Elsevier

Brain Research

Volume 1211, 23 May 2008, Pages 57-71
Brain Research

Research Report
Neurobehavioral basis of the impaired nurturing in mice lacking the immediate early gene FosB

https://doi.org/10.1016/j.brainres.2008.02.100Get rights and content

Abstract

The transcription factor FosB is induced in neurons of the medial preoptic area (MPOA) during parenting, through activation of the extracellular signal-regulated kinase (ERK). FosB mutant (−/−) postpartum mice and virgin mice that are exposed to pups show defective nurturing behavior. The FosB (−/−) MPOA fails to fully up-regulate SPRY1 and Rad, the feedback regulators of ERK and calcium signaling, respectively. Here we studied FosB function by examining the gene expression profiles and the behavioral characteristics of FosB (−/−) mice. We found that FosB (−/|−) mice exhibited not only decreased parenting but also decreased infanticide compared with (+/) littermates. We then performed gene expression analysis in the MPOA of FosB (−/−) mice compared with the wild-type littermates. We found up-regulation of glial fibrillary acidic protein (GFAP), C4, and Ela1 mRNA in the MPOA of FosB (−/−) mice; all of these gene products were implicated in general neuropathological conditions. Immunohistochemical analysis showed that up-regulation of GFAP was not restricted to MPOA but extended throughout the forebrain, including the cerebral cortex and striatum. Such pervasive GFAP up-regulation suggested that FosB (−/−) mice might have other behavioral abnormalities than nurturing. Indeed, these mice showed a clear alteration in emotionality, detected by the acoustic startle, elevated plus maze, and passive avoidance tests. These results suggest that FosB (−/−) mice have broader neurobehavioral dysfunctions, with which the nurturing defect might share the common mechanism.

Introduction

Childhood abuse and neglect become risk factors for a wide range of mental disorders such as depression, anxiety disorders, and personality disorders (Heim and Nemeroff, 2001). Understanding the molecular, cellular, and neurobiological basis of parental behavior would be helpful for the prevention of child maltreatment. Because parental care, such as nursing, is essential for all mammalian infants to grow, the basic brain mechanism of parenting should be conserved among mammals. Therefore, we can expect to gain our knowledge about human parental behavior from basic research using other mammalian models.

The neural mechanism of parental behavior has been studied most extensively in rodents (Krasnegor and Bridges, 1990, Numan and Insel, 2003). Accumulating evidence supports the idea that the medial preoptic area (MPOA) of the hypothalamus plays a key role in the expression of parental retrieving behavior (i.e., gathering scattered pups into the nest) (Morgan et al., 1999, Numan, 1994). When a rat or mouse takes care of pups, c-Fos, which is an important molecule for AP-1 transcription activity (Herdegen and Leah, 1998), is induced in MPOA (Calamandrei and Keverne, 1994, Li et al., 1999, Numan and Numan, 1994). MPOA lesions, especially in the dorsolateral MPOA (MPOAdl), specifically inhibit retrieving, without affecting feeding, general locomotion, female reproductive functions, or sexual behaviors (Jacobson et al., 1980, Kalinichev et al., 2000a, Kalinichev et al., 2000b, Lee and Brown, 2002, Numan et al., 1990, Rosenblatt et al., 1996, Terkel et al., 1979).

Brown et al. (1996) generated genetically engineered mice lacking FosB, another AP-1 transcription factor homologous to c-Fos, and found that these mutant mice had profound defects in nurturing behavior without any cognitive and sensorimotor impairment . Together with c-Fos, FosB is induced in MPOA neurons during performance of parental behavior in mice (Brown et al., 1996) and in rats (Kalinichev et al., 2000a, Kalinichev et al., 2000b, Numan et al., 1998). These studies suggest that c-Fos and FosB are induced in MPOA neurons and then, in turn, induce the expression of downstream genes required to facilitate parental behavior. To identify such downstream genes, we recently investigated the gene expression profiles of the MPOA in parental and nonparental mice (Kuroda et al., 2007). We identified up-regulation of NGFI-B (also designated as Nr4a1/Nur77/TR3/NAK1NP10/GFRP1), SPRY1, and Rad in parental mice, together with c-Fos and FosB. A common inducer of these genes, the extracellular signal-regulated kinase (ERK) was transiently phosphorylated in MPOA neurons on pup exposure. Pharmacologic blockade of ERK phosphorylation inhibited the FosB up-regulation in MPOA and the initiation of pup retrieving in virgin female mice but did not affect the established parenting in parous females. Furthermore, induction of SPRY1 and Rad was impaired in MPOA of nonparental FosB (−/−) mice. Therefore, the ERK-FosB-SPRY1/Rad signaling seemed to play a crucial role in the initiation of parental care.

In this study, to extend our knowledge of the molecular mechanism of mammalian parental behavior, we first re-examined the behavioral characteristics of FosB (−/−) mice and performed the gene expression analysis in the MPOA. We found that: (1) FosB (−/−) mice were defective not only in parenting but also in infanticide; (2) FosB (−/−) mice showed marked up-regulation of glial fibrillary acidic protein (GFAP) throughout the forebrain including the MPOA; and (3) FosB (−/−) mice displayed abnormal emotionality in behavioral test batteries. These results suggest that FosB (−/−) mice have broader neurobehavioral dysfunctions, with which the nurturing defect might share the common mechanism.

Section snippets

Nurturing behavior of FosB (−/−) mice

To clarify the molecular mechanism of nurturing defects caused by the lack of FosB gene, we bred the FosB (−/−) mouse strain by FosB (+/−) intercross; that is, all of the subject mice used in this study were reared by FosB (+/−) mothers. And since Brown et al, as well as ourselves (data not shown), did not detect any nurturing defects in FosB (+/−) mice in comparison with (+/+) littermates, we combined the data of (+/−) with those of (+/+) throughout the parental behavior analyses and denoted

Discussion

In this study, we confirmed and extended the previous finding that FosB (−/−) mice showed impairment of nurturing behavior (Brown et al., 1996). We noticed that the pup-directed behavior of not only FosB (−/−) mice but also of (+/) mice is affected by genetic background and the experimental conditions, such as the cage bedding used during retrieval assay (Table 2). Infanticide was strongly inhibited in the MTL condition, even if the case size, the cage bedding, and the genetic background were

Animals

All animal experiments were conducted in accordance with the National Institutes of Health guide “Principles of Laboratory Animal Care” (NIH publication no. 85–23, revised 1985) and were approved by the Animal Experiment Judging Committee of McGill University and RIKEN. Wild-type C57BL/6J mice were purchased from Japan SLC (Hamamatsu, Japan). A FosB (−/−) mouse strain was obtained from the Jackson Laboratory (strain C;129S-Fosbtm1Meg/J; stock number 3077). All of the subject mice used in this

Acknowledgments

We thank Michel L. Tremblay for kindly providing working space and laboratory equipment; Michael E. Greenberg for the discussions and for the protocol of PCR genotyping of the FosB (−/−) strain; Chikuma Hamada, Hirotaka Onishi and Masahiro Kaneseki for the statistical method selection; the R Core Team for the software and packages, Fukiko Isono, Tetsuaki Ara, and Taeko Nemoto for their technical assistance; the RIKEN Research Resource Center for the hybridization and scanning of GeneChips and

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