Maternal neglect with reduced depressive-like behavior and blunted c-fos activation in Brattleboro mothers, the role of central vasopressin

Abstract

Early mother–infant relationships exert important long-term effects in offspring and are disturbed by factors such as postpartum depression. We aimed to clarify if lack of vasopressin influences maternal behavior paralleled by the development of a depressive-like phenotype. We compared vasopressin-deficient Brattleboro mothers with heterozygous and homozygous normal ones. The following parameters were measured: maternal behavior (undisturbed and separation-induced); anxiety by the elevated plus maze; sucrose and saccharin preference and forced swim behavior. Underlying brain areas were examined by c-fos immunocytochemistry among rest and after swim-stress. In another group of rats, vasopressin 2 receptor agonist was used peripherally to exclude secondary changes due to diabetes insipidus. Results showed that vasopressin-deficient rats spend less time licking–grooming their pups through a centrally driven mechanism. There was no difference between genotypes during the pup retrieval test. Vasopressin-deficient mothers tended to explore more the open arms of the plus maze, showed more preference for sucrose and saccharin and struggled more in the forced swim test, suggesting that they act as less depressive. Under basal conditions, vasopressin-deficient mothers had more c-fos expression in the medial preoptic area, shell of nucleus accumbens, paraventricular nucleus of the hypothalamus and amygdala, but not in other structures. In these areas the swim-stress-induced activation was smaller. In conclusion, vasopressin-deficiency resulted in maternal neglect due to a central effect and was protective against depressive-like behavior probably as a consequence of reduced activation of some stress-related brain structures. The conflicting behavioral data underscores the need for more sex specific studies.

Introduction

In the emergent field of Social Neuroscience it has been proposed that vasopressin (AVP) exerts an important role in affiliative behaviors in all vertebrates, especially in social recognition/memory and pair bonding (Young and Flanagan-Cato, 2012). However, most of the data about the role of AVP in social behavior was obtained in males and not too much information was available in females (Bosch, 2011, Bosch and Neumann, 2012).

AVP is mainly synthesized in the magnocellular cells of the hypothalamic supraoptic (SON) and paraventricular nuclei (PVN) whose axons project to the posterior pituitary (Rhodes et al., 1981, Sokol et al., 1976). AVP is then released into the blood-stream upon appropriate stimulation (e.g., hemorrhage or dehydration) to act at the kidneys and blood vessels. The brain also contains several populations of smaller, AVP synthesizing parvocellular neurons, whose projections remain within the brain. These populations are located within the PVN, medial amygdala (MeA) and suprachiasmatic nucleus (SCN) (Buijs et al., 1978). The medial part of the parvocellular PVN (mpPVN) contains corticotropin-releasing hormone (CRH) producing neurons in colocalization with AVP projecting to the median eminence as part of the so-called hypothalamic–pituitary–adrenocortical (HPA) axis (Antoni, 1993).

The female brain AVP system becomes activated around parturition and during lactation. AVP levels peak on the day before parturition in PVN and SON (Caldwell et al., 1987). In the septal area of pregnant rats the release of AVP is greater than in virgin rats (Landgraf et al., 1991). Therefore an involvement of AVP in the behavior of lactating mothers can be supposed.

The Brattleboro homozygous rat (di/di) has a spontaneous mutation in the AVP precursor and – as a consequence – AVP is not synthesized, leading to a diabetes insipidus phenotype (Richter and Schmale, 1983, Valtin and Schroeder, 1964). This strain is a good model for studying the role of AVP in physiological and psychological processes without the need of further manipulations (i.e. injections and operations) (Bohus and de Wied, 1998).

The mother–infant relationship is an important factor in the development of offspring and there are broad individual differences in mother styles that could affect emotionality and stress reactivity of offspring at adulthood (Korosi et al., 2012, Meaney and Szyf, 2005, Veenema, 2012). Maternal behaviors in rodents include a number of subcomponents, such as nest building, pup retrieval, nursing, licking and grooming of pups, and maternal defense of the nest against potential intruders (maternal aggression). Although there are no previous detailed evaluations of undisturbed (natural) and separation-induced maternal care in Brattleboro rats, some data already suggest that the quality of the early life environment and development is affected in those animals. Regarding Brattleboro di/di rats, previous studies indicated that litter size and the pup body weight were lower than for +/+ and di/+ dams (Boer et al., 1982, Zelena et al., 2009b). Further work also indicated that – in comparison to Long-Evans rats – Brattleboro di/di dams made nests of less quality, had a higher incidence of cannibalism and had a lower percent of pups that survived until weaning, although in all of these cases the genotype of the pups was also different (Wideman and Murphy, 1990).

Mother's mood could also affect normal mother–infant interaction. Postpartum depression (PPD) is a serious medical condition that affects approximately 10% to 20% of mothers during the first 4 weeks after delivery. Symptoms of PPD can include labile mood with prominent anxiety and irritability and depression (Miller, 2002). In humans, children of depressed mothers tend to show abnormal cognitive, motor and social development and are more likely to experience depression or anxiety later in life (Heim and Nemeroff, 2001). Despite its clinical importance this disease is underdiagnosed and undertreated.

Gold et al. were the first to propose a role for AVP in mood disorders (Gold et al., 1978); and several studies since then supported this idea (Dinan and Scott, 2005, Frank and Landgraf, 2008, Ryckmans, 2010). Patients with major depression have significantly elevated plasma AVP compared to healthy controls (van Londen et al., 1997). Depressed patients with the melancholic subtype have significantly greater AVP mRNA both in the SON and PVN (Meynen et al., 2006). A single nucleotide polymorphism of the V1b receptor was associated to major depression (van West et al., 2004). However, despite the more common prevalence of depression in females (Weissman and Klerman, 1977), most of the studies have been done in males.

Given all the above, the aims of the present work were to study the effects of the lack of AVP in Brattleboro mothers on: (i) undisturbed maternal and separation-induced pup retrieval behavior and the influence of peripheral administration of a V2 receptor agonist on this behavior, (ii) anxiety and depressive-like behavior, and (iii) basal and stress-induced c-fos activation in several brain areas. Our results may give further details to the role of AVP in the behavior of the mothers (both maternal care and development of PPD) and its underlying brain areas without the need of further manipulations which could be very important in the case of undisturbed maternal care.