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. 2023 Apr:150:105314.
doi: 10.1016/j.yhbeh.2023.105314. Epub 2023 Feb 1.

Lasting consequences on physiology and social behavior following cesarean delivery in prairie voles

William M Kenkel  1 , Marcy A Kingsbury  2 , John M Reinhart  3 , Murat Cetinbas  4 , Ruslan I Sadreyev  5 , C Sue Carter  6 , Allison M Perkeybile  6
Affiliations

Lasting consequences on physiology and social behavior following cesarean delivery in prairie voles

William M Kenkel et al. Horm Behav. 2023 Apr.

Abstract

Cesarean delivery is associated with diminished plasma levels of several 'birth-signaling' hormones, such as oxytocin and vasopressin. These same hormones have been previously shown to exert organizational effects when acting in early life. For example, our previous work found a broadly gregarious phenotype in prairie voles exposed to oxytocin at birth. Meanwhile, cesarean delivery has been previously associated with changes in social behavior and metabolic processes related to oxytocin and vasopressin. In the present study, we investigated the long-term neurodevelopmental consequences of cesarean delivery in prairie voles. After cross-fostering, vole pups delivered either via cesarean or vaginal delivery were studied throughout development. Cesarean-delivered pups responded to isolation differently in terms of their vocalizations (albeit in opposite directions in the two experiments), huddled in less cohesive groups under warmed conditions, and shed less heat. As young adults, we observed no differences in anxiety-like or alloparental behavior. However, in adulthood, cesarean-delivered voles of both sexes failed to form partner preferences with opposite sex conspecifics. In a follow-up study, we replicated this deficit in partner-preference formation among cesarean-delivered voles and were able to normalize pair-bonding behavior by treating cesarean-delivered vole pups with oxytocin (0.25 mg/kg) at delivery. Finally, we detected minor differences in regional oxytocin receptor expression within the brains of cesarean-delivered voles, as well as microbial composition of the gut. Gene expression changes in the gut epithelium indicated that cesarean-delivered male voles have altered gut development. These results speak to the possibility of unintended developmental consequences of cesarean delivery, which currently accounts for 32.9 % of deliveries in the U.S. and suggest that further research should be directed at whether hormone replacement at delivery influences behavioral outcomes in later life.

Keywords: Birth; Brain; Cesarean; Development; Monogamy; Oxytocin; Pair-bonding; Prairie vole.

