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Institut National de la Santé et de la Recherche Médicale Unit 344 (B.K.L., N.B., P.A.K.), Endocrinologie Moléculaire, Faculté de Médecine Necker, 75730 Paris Cedex 15, France; Cancer Research Program (C.J.O.), Garvan Institute of Medical Research, Darlinghurst NSW2010, Sydney, Australia; and Tufts University School of Veterinary Medicine (R.S.B.), Department of Biomedical Sciences, North Grafton, Massachusetts 01536
Address all correspondence and requests for reprints to: Brian Lucas, INSERM Unit 344, Faculté de Médecine Necker, 156 rue de Vaugirard 75730 Paris Cedex 15, France. E-mail: lucas{at}necker.fr
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Numerous examinations have been performed in the attempt to elucidate the neural mechanisms underlying nurturing behaviors in rodents. With regard to sensory stimuli, early work in the field has shown that retrieval of pups is unmodified by deafness and that visual cues seem to play little or no role in pup-directed behavior (3). It has, however, been shown that olfactory cues are important in the regulation of nurturing behavior (4, 5). Studies seem to indicate that, whereas pup odors inhibit nurturing behavior in virgin rats (6), in parturient animals, maternal behavior is stimulated by pup odors (5).
There has been increasing correlative evidence of hormonal control of the onset and maintenance of nurturing behavior (7, 8). The lactotrophic hormone PRL, levels of which increase markedly in the blood just before parturition, is often implicated as playing a key role in the regulation of maternal behavior. The action of PRL is mediated through its binding to the PRL receptor (PRLR), a transmembrane protein belonging to the cytokine receptor superfamily (9). Studies have identified PRLR-expressing cells in the medial preoptic area (MPOA) and a significant prepartum increase of those cells (10). Binding studies on ovariectomized rats show that PRLR expression and distribution are differentially regulated in the brain by estradiol (11).
Research in birds has shown that PRL facilitates behavioral responses to reproduction and alters behavior associated with nesting (12). Early work demonstrating a central site of PRL action on maternal behavior in mice used crystalline PRL placed into the anterior hypothalamus adjacent to the preoptic region, which enhanced pup retrieval and nest building (13). Nurturing behavior toward foster young in virgin females is promoted by secretion of PRL in steroid-treated ovariectomized rats and by administration of PRL in hypophysectomized rats, or by treatment with ectopic pituitary grafts in progesterone-treated hypophysectomized rats (7, 14, 15). In nonhypophysectomized, ovariectomized virgin rats, the suppression of endogenous PRL secretion with bromocriptine, a dopamine agonist, blocked the onset of maternal behavior. PRL is required for estrogen and progesterone to be effective in stimulating nurturing behavior (14). A direct correlation between PRL levels and nurturing behavior in pituitary grafted rats has been reported (8). More recent work indicates that nest building and pup retrieval are PRL-regulated via PRLRs in the medial preoptic area of the rat brain (16).
Hitherto, two experimental models are predominant for the examination of the role of PRL and its receptor in the mediation of maternal behavior. Pituitary ablation, achieved by hypophysectomy, or the administration of dopamine D2 receptor agonists, to reduce pituitary PRL secretion, are classical approaches. The possibility of incomplete PRL suppression and/or the possible suppression of other pituitary and nonpituitary hormones leave each of these approaches compromised. By removing PRLR from the set of expressed genes in the mouse, using gene targeting techniques, we are able to examine directly the effects of PRLR-mediated signaling on maternal behavior in the mouse.
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Materials and Methods |
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Nulliparous (pup-induced) nurturing behavior test
Virgin females, 42–54 days old, were individually housed, once
pregnant. Experiments were performed 3–6 h into the light cycle. On
day 1, each female was exposed to three 1- to 3-day-old foster pups,
which were placed in the opposite corner of the cage from the nest. For
the succeeding 30 min, she was continually observed, and the following
endpoints were recorded: latency to retrieve each pup (carrying the pup
by mouth and placing it into the nest), total number of pups retrieved,
latency to crouch over all three pups in the nest for more than 5 min
at a time (with crouching defined as a mother arching her back and
assuming the nursing posture with all three pups under her ventral
surface in the nest, although the pups did not have to be nursing).
