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1.  Impairments in the Initiation of Maternal Behavior in Oxytocin Receptor Knockout Mice 
PLoS ONE  2014;9(6):e98839.
Oxytocin (Oxt) acting through its single receptor subtype, the Oxtr, is important for the coordination of physiology and behavior associated with parturition and maternal care. Knockout mouse models have been helpful in exploring the contributions of Oxt to maternal behavior, including total body Oxt knockout (Oxt −/−) mice, forebrain conditional Oxtr knockout (Oxtr FB/FB) mice, and total body Oxtr knockout (Oxtr −/−) mice. Since Oxtr −/− mice are unable to lactate, maternal behavior has only been examined in virgin females, or in dams within a few hours of parturition, and there have been no studies that have examined their anxiety-like and depression-like behavior following parturition. To improve our understanding of how the absence of Oxt signaling affects maternal behavior, mood and anxiety, we designed a study using Oxtr −/− mice that separated nursing behavior from other aspects of maternal care, such as licking and grooming by thelectomizing (i.e. removing the nipples) of Oxtr +/+ mice and sham-thelectomizing Oxtr −/− mice, and pairing both genotypes with a wet nurse. We then measured pup abandonment, maternal behavior, and postpartum anxiety-like and depression-like behaviors. We hypothesized that genetic disruption of the Oxtr would impact maternal care, mood and anxiety. Specifically, we predicted that Oxtr −/− dams would have impaired maternal care and increased anxiety-like and depression-like behaviors in the postpartum period. We found that Oxtr −/− dams had significantly higher levels of pup abandonment compared to controls, which is consistent with previous work in Oxtr FB/FB mice. Interestingly, Oxtr −/− dams that initiated maternal care did not differ from wildtype controls in measures of maternal behavior. We also did not find any evidence of altered anxiety-like or depressive-like behavior in the postpartum period of Oxtr −/− dams. Thus, our data suggest that Oxt lowers the threshold for the initiation of maternal behavior.
doi:10.1371/journal.pone.0098839
PMCID: PMC4044031  PMID: 24892749
2.  Interaction between Oxytocin Genotypes and Early Experience Predicts Quality of Mothering and Postpartum Mood 
PLoS ONE  2013;8(4):e61443.
Individual differences in maternal behavior are affected by both early life experiences and oxytocin, but little is known about genetic variation in oxytocin genes and its effects on mothering. We examined two polymorphisms in the oxytocin peptide gene OXT (rs2740210 and rs4813627) and one polymorphism in the oxytocin receptor gene OXTR (rs237885) in 187 Caucasian mothers at six months postpartum. For OXT, both rs2740210 and rs4813627 significantly associated with maternal vocalizing to the infant. These polymorphisms also interacted with the quality of care mothers experienced in early life, to predict variation in maternal instrumental care and postpartum depression. However, postpartum depression did not mediate the gene-environment effects of the OXT SNPs on instrumental care. In contrast, the OXTR SNP rs237885 did not associate with maternal behavior, but it did associate with pre-natal (but not post-natal) depression score. The findings illustrate the importance of variation in oxytocin genes, both alone and in interaction with early environment, as predictors of individual differences in human mothering. Furthermore, depression does not appear to have a causal role on the variation we report in instrumental care. This suggests that variation in instrumental care varies in association with a gene-early environment effect regardless of current depressive symptomatology. Finally, our findings highlight the importance of examining multiple dimensions of human maternal behavior in studies of genetic associations.
doi:10.1371/journal.pone.0061443
PMCID: PMC3630168  PMID: 23637833
3.  Genetic Architecture of Nest Building in Mice LG/J × SM/J 
Maternal care is critical to offspring growth and survival, which is greatly improved by building an effective nest. Some suggest that genetic variation and underlying genetic effects differ between fitness-related traits and other phenotypes. We investigated the genetic architecture of a fitness-related trait, nest building, in F2 female mice intercrossed from inbred strains SM/J and LG/J using a QTL analysis for six related nest phenotypes (Presence and Structure pre- and postpartum, prepartum Material Used and postpartum Temperature). We found 15 direct-effect QTLs explaining from 4 to 13% of the phenotypic variation in nest building, mostly with non-additive effect. Epistatic analyses revealed 71 significant epistatic interactions which together explain from 28.4 to 75.5% of the variation, indicating an important role for epistasis in the adaptive process of nest building behavior in mice. Our results suggest a genetic architecture with small direct effects and a larger number of epistatic interactions as expected for fitness-related phenotypes.
doi:10.3389/fgene.2012.00090
PMCID: PMC3361010  PMID: 22654894
maternal behavior; fitness; QTL; epistasis; mice
4.  Hidden Markov Model Analysis of Maternal Behavior Patterns in Inbred and Reciprocal Hybrid Mice 
PLoS ONE  2011;6(3):e14753.