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Figures

Figure 1
Figure 1
Production of ultrasonic vocalizations (USVs) by vole pups delivered either via cesarean section (CS) or vaginal delivery (VD). In Experiment 1 (panel A), CS pups produced significantly more USVs on postnatal day (PND) 4 and VD pups produced significantly fewer USVs on PND 4 compared to PND 1 (* denotes p = 0.018 and p = 0.002 respectively, n = 288 total recordings from 43 litters (n = 22 VD, n = 21 CS)). However, in Experiment 2 (panel B), CS pups tended to produce fewer USVs than VD pups on PND-4 (p = 0.061, n = 172 total recordings from 23 litters (n = 8 VD, n = 8 CS, n = 7 CS+OXT)).
Figure 2
Figure 2
Thermoregulatory behavior in CS and VD vole litters on PND-7. Nineteen CS and 21 VD litters were tested for 30 minutes at 33°C followed by 30 minutes at 22°C. Representative thermographic images isare shown in panel A (warm) and B (cool). CS litters had less warm surface temperatures compared to VD litters during the warm phase (panel C, * denotes p < 0.025 for all comparisons). A representative image is shown in panel D having undergone automated identification of separate blobs (note that the seemingly disconnected hindleg in blue would have been excluded for having been too small). CS litters’ huddles were less cohesive throughout the majority of the testing session, during both the warm and cool phases (panel E, * denotes p < 0.041). Data represent mean ± SEM.
Figure 3
Figure 3
Alloparental responsiveness toward novel, unrelated pups. In neither Experiment 1 (A) nor Experiment 2 (B) did we detect a difference in alloparental behavior between CS and VD animals (p > 0.05 for all comparisons). In both experiments, males were found to be more alloparental than females, as has been observed previously. Data represent mean ± SEM.
Figure 4
Figure 4
Partner preference formation in CS and VD voles on PND 60–68. The partner preference test (PPT) paradigm is shown in panel A. In Experiment 1, both female (F) and male (M) VD voles showed significant preferences for the Partner over the Stranger in terms of time spent in close social contact, as expected given prairie voles’ well-established social monogamy (panel B, * denotes p < 0.05 for both comparisons). Results from Experiment 1 include data from 17 CS males, 11 CS females, 22 VD males, and 23 VD females. In Experiment 2, VD voles again showed a significant partner preference, as did CS+OXT voles (panel C, * denotes p < 0.05 for all comparisons), whereas once again, CS animals showed no such preference. Results from Experiment 2 include data from 4 CS males, 13 CS females, 6 VD males, 9 VD females, 10 CS+OXT males and 10 CS+OXT females were tested. Data represent mean ± SEM.
Figure 5
Figure 5
CS dose not shift the diversity or overall composition of the gut microbiome as compared to VD using metrics of alpha and beta diversity. A-D, Observed OTUs and Pielou’s evenness were not significantly different in CS males as compared to VD males (A, OTUs, N=10/group, p=0.73; B, Pielou’s evenness N=10/group, p=0.76) or in CS females as compared to VD females (C, OTUs, N=10/group, p=0.22; D, Pielou’s evenness N=9–10/group, p=0.51). E-F, There were no significant differences in the clustering of gut microbiota between CS and VD animals for either males (E, N=10/group, Bray-curtis dissimilarity, p=0.068; N=10/group, Jaccard dissimilarity, p=0.056, data not shown) or females (F, N=9–10/ group, Bray-Curtis dissimilarity, p=0.607; N=9–10/group, Jaccard dissimilarity, p=0.123, data not shown).
Figure 6
Figure 6
Linear discriminant analysis effect size (LEfSe) indicated differentially abundant bacteria in male VD and CS offspring at the order (A), family (B) and genus (C) levels. A, Clostridiales was more abundant in CS males than VD males. B, Prevotellaceae was more abundant in VD males than CS males. C, Ruminoococcus was more abundant in CS males than VD males. LDA >4, P < 0.05.
Figure 7
Figure 7
Significant differences in the gene expression of tight junction proteins (TJs) and enteric glial markers within the colon of CS versus VD males. A, Schematic representing the section of the terminal ileum assessed and the quantification of gene expression for TJ proteins occludin (OCLN) and tight junction protein-1 (TJP) and enteric glia markers S100 calcium-binding protein B (S100B) and glial fibrillary acidic protein (GFAP). No significant differences were observed in the ileum of CS versus VD males except for OCLN (N=3–10/group, unpaired t-test; OCLN: treatment: p=0.018, TJP: treatment: p=0.123, S100B: treatment: p=0.109 and GFAP: treatment: p=0.349). No significant differences were observed for CS versus VD females (N=5–10/group, unpaired t-test; OCLN: treatment: p=0.942, TJP: treatment: p=0.567, S100B: treatment: p=0.600 and GFAP: treatment: p=0.218). B, Schematic representing the section of the proximal colon assessed and the quantification of gene expression for TJ proteins OCLN and TJP, enteric glia markers S100B and GFAP, and mucin 2 (MUC2), a major component of intestinal mucus. There was a significant decrease in OCLN, TJP, S100B and GFAP in CS males compared to VD males (N=4–9/group, unpaired t-test; OCLN: treatment: p=0.012, TJP: treatment: p=0.011, S100B: treatment: p=0.006 and GFAP: treatment: p=0.046) while no differences were observed for females based on birth mode (N=4–10/group, unpaired t-test; OCLN: treatment: p=0.944, TJP: treatment: p=0.443, S100B: treatment: p=0.392 and GFAP: treatment: p=0.654). Data represent mean ± SEM, *p<0.05. CS: cesarean section, VD: vaginal delivery. No differences were observed for MUC2 based on birth mode for males or females (males, N=7–8/group, unpaired t-test; MUC2: treatment: p=0.208; females, N=5–10/group, unpaired t-test; MUC2: treatment: p=0.777).
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