Twenty-four hours later, and for the next 5 days, the females were
exposed to 1- to 3-day-old foster pups and were observed for 30 min.
For statistical analysis, animals were scored for their latency to
exhibit the above behaviors, beginning with a score of 0 for those
females exhibiting the behavior on the first day. Animals not
exhibiting a given behavior at all during the 6 days of testing were
given a score of 6 for that behavior. Full maternal behavior was
defined as retrieval of all three pups to the nest and crouching over
them in the nest during the 30 min test period. All test pups were 129
wild-type (PRLR +/+). Test pups were returned to the donor
mothers after the 30-min test was completed. All experiments were
performed blind to genotype.
Primiparous nurturing behavior test
All females were individually housed, once pregnant. Experiments
were performed 3–6 h into the light cycle. Births were recorded each
morning, at which time young were removed to be raised by foster
mothers. On the day of behavioral testing, the female was exposed to
three 1- to 3-day-old pups placed in the corner of the cage opposite
the nest. During the next 30 min, she was continually observed, and the
following endpoints were recorded: latency to retrieve each pup, total
number of pups retrieved, and the total time spent crouching over all
of the pups in the nest. All experiments were performed blind to
genotype.
Morris water maze cognitive test
The Morris water maze testing was performed essentially as
described (18). Naive 2- to 3-month-old mice were used. Mice were
placed into the pool in one of the four quadrants chosen at random and
allowed to search the pool for, at most, 60 sec, at which time those
still swimming were placed onto the platform. Animals were allowed to
rest 30 sec on the platform before being placed back into their cage.
The animals were trained, four trials (one per hour) per day for 7
days. On the day after the conclusion of training, the learning of the
mice was assessed using a probe test, in which the platform was removed
and the mice were allowed to search the pool for 60 sec. The amount of
time spent in the trained vs. other quadrants and the number
of times the mice crossed the location of the trained platform were
recorded. A quadrant search time was obtained by dividing the pool into
four equal quadrants and measuring the amount of time spent in each
quadrant. Experiments were performed 3–6 h into the light cycle. All
experiments were performed blind to the genotype of the mice.
Olfactory discrimination testing
Olfactory discrimination was assessed as described (19). In
brief, male and female mice were housed individually, with access to
water restricted to 30 min per day for 10 days. During this time, the
animals were trained to drink from within a small cage, which allowed
them to get no closer than 3 cm from the drinking nozzle before the
cage was slid forward and the animal had access to the nozzle. For the
olfactory testing, a solution of 0.1% isoamyl acetate was used as the
odorant associated with 0.1% quinine HCl, the tastant. The mice were
placed in the cage 3 cm from the drinking nozzle for 30 sec before the
cage was slid forward, at which time, latency to drink was measured.
Five trials using water and five trials using the isoamyl
acetate/quinine HCl solution were alternatively performed on
each mouse. Experiments were performed 3–6 h into the light cycle. All
experiments were performed blind to the genotype of the mice.
Statistical analysis
Data were analyzed using the Kruskal-Wallis test for multiple
group comparisons and the Mann-Whitney U test for
comparisons between groups.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Full maternal behavior, defined as
retrieving all three pups and crouching over them in the nest, was
displayed by PRLR +/+ virgin females with a latency of 1 or 2 days,
whereas PRLR +/- virgin females showed an average latency of 4 days
before displaying this behavior, and PRLR -/- virgins did not exhibit
such behavior at all during the 6-day testing period.
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). PRLR +/- mice took notice of
and made immediate contact with and sniffed the pups, as did the PRLR
+/+ animals. PRLR +/- females then typically returned to the nest,
returning once or twice to sniff the pups before retrieving one, or (at
most) two pups, over the next several minutes, before settling into the
nest and ignoring the unretrieved pups for the remainder of the test.