Individual variation in maternal care in mammals shows a significant heritable component, with the maternal behavior of daughters resembling that of their mothers. In laboratory mice, genetically distinct inbred strains show stable differences in maternal care during the first postnatal week. Moreover, cross fostering and reciprocal breeding studies demonstrate that differences in maternal care between inbred strains persist in the absence of genetic differences, demonstrating a non-genetic or epigenetic contribution to maternal behavior. In this study we applied a mathematical tool, called hidden Markov model (HMM), to analyze the behavior of female mice in the presence of their young. The frequency of several maternal behaviors in mice has been previously described, including nursing/grooming pups and tending to the nest. However, the ordering, clustering, and transitions between these behaviors have not been systematically described and thus a global description of maternal behavior is lacking. Here we used HMM to describe maternal behavior patterns in two genetically distinct mouse strains, C57BL/6 and BALB/c, and their genetically identical reciprocal hybrid female offspring. HMM analysis is a powerful tool to identify patterns of events that cluster in time and to determine transitions between these clusters, or hidden states. For the HMM analysis we defined seven states: arched-backed nursing, blanket nursing, licking/grooming pups, grooming, activity, eating, and sleeping. By quantifying the frequency, duration, composition, and transition probabilities of these states we were able to describe the pattern of maternal behavior in mouse and identify aspects of these patterns that are under genetic and nongenetic inheritance. Differences in these patterns observed in the experimental groups (inbred and hybrid females) were detected only after the application of HMM analysis whereas classical statistical methods and analyses were not able to highlight them.
doi:10.1371/journal.pone.0014753
PMCID: PMC3050935  PMID: 21408086
5.  Normal Maternal Behavior, But Increased Pup Mortality, in Conditional Oxytocin Receptor Knockout Females 
Behavioral neuroscience  2010;124(5):677-685.
Oxytocin (Oxt) and the Oxt receptor (Oxtr) are implicated in the onset of maternal behavior in a variety of species. Recently, we developed two Oxtr knockout lines: a total body knockout (Oxtr−/−) and a conditional Oxtr knockout (OxtrFB/FB) in which the Oxtr is lacking only in regions of the forebrain, allowing knockout females to potentially nurse and care for their biological offspring. In the current study, we assessed maternal behavior of postpartum OxtrFB/FB females toward their own pups and maternal behavior of virgin Oxtr−/− females toward foster pups and compared knockouts of both lines to wildtype (Oxtr+/+) littermates. We found that both Oxtr−/− and OxtrFB/FB females appear to have largely normal maternal behaviors. However, with first litters, approximately 40% of the OxtrFB/FB knockout dams experienced high pup mortality, compared to fewer than 10% of the Oxtr+/+ dams. We then went on to test whether or not this phenotype occurred in subsequent litters or when the dams were exposed to an environmental disturbance. We found that regardless of the degree of external disturbance, OxtrFB/FB females lost more pups on their first and second litters compared to wildtype females. Possible reasons for higher pup mortality in OxtrFB/FB females are discussed.
doi:10.1037/a0020799
PMCID: PMC3175421  PMID: 20939667
conditional knockout; stress; maternal behavior; aggression
6.  Nonsocial Functions of Hypothalamic Oxytocin 
ISRN Neuroscience  2013;2013:179272.
Oxytocin (OXT) is a hypothalamic neuropeptide composed of nine amino acids. The functions of OXT cover a variety of social and nonsocial activity/behaviors. Therapeutic effects of OXT on aberrant social behaviors are attracting more attention, such as social memory, attachment, sexual behavior, maternal behavior, aggression, pair bonding, and trust. The nonsocial behaviors/functions of brain OXT have also received renewed attention, which covers brain development, reproduction, sex, endocrine, immune regulation, learning and memory, pain perception, energy balance, and almost all the functions of peripheral organ systems. Coordinating with brain OXT, locally produced OXT also involves the central and peripheral actions of OXT. Disorders in OXT secretion and functions can cause a series of aberrant social behaviors, such as depression, autism, and schizophrenia as well as disturbance of nonsocial behaviors/functions, such as anorexia, obesity, lactation failure, osteoporosis, diabetes, and carcinogenesis. As more and more OXT functions are identified, it is essential to provide a general view of OXT functions in order to explore the therapeutic potentials of OXT. In this review, we will focus on roles of hypothalamic OXT on central and peripheral nonsocial functions.
doi:10.1155/2013/179272
PMCID: PMC4045544  PMID: 24967304
7.  Maternal Behavior is Impaired in Female Mice Lacking Type 3 Adenylyl Cyclase 
Neuropsychopharmacology  2010;36(4):772-781.
