Lactating female mice fiercely defend offspring while exhibiting decreased fear and anxiety. Recent work (J. S. Lonstein & S. C. Gammie, 2002) found that intracerebroventricular (icv) injections of corticotropin releasing factor (CRF), a putative anxiogenic peptide, inhibit maternal defense behavior. This study examines effects of CRF-related peptides, urocortin (Ucn) 1 and Ucn 3, on maternal aggression in mice. Intracerebroventricular injections of both Ucn 1 (0.2 microg) and Ucn 3 (0.5 microg) reduced aggression but not pup retrieval. c-Fos levels were elevated by intracerebroventricular injections of Ucn 1 (0.2 microg) and Ucn 3 (0.5 microg) in 2 and 6 brain regions, respectively; however, both triggered increases in bed nucleus of the stria terminalis dorsal (BNSTd) and lateral septum (LS). These findings suggest that CRF-related peptides similarly modulate maternal aggression and that BNSTd/LS may be critical sites for negative regulation of maternal aggression.

BackgroundThe mother-child relationship is the most fundamental social bond in mammals, and previous studies indicate that the medial preoptic area (MPOA) contributes to this increase in sociability. It is possible that the same genes that lead to elevated sociability in one condition (the maternal state) might also be dysregulated in some disorders with social deficits (e.g. autism). In this study, we examined whether there was enrichment (greater than chance overlap) for social deficit disorder related genes in MPOA microarray results between virgin and postpartum female mice. We utilized microarrays to assess large scale gene expression changes in the MPOA of virgin and postpartum mice. The Modular Single Set Enrichment Test (MSET) was used to determine if mental health disorder related genes were enriched in significant microarray results. Additional resources, such as ToppCluster, NIH DAVID, and weighted co-expression network analysis (WGCNA) were used to analyze enrichment for specific gene clusters or indirect relationships between significant genes of interest. Finally, a subset of microarray results was validated using quantitative PCR.ResultsSignificant postpartum MPOA microarray results were enriched for multiple disorders that include social deficits, including autism, bipolar disorder, depression, and schizophrenia. Together, 98 autism-related genes were identified from the significant microarray results. Further, ToppCluser and NIH DAVID identified a large number of postpartum genes related to ion channel activity and CNS development, and also suggested a role for microRNAs in regulating maternal gene expression. WGCNA identified a module of genes associated with the postpartum phenotype, and identified indirect links between transcription factors and other genes of interest.ConclusionThe transition to the maternal state involves great CNS plasticity and increased sociability. We identified multiple novel genes that overlap between the postpartum MPOA (high sociability) and mental health disorders with low sociability. Thus, the activity or interactions of the same genes may be altering social behaviors in different directions in different conditions. Maternity also involves elevated risks for disorders, including depression, psychosis, and BPD, so identification of maternal genes common to these disorders may provide insights into the elevated vulnerability of the maternal brain.

Vocal production is crucial for successful social interactions in multiple species. Reward can strongly influence behavior; however, the extent to which reward systems influence vocal behavior is unknown. In songbirds, singing occurs in different contexts. It can be spontaneous and undirected (e.g., song produced alone or as part of a large flock) or directed towards a conspecific (e.g., song used to attract a mate or influence a competitor). In this study, we developed a conditioned place preference paradigm to measure reward associated with different types of singing behavior in two songbird species. Both male zebra finches and European starlings developed a preference for a chamber associated with production of undirected song, suggesting that the production of undirected song is tightly coupled to intrinsic reward. In contrast, neither starlings nor zebra finches developed a place preference in association with directed song; however, male starlings singing directed song that failed to attract a female developed a place aversion. Unsuccessful contact calling behavior was also associated with a place aversion. These findings suggest that directed vocal behavior is not tightly linked to intrinsic reward but may be externally reinforced by social interactions. Data across two species thus support the hypothesis that the production of undirected but not directed song is tightly coupled to intrinsic reward. This study is the first to identify song-associated reward and suggests that reward associated with vocal production differs depending upon the context in which communication occurs. The findings have implications for understanding what motivates animals to engage in social behaviors and ways in which distinct reward mechanisms function to direct socially appropriate behaviors.

Birdsong consists of species-specific learned vocal sequences that are used primarily to attract mates and to repel competitors during the breeding season. However, many birds continue to sing at times when vocal production has no immediate or obvious impact on conspecific behavior. The mechanisms that ensure that animals produce important behaviors in contexts in which the function of these behaviors is not immediate or obvious are not known. One possibility is that animals engage in such behaviors because they are associated with pleasure. Here we examined the hypothesis that male European starlings sing outside of the breeding season in part because the act of singing in this context is facilitated and/or maintained by opioid-mediated reward. We measured song-associated reward using a conditioned place preference (CPP) test in male starlings producing fall, non-breeding season-typical song. We used quantitative real time PCR to measure expression of the enkephalin opioid precursor preproenkephalin (PENK) and mu opioid receptors (MOR) in the medial preoptic nucleus (POM; a region in which opioids are implicated in both reward and starling fall song) and additionally the song control region HVC as a control. Starlings developed a strong preference for a place that had been paired previously with the act of producing fall-typical song, indicating that fall song production was associated with a positive affective state. Both PENK and MOR mRNA expression in the POM, but not HVC, correlated positively with both individual reward state (as reflected in CPP) and undirected singing behavior. These results suggest that singing induces opioid receptor and enkephalin expression in the POM and consequent reward, and/or that opioid release in the POM induced by individual or environmental factors (e.g., the presence of food, safety of a flock or the absence of predators) induces a positive affective state which then facilitates singing behavior.

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Corticotropin-releasing factor (CRF) binding protein (CRF-BP) is a secreted protein that acts to bind and limit the activity of the neuropeptides, CRF and urocortin (Ucn) 1. We previously selected for high maternal defense (protection of offspring) in mice and found CRF-BP to be elevated in the CNS of selected mice. We also previously determined that both CRF and Ucn 1 are potent inhibitors of offspring protection when administered centrally. Thus, elevated CRF-BP could promote defense by limiting endogenous actions of CRF or Ucn 1. To test this hypothesis, we crossed the deletion for CRF-BP into the mice selected for high maternal defense and evaluated offspring protection and other maternal behaviors. CRF-BP knockout (KO) mice exhibited significant deficits in maternal aggression relative to wild-type (WT) mice in three different measures. Other maternal features were almost identical between groups, including dam and pup weight, litter size, nursing time, and pup retrieval. Both groups performed similarly in a forced swim stress test and aggression in both groups was reduced following the swim test. Virgin KO female mice exhibited higher levels of anxiety-like behavior in terms of decreased time in the light portion of the light/dark box test. For males, no differences in light/dark box or swim test were found. However, increased anxiety-like behavior in male KO mice was identified in terms of contact and approach to a novel object both with and without previous exposure to the swim test. No differences in isolation induced resident intruder male aggression were found between groups. Together, these results indicate that loss of CRF-BP selectively impairs maternal, but not intermale aggression and that loss of the gene induces anxiety-like behavior in males and females, but there are sex differences in terms of how that anxiety is revealed.