-and-cell-type-specific effects of OTR signaling. Development of therapeutics that could target specific cell types or circuits could be more effective than existing systemic treatments. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Horm Behav. Published in final edited form as: Horm Behav. Find articles by Pei X Luo. Find articles by Hannah Cortez Zakharenkov. Find articles by Lisette Y Torres. Find articles by Roberto A Rios. Find articles by Bruno Gegenhuber. Find articles by Alexis M Black. Find articles by Christine K Xu. Find articles by Vanessa A Minie. Find articles by Amy M Tran. Find articles by Jessica Tollkuhn. Find articles by Brian C Trainor. Issue date Jul. PMC Copyright notice. The publisher's version of this article is available at Horm Behav. Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.
Oxytocin receptor behavioral effects and cell types in the bed nucleus of the stria terminalis
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