Although chemosensory signals generated by mouse pups may trigger maternal behavior of females, the mechanism for detection of these signals has not been fully defined. As some odorant receptors are coupled to the type 3 adenylyl cyclase (AC3), we evaluated the role of AC3 for maternal behavior using AC3−/− female mice. Here, we report that maternal behavior is impaired in virgin and postpartum AC3−/− mice. Female AC3−/− mice failed the pup retrieval assay, did not construct well-defined nests, and did not exhibit maternal aggression. Furthermore, AC3−/− females could not detect odorants or pup urine in the odorant habituation test and were unable to detect pups by chemoreception. In contrast to wild-type mice, AC activity in main olfactory epithelium (MOE) preparations from AC3−/− female mice was not stimulated by odorants or pheromones. Moreover, odorants and pheromones did not evoke electro-olfactogram (EOG) responses in the MOE of AC3−/− female mice. We hypothesize that the detection of chemical signals that trigger maternal behavior in female mice depends upon AC3 in the MOE.
doi:10.1038/npp.2010.211
PMCID: PMC3055720  PMID: 21150908
maternal behavior; type 3 adenylyl cyclase; cAMP; behavioral science; neurogenetics; signal transduction; animal models; maternal behavior; type 3 adenylyl cyclase; cAMP
8.  Enhanced Maternal Aggression and Associated Changes in Neuropeptide Gene Expression in Multiparous Rats 
Behavioral neuroscience  2009;123(5):949-957.
While it has often been speculated that prior reproductive experience improves subsequent maternal care, few studies have examined specific changes in behavior during a first versus second lactation. During lactation mothers display heightened aggression toward male intruders, purportedly to protect vulnerable young. In the current study, maternal aggression was examined in primiparous and age-matched, multiparous females on postpartum days 5 (PPD5) and PPD15. Expression of oxytocin (OXT), oxytocin receptor (OXT-R), arginine vasopressin (AVP), arginine vasopressin V1a receptors (V1a), and corticotrophin releasing hormone (CRH) mRNA was measured following aggression testing at both time points using real-time quantitative PCR (qPCR) in brain regions previously implicated in the regulation of maternal aggression. Multiparity significantly enhanced maternal aggression on PPD5 but not on PPD15. In addition, this increased aggression was associated with region and gene specific changes in mRNA expression. These findings indicate that reproductive experience enhances maternal aggression, an effect that may be mediated by region specific alterations in neuropeptidergic activity. The adaptations observed in multiparous females provide an innate model for the study of neuroplasticity in the regulation of aggression.
doi:10.1037/a0016734
PMCID: PMC2789430  PMID: 19824761
Offspring protection; oxytocin; vasopressin; corticotrophin releasing hormone; paraventricular nucleus
9.  Maternal Behavior is Impaired in Female Mice Lacking Type 3 Adenylyl Cyclase 
Although chemosensory signals generated by mouse pups may trigger maternal behavior of females, the mechanism for detection of these signals has not been fully defined. Since some odorant receptors are coupled to the type 3 adenylyl cyclase (AC3), we evaluated the role of AC3 for maternal behavior using AC3−/− female mice. Here, we report that maternal behavior is impaired in virgin and postpartum AC3−/− mice. Female AC3−/− mice failed the pup retrieval assay, did not construct well-defined nests, and did not exhibit maternal aggression. Furthermore, AC3−/− females could not detect odorants or pup urine in the odorant habituation test and were unable to detect pups by chemoreception. In contrast to wild-type mice, adenylyl cyclase activity in main olfactory epithelium (MOE) preparations from AC3−/− female mice was not stimulated by odorants or pheromones. Moreover, odorants and pheromones did not evoke electro-olfactogram (EOG) responses in the MOE of AC3−/− female mice. We hypothesize that the detection of chemical signals that trigger maternal behavior in female mice depends upon AC3 in the MOE.
doi:10.1038/npp.2010.211
PMCID: PMC3055720  PMID: 21150908
Maternal behavior; type 3 adenylyl cyclase; cAMP
10.  Plasma Oxytocin Concentration during Pregnancy is associated with Development of Postpartum Depression 
Neuropsychopharmacology  2011;36(9):1886-1893.
Postpartum depression (PPD) affects up to 19% of all women after parturition. The non-apeptide oxytocin (OXT) is involved in adjustment to pregnancy, maternal behavior, and bonding. Our aim was to examine the possible association between plasma OXT during pregnancy and the development of PPD symptoms. A total of 74 healthy, pregnant women were included in this prospective study. During the third trimester of pregnancy and within 2 weeks after parturition, PPD symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS). Blood samples for plasma OXT assessment were collected in the third trimester. Following the literature, participants with postpartum EPDS scores of 10 or more were regarded as being at risk for PPD development (rPPD group). In a logistic regression analysis, plasma OXT was included as a potential predictor for being at risk for PPD. Results were controlled for prepartal EPDS score, sociodemographic and birth-outcome variables. Plasma OXT concentration in mid-pregnancy significantly predicted PPD symptoms at 2 weeks postpartum. Compared with the no-risk-for-PPD group, the rPPD group was characterized by lower plasma OXT concentrations. To our knowledge, this is the first study to show an association between prepartal plasma OXT concentration and postpartal symptoms of PPD in humans. Assuming a causal relationship, enhancing OXT release during pregnancy could serve as a potential target in prepartum PPD prevention, and help to minimize adverse effects of PPD on the mother–child relationship.
doi:10.1038/npp.2011.74
PMCID: PMC3154107  PMID: 21562482
postpartum depression; oxytocin; pregnancy; EPDS; adaptation to motherhood; biological psychiatry; depression; unipolar/bipolar; neuroendocrinology; epidemiology; postpartum depression; oxytocin; pregnancy; epds; adaptation to motherhood
11.  Identification of QTL for locomotor activation and anxiety using closely-related inbred strains 
Genes, brain, and behavior  2008;7(7):761-769.
