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Department of Comparative Medicine (R.S.B., J.D.S., B.M.H., P.E.M.), Tufts University School of Veterinary Medicine, North Grafton, Massachusetts 01536; and the Department of Physiology (M.C.R., R.P.C.S.), University of Manitoba School of Medicine, Winnipeg, Manitoba, Canada R3E 0W3
Address all correspondence and requests for reprints to: Robert S. Bridges, Ph.D., Department of Comparative Medicine, Peabody Pavilion, Tufts University School of Veterinary Medicine, 200 Westboro Road, North Grafton, Massachusetts 01536. E-mail: RBRIDGES{at}INFONET.TUFTS.EDU
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Abstract |
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Together these studies indicate that 1) both P and E2 are required for lactogenic stimulation of maternal behavior; 2) the stimulatory actions of PRL and rPLs on maternal behavior are related to their lactogenic properties; 3) extended treatment of females with lactogenic hormones is more effective in stimulating the onset of maternal behavior; and 4) the neural potencies of rPRL and rPL-I are similar. These findings provide support for the idea that the induction of maternal behavior is stimulated by the central actions of lactogenic hormones.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study seeks to determine answers to three questions relevant to the central stimulation of maternal behavior by PRL and PLs. First, it is asked whether the central actions of lactogenic hormones are dependent upon both E2 and P. Although all studies to date have required the presence of E2 and P for PRL’s central action, a systematic evaluation of the roles of these steroids in PRL’s action is needed to begin to understand possible mechanisms underlying the neurochemical regulation of maternal behavior. Second, all earlier studies demonstrating a central action of PRL or the rPLs typically used vehicle-infused controls (3, 4, 5). It is not known, for example, whether the infusion of large proteins that are evolutionarily related or unrelated to these lactogenic hormones would have similar stimulatory actions. Therefore, in the second experiment, the effects of central infusions of nonlactogenic bovine (b) GH and ovine (o) LH on the expression of maternal behavior in inexperienced nulli- parous rats were evaluated to assess the specificity of the behavioral actions of PRL and PLs. In the final study, we sought to determine whether the behavioral potencies of rPRL and rPLs were equally effective in inducing maternal behavior. Might the brain be more responsive to one of these lactogenic hormones? Our approach to address this question was to vary the number of central infusions of rPRL and rPL-I into the MPOA to see whether a single or multiple (3) infusions of a given hormone might be more effective in stimulating maternal care than an equal number of infusions of the other lactogen.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Stereotaxic surgery
Seven to 10 days before the start of steroid treatment, female
rats were fitted with 22-gauge bilateral guides (Plastics One, Roanoke,
VA) directed toward the MPOA. Implant coordinates were derived from
Pellegrino et al. (12) [anterior-posterior (AP) = +7.5;
lateral (L) = ±1.0; height (H) = +4.0] with the tooth bar setting
adjusted to 5 mm above intraaural zero. Dummy cannulas were cut to be
flush with the guide cannula. Infusion cannula (28-gauge) were designed
to extend 5 mm beyond the tip of the guide cannula (MPOA, H =
-1.0). Cannulations were performed under chloropent anesthesia, at
which time females were also ovariectomized (ovx).
SILASTIC brand capsule implants
Test animals were sequentially exposed to a steroid regimen that
consisted of P and E2 (Steraloids, Wilton, NH). On
treatment day 1, 7–10 days after cannulation and ovariectomy, rats
were implanted sc with three 30-mm P-filled SILASTIC brand capsules
(602–305, Dow Corning, Midland, MI) (13). On treatment day 11, P
capsules were removed, and each rat was given a single 2-mm
E2 implant sc. All SILASTIC capsules were implanted under
Metofane (Mallinckrodt Veterinary, Inc., Mundelein, IL) anesthesia.
Although the pattern of steroid exposure generated by this hormone
regimen is not identical to that found during gestation when both
E2 and P levels are generally elevated, this hormone
regimen does produce pregnancy-like serum levels of these steroids (14)
and stimulates a rapid onset of maternal behavior in
nonbromocriptine-treated, virgin rats (13). Moreover, the decline in
circulating P levels before behavioral testing, which mimics the P
pattern found in prepartum rats, is required to induce a rapid onset of
maternal behavior. Maintenance of high blood levels of P prevents
establishment of the rapid onset of maternal behavior at the end of
gestation (15).
Injections and infusions
Animals were injected sc twice daily at 0900 and 1600 h
from treatment day 11 through day 17 with bromocriptine (Sandoz
Pharmaceuticals Corp., Hanover, NJ) at a dose of 2 mg/kg. This dose of
bromocriptine suppresses endogenous PRL secretion throughout the period
of E2 exposure and behavioral testing (13).