Full maternal behavior was typically displayed by PRLR +/+ females
within several minutes, whereas none of the PRLR +/- mice exhibited
such behavior within the testing period.
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). Once learning had been
confirmed in the PRLR +/+ mice, a probe test was performed in which the
platform was removed and the mice were allowed to search the pool for
60 sec. PRLR +/+, PRLR +/-, and PRLR -/- mice selectively searched
the quadrant in which the platform had been located vs. the
other quadrants (Fig. 3B). Thus, the results of Morris maze testing
demonstrate that PRLR mutant mice acquire spatial learning at the same
rate as PRLR +/+ animals and perform as well in the probe test.
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). Most mice then sampled the solution
again after several seconds, only to withdraw again. Subsequently, each
time the animals were presented with water, they immediately began
drinking. When the quinine hydrochloride/isoamyl acetate solution was
presented, all of the animals sniffed at the nozzle during the 30 sec
before being given access, the mice showed increasing latencies to
drink, or did not drink at all during the test period. Each animal was
tested 5 times with water and 5 times with the quinine
hydrochloride/isoamyl acetate solution. These results clearly establish
that the PRLR mutants are not anosmic.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Regarding maternal behavior in primiparous PRLR null mutant females, the heterozygotes are the only animals studied, because PRLR -/- females suffer a failure of embryonic implantation, as well as a defect in preimplantation embryonic development (17). The heterozygotes exhibit a small (but significant) defect in their ability to retrieve the first of three foster pups, relative to their PRLR +/+ littermates. In subsequent retrievals, however, PRLR +/- females show increasing difficulty. Upon examination of the performance of individual animals, PRLR +/- mice reveal heterogeneity regarding latencies to retrieve the first two pups, with some mice showing a clear defect and others performing nearly as well as the PRLR +/+ mice. Correlating the level of PRLR expression with latency to engage in nurturing activity might resolve this issue by revealing a threshold of PRLR signaling below which postpartum maternal behavior is impacted.
Testing for pup contact-induced maternal behavior in virgin mice allowed us to examine the role of PRLR by using, in addition to PRLR +/- females, the PRLR -/- females, in which mammary gland development is not morphologically different from PRLR +/+ virgins. Examination of PRLR -/- behavior reveals that total ablation of the PRLR results in a dramatic defect in both retrieving and crouching behaviors. The typical response of PRLR +/+ virgins is to examine the pups almost immediately after their introduction into the home cage, then to leave the pups and return to the nest for a few minutes, leaving the nest occasionally to reexamine the pups several times during the first 30-min exposure session. On subsequent days, however, time spent by virgin females alone in the nest is decreased and more time is spent examining the pups until retrieval is attempted, usually unsuccessfully at first, and finally achieved. Retrieval of all three pups, grouping, and crouching over them usually follow rather quickly. PRLR -/- females exhibit similar exploratory behavior toward the pups in early contact sessions, but subsequent sessions are typically characterized by decreasing pup examinations, as the females spend most of the session alone in the nest. The nulliparous PRLR +/- females were, as in the case of postpartum behavior, quite heterogeneous for retrieval and crouching behaviors, with some animals showing a clear defect in their nurturing reaction to the presence of foster pups, whereas others exhibit nearly PRLR +/+ levels of latencies to respond to pups. This finding among PRLR +/- females, all of which are receiving some level of PRLR-mediated signaling, calls again into question the level of PRLR expression in the individual animals.
That a clear defect in maternal behavior is seen in primiparous PRLR +/- females, whereas virgin heterozygous mice show less of a defect, can be interpreted as revealing a titration effect of PRLR signaling similar to that seen in these animals regarding mammary gland development (17). Virgin PRLR +/- and PRLR -/- mammary glands show no developmental deficiencies; ductal tissue and end buds are evident. Mammary gland development through the adolescent developmental stage is under the control of estrogen, adrenocorticoid, and GH (20). That the explosive round of mammary gland development associated with pregnancy is diminished or eliminated in PRLR heterozygotes mice indicates that, although PRLR signaling is occurring, it is not reaching a threshold level in the animals affected. It may be that a threshold level of PRLR signaling is also necessary for the induction of maternal behavior.