We carried out a QTL mapping experiment in two phenotypically similar inbred mouse strains, C57BL/6J and C58/J, using the open field assay, a well-established model of anxiety-related behavior in rodents. This intercross was initially carried out as a control cross for an ENU-mutagenesis mapping study. Surprisingly, although open field behavior is similar in the two strains, we identified significant QTL in their F2 progeny. Marker regression identified a locus on chromosome 8 having associations with multiple open field measures and a significant interaction between loci on chromosomes 13 and 17. Together, the chromosome 8 locus and the interaction effect form the core set of QTL controlling these behaviors with additional loci on chromosomes 1 and 6 present in a subset of the behaviors.
PMCID: PMC2888940  PMID: 19130624
quantitative trait locus; locomotor activation; anxiety; open-field assay
12.  Changes in Maternal Gene Expression in Olfactory Circuits in the Immediate Postpartum Period 
Regulation of maternal behavior in the immediate postpartum period involves neural circuits in reward and homeostasis systems responding to cues from the newborn. Our aim was to assess one specific regulatory mechanism: the role that olfaction plays in the onset and modulation of parenting behavior. We focused on changes in gene expression in olfactory brain regions, examining nine genes found in previous knockout studies to be necessary for maternal behavior. Using a quantitative PCR (qPCR)-based approach, we assessed changes in gene expression in response to exposure to pups in 11 microdissected olfactory brain regions. Over the first postpartum days, all nine genes were detected in all 11 regions (at differing levels) and their expression changed in response to pup exposure. As a general trend, five genes (Dbh, Esr1, FosB, Foxb1, and Oxtr) were found to decrease their expression in most of the olfactory regions examined, while two genes (Mest and Prlr) were found to increase expression. Nos1 and Peg3 levels remained relatively stable except in the accessory olfactory bulb (AOB), where greater than fourfold increases in expression were observed. The largest magnitude expression changes in this study were found in the AOB, which mediates a variety of olfactory cues that elicit stereotypic behaviors such as mating and aggression as well as some non-pheromone odors. Previous analyses of null mice for the nine genes assessed here have rarely examined olfactory function. Our data suggest that there may be olfactory effects in these null mice which contribute to the observed maternal behavioral phenotypes. Collectively, these data support the hypothesis that olfactory processing is an important sensory regulator of maternal behavior.
doi:10.3389/fpsyt.2011.00040
PMCID: PMC3130163  PMID: 21747772
olfactory bulb; accessory olfactory bulb; olfactory tubercle; piriform cortex; entorhinal cortex; amygdala; hippocampus
13.  Differences in Mouse Maternal Care Behavior – Is There a Genetic Impact of the Glucocorticoid Receptor? 
PLoS ONE  2011;6(4):e19218.
Depressive episodes are frequently preceded by stressful life events. Evidence from genetic association studies suggests a role for the glucocorticoid receptor (GR), an essential element in the regulation of stress responses, in the pathophysiology of the disorder. Since the stress response system is affected by pregnancy and postpartum-associated changes, it has also been implicated in the pathophysiology of postpartum depression. Using a 2×2 factorial design, we investigated whether a heterozygous deletion of GR would influence maternal care behavior in C57BL/6 and Balb/c mice, two inbred strains known to display qualitative differences in this behavior. Behavioral observation was carried out between postnatal days 1 and 7, followed by a pup retrieval test on postnatal days 7 or 8. While previously noted inter-strain differences were confirmed for different manifestations of caring behavior, self-maintenance and neglecting behaviors as well as the pup retrieval test, no strain-independent effect of the GR mutation was noted. However, an interaction between GR genotype and licking/grooming behavior was observed: it was down-regulated in heterozygous C57BL/6 mice to the level recorded for Balb/c mice. Home cage observation poses minimal disturbance of the dam and her litter as compared to more invasive assessments of dams' emotional behavior. This might be a reason for the absence of any overall effects of the GR mutation, particularly since GR heterozygous animals display a depressive-like phenotype under stressful conditions only. Still, the subtle effect we observed may point towards a role of GR in postpartum affective disorders.
doi:10.1371/journal.pone.0019218
PMCID: PMC3084270  PMID: 21552522
14.  Genes Controlling Affiliative Behavior as Candidate Genes for Autism 
Biological psychiatry  2008;63(10):911-916.
Background
Autism Spectrum Disorders (ASD) are neurodevelopmental disorders of complex etiology, with a recognized substantial contribution of heterogeneous genetic factors; one of the core features of ASD is a lack of affiliative behaviors.
