Abstract
In mammals, the extended amygdala is a neural hub for social and emotional information processing. In the rat, the extended amygdala receives inhibitory GABAergic projections from the nucleus incertus (NI) in the pontine tegmentum. NI neurons produce the neuropeptide relaxin-3, which acts via the Gi/o-protein-coupled receptor, RXFP3. A putative role for RXFP3 signalling in regulating social interaction was investigated by assessing the effect of intracerebroventricular infusion of the RXFP3 agonist, RXFP3-A2, on performance in the 3-chamber social interaction paradigm. Central RXFP3-A2, but not vehicle, infusion, disrupted the capacity to discriminate between a familiar and novel conspecific subject, but did not alter differentiation between a conspecific and an inanimate object. Subsequent studies revealed that agonist-infused rats displayed increased phosphoERK(pERK)-immunoreactivity in specific amygdaloid nuclei at 20 min post-infusion, with levels similar to control again after 90 min. In parallel, we used immunoblotting to profile ERK phosphorylation dynamics in whole amygdala after RXFP3-A2 treatment; and multiplex histochemical labelling techniques to reveal that after RXFP3-A2 infusion and social interaction, pERK-immunopositive neurons in amygdala expressed vesicular GABA-transporter mRNA and displayed differential profiles of RXFP3 and oxytocin receptor mRNA. Overall, these findings demonstrate that central relaxin-3/RXFP3 signalling can modulate social recognition in rats via effects within the amygdala and likely interactions with GABA and oxytocin signalling.
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Notes
The bed nucleus of the stria terminalis is abbreviated as BNST, BST or ST. However, when describing subdivisions of the area, the abbreviations become long and less useful. Thus, in the 7th Edition of The Rat Brain in Stereotaxic Coordinates, the whole bed nucleus of the stria terminalis was abbreviated as ST (Olucha-Bordonau et al. 2014; Paxinos and Watson 2014).
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Acknowledgements
The authors thank Dr. Mohammad Akhter Hossain (The Florey Institute of Neuroscience and Mental Health, Parkville, Australia) for providing the RXFP3-A2 peptide used in these studies. This research was supported by the following grants: Universitat Jaume I research grant UJI-B2016-40 and Program of Mobilities of the Spanish Ministerio de Educación y Cultura, PRX17/00646 (FEO-B); Universitat Jaume I FPI-UJI Predoctoral Research Scholarship PREDOC/2014/35 (HAG); E-2016-43 Research Travel Grant (HAG); Plan Propi Universitat Jaume I P1.1A2014-06 (AMS-P); NHMRC (Australia) Project Grant 1067522 (ALG); and Dorothy Levien Foundation research grant (ALG).
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HA-G, performed most experiments, wrote the first draft of the manuscript, compiled and edited the figures, and edited successive drafts of the manuscript. SS-S, helped perform the behavioural experiments, and conducted analysis of behavioural data. SM, helped design and perform the multiplex in situ hybridization experiments, and edited successive drafts of the manuscript. CG-D, helped perform the behavioural experiments and the combined multiplex in situ hybridization and immunofluorescence studies, and analysed these data. ALG, participated in the design of the experiments, and edited the figures and successive drafts of the manuscript. AMS-P, participated in the conception of the study and directed the research, and edited successive drafts of the manuscript. FEO-B, conceived the study and directed the research, designed the experiments, and edited successive drafts of the manuscript.
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Supplementary Fig. 1
. (a) Heat maps for the three-chamber social interaction paradigm for the sociability and preference tests. Percentages on the corners of the trackings refer to the average percentage time spent in each room. Percentages on the heat maps next to “subject”, “object” u “conspecifics” refer to the average percentage time spent sniffing. (b) Percentage time sniffing the conspecific rat (green bars) and inanimate object (black bars), or (c) the familiar (white bars) and novel rat (red bars) for the different experimental groups. * p<0.05, **** p<0.0001, ns: not significant (TIF 8458 KB)
Supplementary Fig. 2
. Characterisation of the neurochemical phenotype of Rxfp3 mRNA-positive neurons in STMV an STOV. (a) Schematic illustrating Rxfp3 distribution and co-expression with Oxtr mRNA in STMV (a and b) Representative fluorescent images. Representative images of fluorescent ISH and quantification of co-expression percentages indicated (lower right corner). (c) Schematic illustrating Rxfp3 mRNA distribution and co-expression with Oxtr and Slc32a1 mRNAs in the MePV. (c and d). Scale barS: 100 µm (a′), 10µm (b) (TIF 8130 KB)
Supplementary Fig. 3
. pERK immunostaining in the CeA after social encounters. (a) Schematic illustrating the CeA sub-nuclei analysed. (b) Density of pERK-stained neurons was significantly increased in A2-Pref rats (red bars) compared to vehicle treated rats (dashed black line). Representative images of pERK immunostaining in the CeA of (c) vehicle, (d) A2-Pref and (e) A2-Soc group rats. *p < 0.05; **p < 0.01. Scale bar: 100 µm (c) (TIF 8955 KB)
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Albert-Gasco, H., Sanchez-Sarasua, S., Ma, S. et al. Central relaxin-3 receptor (RXFP3) activation impairs social recognition and modulates ERK-phosphorylation in specific GABAergic amygdala neurons. Brain Struct Funct 224, 453–469 (2019). https://doi.org/10.1007/s00429-018-1763-5
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DOI: https://doi.org/10.1007/s00429-018-1763-5