Because maternal behavior is known to be regulated by the hypothalamus, the defect in PRLR mutants could be limited to the hypothalamus, but it might involve several of its functions. A number of different processes are known to be regulated by the hypothalamus, including appetite (27), sexual behavior (28), and locomotive activity (29). Morris maze results suggest that mutants are normal in locomotive activity. A comparison of body weights of PRLR +/+ and mutant mice indicated no differences (data not shown). Normal rates of vaginal plugging indicated that sexual behavior in the mutant females is not dramatically altered (17), although a more detailed evaluation of sexual behavior would be of interest. These results suggest that the PRLR-dependent defect in maternal behavior may be specifically mediated by brain regions whose primary function is to control maternal responsiveness.
Whereas maternal behavior in primiparous females has been shown to implicate the MPOA (30), Sugiyama et al. observe an increase in PRL binding sites in the choroid plexus in virgin rats after pup contact (31). This finding suggests a second explanation for the difference in the nurturing behavioral defect seen in primiparous vs. virgin heterozygotes: that the two phenomenon are regulated by different, if overlapping, neural mechanisms.
Numerous investigators have indicated that olfactory information is important for the nurturing response to pups in postpartum animals (4, 5, 32). Very low PRLR expression has been seen in the adult rat olfactory bulb, but there is a high level of PRLR expression in fetal rat olfactory bulbs (33). This would seem to imply a role for the receptor in the migration or differentiation of GnRH neurons derived from the olfactory placode (34). For this reason, we thought an olfactory defect might be likely in PRLR- mice. Olfactory information is transmitted from the main olfactory bulb to the amygdala and from there to the preoptic area of the hypothalamus, where regulation of maternal behavior is regulated in postpartum females (32, 35). Our findings show that the PRLR mutant animals perform as well as their PRLR +/+ litter mates in an odor-cued taste avoidance assay. The test we used is limited in its sensitivity and may not detect subtle defects in olfactory performance, because quinine hydrochloride (the tastant) has a detectable odor. So, although PRLR -/- mice are not anosmic, olfactory defects of a less dramatic nature cannot be ruled out and, indeed, may become evident in future examinations. Neither can we rule out a defect in the discrimination of odors, involving the olfactory bulb, or in neurons involved in the transmission and regulation of olfactory signals.
The Morris maze hidden platform (placement) test has been shown to
require the integrity of the hippocampus in rats in the integration of
multiple cues, that is, configural learning (36); and the same would
seem to be true in mice (37). That PRLR -/- mice show normal learning
in the Morris water maze is in keeping with previous observations in
Snell dwarf mice with ectopic pituitary grafts, in which spatial
orientation was unaffected (38). In that experiment, however,
exploratory activity was increased. Contrary to postpartum females,
virgin rats exhibit an adverse reaction to pup odors (4, 6, 39). It has
been shown that the latencies to exhibit maternal behavior seen in
virgin rats can be reduced either by producing anosmia or by handling
to reduce fear of novelty (6, 40). That aversive responses to newborn
pups by virgin females may be related to fear and timidity has been
postulated (41). Reduced fearfulness in postpartum females has been
shown; this is thought to implicate the neurotransmitter
-aminobutyric acid (GABA) (42, 43). PRL stimulates the release of
GABA, and pup contact increases GABA activity in lactating (not virgin)
females, ostensibly via PRL (44). GABAergic neurons in the hypothalamus
act to decrease anxiety and to increase punished response (45). If this
action is mediated by the PRLR, PRLR -/- mice might suffer decreased
GABA release and increased anxiety, which would manifest itself as an
increased aversion to pup odors in primiparous females. The possible
connection, then, between the lack of a PRLR-mediated decrease in
timidity and the latency of PRLR -/- virgin mice to respond to
newborn pups is intriguing and should be examined.
Received March 25, 1998.
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