Methods
Based on the existing literature, in this study we examined the hypothesis of allelic associations between genetic variants in six genes involved in control of maternal and affiliative behaviors (OXT, OXTR, PRL, PRLR, DβH, and FOSB). One hundred and seventy-seven probands with ASD from 151 families (n=527) were assessed with a set of related instruments capturing multiple facets of ASD. Multivariate and univariate phenotypes were constructed from these assessments and subjected to genetic linkage and association analyses using PBAT and FBAT software.
Results
The resulting pattern of findings, in general, confirmed the hypotheses of the significance of the genes involved in the development of affiliative behaviors in the manifestation of ASD (P-values ranging from 0.000005 to 0.05); statistically speaking, the strongest results were obtained for allelic associations with the PRL, PRLR, and OXTR genes.
Conclusions
Here we provided further evidence of an association between the allelic variants in a number of genes controlling affiliative behaviors and ASD. The outcomes of this study (a) contribute to a number of existing literatures on ASD, (b) allow formulation of new hypotheses of the involvement of the genes studied in this report, and (c) may enhance our understanding of previous reports of associations between ASD and other candidate genes (e.g., serotonergic and GABAergic).
doi:10.1016/j.biopsych.2007.11.015
PMCID: PMC2386897  PMID: 18207134
Autism Spectrum Disorders; Affiliative behaviors; Allelic association studies; OXT; OXTR; PRL; PRLR; DβH; FOSB
15.  Implications of temporal variation in maternal care for the prediction of neurobiological and behavioral outcomes in offspring 
Behavioral neuroscience  2013;127(1):33-46.
Previous studies in Long-Evans rats demonstrated a significant relationship between variation in pup licking/grooming and arched-back nursing (LG-ABN) and offspring development. However, maternal care is dynamic and exhibits significant temporal variation. In the current study, we assessed temporal variation in LG and ABN in lactating rats across the circadian cycle and determined the impact of these behaviors for the prediction of offspring hypothalamic gene expression, anxiety-like behavior, and responsiveness to high fat diet (HFD). We find that distinguishing between dams that engage in stable individual differences in maternal behavior (Low, Mid, High) requires assessment across the light-dark phases of the light cycle and across multiple postpartum days. Amongst juvenile female offspring, we find a positive correlation between maternal LG and mRNA levels of estrogen receptor alpha and beta and the oxytocin receptor (when LG is assessed across the light-dark cycle or in the dark phase). In young adults, we find sex-specific effects, with female High LG offspring exhibiting increased exploration of a novel environment and increased latency to approach HFD and male High LG offspring displaying increased activity in a novel environment and reduced HFD consumption. Importantly, these effects on behavior were primarily evident when LG was assessed across the light-dark cycle and ABN was not associated with these measures. Overall, our findings illustrate the dissociation between the effects of LG and ABN on offspring development and provide critical insights into the temporal characteristics of maternal behavior that have methodological implications for the study of maternal effects.
doi:10.1037/a0031219
PMCID: PMC3947603  PMID: 23398440
medial preoptic area; open-field test; high fat diet; circadian; Long Evans rats
16.  Obesity–insulin targeted genes in the 3p26-25 region in human studies and LG/J and SM/J mice 
Identifying metabolic syndrome (MetS) genes is important for novel drug development and health care. This study extends the findings on human chromosome 3p26-25 for an identified obesity–insulin factor QTL, with an LOD score above 3. A focused association analysis comprising up to 9578 African American and Caucasian subjects from the HyperGEN Network (908 African Americans and 1025 whites), the Family Heart Study (3035 whites in time 1 and 1943 in time 2), and the Framingham Heart Study (1317 in Offspring and 1320 in Generation 3) was performed. The homologous mouse region was explored in an F16 generation of an advanced intercross between the LG/J and SM/J inbred strains, in an experiment where 1002 animals were fed low-fat (247 males; 254 females) or high-fat (253 males; 248 females) diets. Association results in humans indicate pleiotropic effects for SNPs within or surrounding CNTN4 on obesity, lipids and blood pressure traits and for SNPs near IL5RA, TRNT1, CRBN, and LRRN1 on central obesity and blood pressure. Linkage analyses of this region in LG/J × SM/J mice identify a highly significant pleiotropic QTL peak for insulin and glucose levels, as well as response to glucose challenge. The mouse results show that insulin and glucose levels interact with high and low fat diets and differential gene expression was identified for Crbn and Arl8b. In humans, ARL8B resides ~137 kbps away from BHLHE40, expression of which shows up-regulation in response to insulin treatment. This focused human genetic analysis, incorporating mouse research evidenced that 3p26-25 has important genetic contributions to MetS components. Several of the candidate genes have functions in the brain. Their interaction with MetS and the brain warrants further investigation.
doi:10.1016/j.metabol.2012.01.008
PMCID: PMC3586585  PMID: 22386932
17.  Social Enrichment during Postnatal Development Induces Transgenerational Effects on Emotional and Reproductive Behavior in Mice 
Across species there is evidence that the quality of the early social environment can have a profound impact on neurobiology and behavior. In the present study we explore the effect of communal rearing conditions (three dams with three litters per cage) during the postnatal period on offspring (F1) and grand-offspring (F2) anxiety-like and maternal behavior in Balb/c mice. Females rearing pups in communal nests exhibited increased levels of postpartum maternal care and communal rearing was found to abolish sex-differences in weaning weights. In adulthood, communally reared offspring were observed to display reduced anxiety-like behavior when placed in a novel environment. When rearing their own offspring under standard conditions, communally reared females demonstrated higher levels of motivation to retrieve pups, built higher quality nests, and exhibited higher levels of postpartum care compared to standard reared females. When exposed to an intruder male, communally reared females were more subordinate and less aggressive. F2 offspring of communally reared females were observed to engage in reduced anxiety-like behavior, have larger litter sizes and an increased frequency of nursing on PND 1. Analysis of neuropeptide receptor levels suggest that a communal rearing environment may exert sustained effects on behavior through modification of oxytocin and vasopressin (V1a) receptor densities. Though Balb-C mice are often considered “socially-incompetent” and high in anxiety-like behavior, our findings suggest that through enrichment of the postnatal environment, these behavioral and neuroendocrine deficits may be attenuated both within and across generations.
doi:10.3389/neuro.08.025.2009
PMCID: PMC2759344  PMID: 19826497
communal nesting; maternal care; anxiety; oxytocin; vasopressin; Balb/c
18.  Identification of genetic determinants of IGF-1 levels and longevity among mouse inbred strains 
Aging cell  2010;9(5):823-836.
Summary
The IGF-1 signaling pathway plays an important role in regulating longevity. To identify the genetic loci and genes that regulate plasma IGF-1 levels, we intercrossed MRL/MpJ and SM/J, inbred mouse strains that differ in IGF-1 levels. Quantitative trait loci (QTL) analysis of IGF-1 levels of these F2 mice detected four QTL on chromosomes (Chrs) 9 (48 Mb), 10 (86 Mb), 15 (18 Mb) and 17 (85 Mb). Haplotype association mapping of IGF-1 levels in 28 domesticated inbred strains identified three suggestive loci in females on Chrs 2 (13 Mb), 10 (88 Mb) and 17 (28 Mb) and in males on Chrs 1 (159 Mb), 3 (52 and 58 Mb) and 16 (74 Mb). Except for the QTL on Chr 9 and 16, all loci co-localized with IGF-1 QTL previously identified in other mouse crosses. The most significant locus was the QTL on Chr 10, which contains the Igf1 gene and which had a LOD score of 31.8. Haplotype analysis among 28 domesticated inbred strains revealed a major QTL on Chr 10 overlapping with the QTL identified in the F2 mice. This locus showed three major haplotypes; strains with haplotype 1 had significantly lower plasma IGF-1 and extended longevity (P < 0.05) than strains with haplotype 2 or 3. Bioinformatic analysis, combined with sequencing and expression studies, showed that Igf1 is the most likely QTL gene, but that other genes may also play a role in this strong QTL.
doi:10.1111/j.1474-9726.2010.00612.x
PMCID: PMC3025299  PMID: 20735370
IGF-1; QTL; longevity; mouse; haplotype analysis
19.  Evidence of maternal QTL affecting growth and obesity in adult mice 
Mammalian Genome  2009;20(5):269-280.
Most quantitative trait loci (QTL) studies fail to account for the effect that the maternal genotype may have on an individual’s phenotypes, even though maternal effect QTL have been shown to account for considerable variation in growth and obesity traits in mouse models. Moreover, the fetal programming theory suggests that maternal effects influence an offspring’s adult fitness, although the genetic nature of fetal programming remains unclear. Within this context, our study focused on mapping genomic regions associated with maternal effect QTL by analyzing the phenotypes of chromosomes 2 and 7 subcongenic mice from genetically distinct dams. We analyzed 12 chromosome 2 subcongenic strains that spanned from 70 to 180 Mb with CAST/EiJ donor regions on the background of C57BL/6 J, and 14 chromosome 7 subcongenic strains that spanned from 81 to 111 Mb with BALB/cByJ donor regions on C57BL/6ByJ background. Maternal QTL analyses were performed on the basis of overlapping donor regions between subcongenic strains. We identified several highly significant (P < 5 × 10−4) maternal QTL influencing total body weight, organ weight, and fat pad weights in both sets of subcongenics. These QTL accounted for 1.9-11.7% of the phenotypic variance for growth and obesity and greatly narrowed the genomic regions associated with the maternal genetic effects. These maternal effect QTL controlled phenotypic traits in adult mice, suggesting that maternal influences at early stages of development may permanently affect offspring performance. Identification of maternal effects in our survey of two sets of subcongenic strains, representing approximately 5% of the mouse genome, supports the hypothesis that maternal effects represent significant sources of genetic variation that are largely ignored in genetic studies.
doi:10.1007/s00335-009-9182-9
PMCID: PMC2690847  PMID: 19399551
20.  Preferences for cocaine- or pup-associated chambers differentiates otherwise behaviorally identical postpartum maternal rats 
Psychopharmacology  2003;167(1):1-8.
Rationale and objectives
Our previous work uncovered a differential preference of maternal female rats for cues associated with pups versus cues associated with cocaine at three different postpartum time points. Our current study examines the preference for these cues in conjunction with an assessment of the capacity to express the maternal behavior at one of these time points. We examined dams at day 10 postpartum using a procedure that included two additional controls, and a complete assessment of the expression of maternal behavior and locomotor activity.
Methods
A conditioned place-preference procedure was used to determine the preference for cocaine- or pup-associated cues. The two controls were (1) a preconditioning test to verify no initial chamber preference and (2) a separate control group of postpartum day-10 dams exposed to chambers and cues but not to unconditioned stimuli. The expression of maternal behavior was determined by measurement of maternal nest building, retrieval of pups to the nest, grooming, crouching over pups, nursing, and maternal aggression. Locomotor activity was measured with an automated apparatus.
Results
Dams conditioned with cocaine or pups showed a preference for either the cocaine-associated chamber or the pup-associated chamber, confirming the existence of two similar-sized preference groups at this time point. Regardless of preference, dams had equal and robust expression of maternal behavior and similar locomotor capacity. The pre-conditioning test showed no initial chamber preferences and did not alter the conditioned preference response. The use of unconditioned stimuli in the place-preference conditioning procedure was effective and necessary for the preference response.
Conclusion
Our current study has revealed that differences in the motivational state of the maternal dam emerge even while the expression of maternal behavior is constant and substantial. The data suggest that the difference in preference is a very specific appetitive response that is not linked to expression of maternal behavior or locomotor capacity.
doi:10.1007/s00213-002-1351-4
PMCID: PMC2430092  PMID: 12607073
Maternal behavior; Conditioned place preference; Cocaine; Locomotor activity; Maternal aggression; Postpartum period
21.  Effects of Daily and Acute Restraint Stress During Lactation on Maternal Aggression and Behavior in Mice 
Stress (Amsterdam, Netherlands)  2006;9(3):171-180.
A decreased reactivity to stressors during lactation might heighten the expression of maternal care (including defense of offspring) by minimizing the extent to which stress can impact maternal care. Although stressors applied during pregnancy have variable effects on maternal aggression (or defense of offspring), to date no study has examined the effects of stress applied during the postpartum period on maternal aggression. In this study, we examined the effects of both daily and acute restraint stress (30 min) applied postpartum on maternal aggression and other maternal behaviors. Daily restraint (ending 2 hours before testing) did not alter any measure of maternal behavior, including nursing, licking and grooming of pups, and pup retrieval, or any measure of maternal aggression. In contrast, acute stress significantly impaired total time aggressive and number of attacks, but pup retrieval was normal. c-Fos levels were significantly elevated in a number of brain regions in association with acute stress, including lateral septum, caudal periaqueductal gray, and medial amygdala, suggesting possible sites where stress reactivity could alter aggression. Together, the results indicate that acute restraint stress impairs maternal aggression and provide a starting point for future studies examining how stress reactivity pathways may intersect with maternal aggression pathways.
doi:10.1080/10253890600969106
PMCID: PMC2409053  PMID: 17060051
maternal aggression; corticotropin releasing factor; mice; depression; fear; anxiety; CRF receptors
22.  FIRING PATTERNS OF MATERNAL RAT PRELIMBIC NEURONS DURING SPONTANEOUS CONTACT WITH PUPS 
Brain research bulletin  2012;88(5):534-542.
Extracellular single unit activity was recorded from medial prefrontal cortex (mPFC) of postpartum dams over the course of 3 days while they engaged in spontaneous pup-directed behaviors and non-specific exploratory behavior. Out of 109 units identified over the course of the experiment, 15 units were observed to be pup-responsive and 15 increased their discharge rates non-specifically while not attending to pups. An association between neuronal activity and typical maternal behaviors (e.g., retrieval, pup-grooming, nursing) was not observed. Instead, brief bouts of snout contact with pups were accompanied by phasic increases and decreases in spike rates. The observed pup contact responsive cells might play a role in processing of sensory feedback from pups or the transmission of modulatory output to other subcortical maternal brain areas.
doi:10.1016/j.brainresbull.2012.05.012
PMCID: PMC3525960  PMID: 22643133
prelimbic area; medial prefrontal cortex; neuronal firing rate; neuronal activity; maternal behavior; rat; motivation; goal-directed behavior; pups; open field behavior; excitatory neurons; glutamatergic neurons; principal cells; retrieval; rearing
23.  DISTRIBUTION OF OXYTOCIN IN THE BRAIN OF A EUSOCIAL RODENT 
Neuroscience  2008;155(3):809-817.
Naked mole-rats are highly social rodents that live in large colonies characterized by a rigid social and reproductive hierarchy. Only one female, the queen, breeds. Most colony members are non-reproductive subordinates that work cooperatively to rear the young and maintain an underground burrow system. Little is known about the neurobiological basis of the complex sociality exhibited by this species. The neuropeptide oxytocin (Oxt) modulates social bonding and other social behaviors in many vertebrates. Here we examined the distribution of Oxt immunoreactivity in the brains of male and female naked mole-rats. As in other species, the majority of Oxt-immunoreactive (Oxt-ir) cells were found in the paraventricular and supraoptic nuclei, with additional labeled cells scattered throughout the preoptic and anterior hypothalamic areas. Oxt-ir fibers were found traveling toward and through the median eminence, as well as in the tenia tecta, septum, and nucleus of diagonal band of Broca. A moderate network of fibers covered the bed nucleus of the stria terminalis and preoptic area, and a particularly dense fiber innervation of the nucleus accumbens and substantia innominata was observed. In the brainstem, Oxt-ir fibers were found in the periaqueductal grey, locus coeruleus, parabrachial nucleus, nucleus of the solitary tract, and nuclueus ambiguus. The high levels of Oxt immunoreactivity in the nucleus accumbens and preoptic area are intriguing, given the link in other rodents between Oxt signaling in these regions and maternal behavior. Although only the queen gives birth or nurses pups in a naked mole-rat colony, most individuals actively participate in pup care.
doi:10.1016/j.neuroscience.2008.05.039
PMCID: PMC2614305  PMID: 18582538
sex differences; social hierarchy; naked mole-rat; Heterocephalus glaber; sociality; vasopressin
24.  Oxytocin receptor ligand binding in embryonic tissue and postnatal brain development of the C57BL/6J mouse 
Oxytocin (OXT) has drawn increasing attention as a developmentally relevant neuropeptide given its role in the brain regulation of social behavior. It has been suggested that OXT plays an important role in the infant brain during caregiver attachment in nurturing familial contexts, but there is incomplete experimental evidence. Mouse models of OXT system genes have been particularly informative for the role of the OXT system in social behavior, however, the developing brain areas that could respond to ligand activation of the OXT receptor (OXTR) have yet to be identified in this species. Here we report new data revealing dynamic ligand-binding distribution of OXTR in the developing mouse brain. Using male and female C57BL/6J mice at postnatal days (P) 0, 7, 14, 21, 35, and 60 we quantified OXTR ligand binding in several brain areas which changed across development. Further, we describe OXTR ligand binding in select tissues of the near-term whole embryo at E18.5. Together, these data aid in the interpretation of findings in mouse models of the OXT system and generate new testable hypotheses for developmental roles for OXT in mammalian systems. We discuss our findings in the context of developmental disorders (including autism), attachment biology, and infant physiological regulation.
Summary: Quantitative mapping of selective OXTR ligand binding during postnatal development in the mouse reveals an unexpected, transient expression in layers II/III throughout the mouse neocortex. OXTR are also identified in several tissues in the whole late embryo, including the adrenal glands, brown adipose tissue, and the oronasal cavity.
doi:10.3389/fnbeh.2013.00195
PMCID: PMC3858721  PMID: 24376405
oxytocin; adrenal gland; kidney; oronasal cavity; autism; autoradiography; experience-dependent plasticity; neocortex
25.  Foster Dams Rear Fighters: Strain-Specific Effects of Within-Strain Fostering on Aggressive Behavior in Male Mice 
PLoS ONE  2013;8(9):e75037.
It is well known that genes and environment interact to produce behavioral phenotypes. One environmental factor with long-term effects on gene transcription and behavior is maternal care. A classic paradigm for examining maternal care and genetic interactions is to foster pups of one genetic strain to dams of a different strain ("between-strain fostering"). In addition, fostering to a dam of the same strain ("within-strain fostering") is used to reduce indirect effects, via behavioral changes in the dams, of gestation treatments on offspring. Using within-and between-strain fostering we examined the contributions of genetics/prenatal environment, maternal care, and the effects of fostering per se, on adult aggressive behavior in two inbred mouse strains, C57BL/6J (B6) and DBA/2J (DBA). We hypothesized that males reared by dams of the more aggressive DBA strain would attack intruders faster than those reared by B6 dams. Surprisingly, we found that both methods of fostering enhanced aggressive behavior, but only in B6 mice. Since all the B6 offspring are genetically identical, we asked if maternal behavior of B6 dams was affected by the relatedness of their pups. In fact, B6 dams caring for foster B6 pups displayed significantly reduced maternal behaviors. Finally, we measured vasopressin and corticotrophin releasing hormone mRNA in the amygdalae of adult B6 males reared by foster or biological dams. Both genes correlated with aggressive behavior in within-strain fostered B6 mice, but not in mice reared by their biological dams. In sum, we have demonstrated in inbred laboratory mice, that dams behave differently when rearing their own newborn pups versus pups from another dam of the same strain. These differences in maternal care affect aggression in the male offspring and transcription of Avp and Crh in the brain. It is likely that rearing by foster dams has additional effects and implications for other species.
doi:10.1371/journal.pone.0075037
PMCID: PMC3769275  PMID: 24040381

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