Experimental animals were infused centrally with the following hormones: rPRL (lot AFP-7545E, National Hormone and Pituitary Program), rPL-I (recombinant, supplied by Drs. Robertson and Shiu) (16), bGH (USDA bGH B-1) or oLH (NIDDK oLH-26). These hormones were solubilized in 0.03 M NaHCO2 in 0.15 M NaCl. Doses of 40 ng of each hormone or vehicle (0.4 µl) were infused into each side of the MPOA over a 22-sec period with a Stoelting infusion pump fitted with a 10-µl Hamilton syringe (Hamilton, Reno, NV). After infusion, the internal cannula remained in the guides for 30 sec to facilitate diffusion of the infusate into the neuropil. Infusions were performed once, three or five times depending upon the experiment, beginning on treatment day 11 (1000 h). Animals receiving three infusions were also infused at 1600 h on day 11 (the day before testing) and at 1000 h on the first day of testing (day 12). Rats receiving five infusions were given additional hormone or vehicle infusions at 1600 h on day 12 and at 1000 h on day 13. Infusions at 1000 h on treatment days 12 and 13 were administered approximately 30 min before behavioral testing.
Behavioral testing
Animals were tested daily for maternal responsiveness
beginning on treatment day 12 as previously described (13). Briefly,
animals were observed for 1 h in their home cages: continuously
for the initial 15 min and then at 15-min intervals for the remainder
of the hour. Incidences and latencies to contact the pups and retrieve,
group, and crouch over them were recorded during each test session. For
example, if a test animal retrieved a pup on the first test day, its
retrieval latency score was 0. Behavioral testing was performed for 6
days or until the female displayed full maternal behavior for 2
consecutive days. Test animals were considered fully maternal if they
retrieved all three pups to the nest, grouped them in the nest, and
crouched over them within the 60-min test session. Animals that failed
to become fully maternal after 6 test days were assigned a response
latency of 6 for subsequent statistical analyses.
Histology
At the completion of behavioral testing, rats were anesthetized
with ketamine/xylazine, given bilateral infusions of India ink into the
MPOA, and perfused intracardially with physiological saline followed by
10% formalin. Brains were removed and stored in formalin before
sectioning. MPOA cannula placements were determined independently by a
minimum of three investigators. Only data from animals that were scored
as having bilateral placements within the MPOA were used in statistical
analyses. In most instances, locations of cannula tips were
characterized by small, neuropil-lacking lesions that were stained with
the India ink.
Statistical analysis
Behavioral data were analyzed using the Kruskal-Wallis ANOVA for
multiple group comparisons and the Mann-Whitney U test for comparisons
between control and experimental groups. The Fisher test for exact
probability was used to compare the percentages of animals responding
on given test days. A Pearson product-moment correlation was used to
evaluate possible correlations between induction latencies and
neuroanatomical infusion sites. All probabilities are expressed as
two-tailed tests unless otherwise indicated.
Experiments
Exp 1: roles of P and E2 in the stimulation of
maternal behavior by central PRL administration in nulliparous
rats.
The objective of the first experiment was to determine the
steroid requirements essential for central (MPOA) PRL stimulation of
maternal behavior.
Four groups of adult nulliparous rats were ovx and fitted with bilateral cannulas. On treatment day 1, animals were implanted sc with either three P or three blank (B) capsules. On treatment day 11, P or B capsules were removed, and an E2 or B capsule was implanted sc. The four groups consisted of animals that received B plus B capsules, B and E2, P and B, or P and E2 on treatment days 1 and 11, respectively. Beginning on treatment day 11 and throughout the study, animals were injected with bromocriptine twice daily to suppress endogenous PRL secretion (13). All rats were also infused five times with rPRL: twice on treatment days 11 and 12 and once on the morning of treatment day 13 at the times previously described. Behavioral testing began on treatment day 12. At the end of the experiment, brains were collected and histologically analyzed to verify cannula placement sites.
Exp 2: specificity of PRL’s action; assessment of possible
effects of the nonlactogenic hormones bGH and oLH.
The goal of the
second experiment was to determine whether PRL’s stimulatory action on
maternal behavior is shared by nonlactogenic members of the PRL gene
family or another unrelated pituitary hormone, i.e. bGH and
oLH, respectively.
Three groups of adult nulliparous rats were ovx and fitted with bilateral cannulas directed at the MPOA. On treatment day 1, animals were implanted sc with three P-filled SILASTIC capsules. These implants were removed on treatment day 11, at which time an E2 capsule was implanted sc. All subjects were injected with bromocriptine from days 11–17 as previously described. The experimental groups were infused bilaterally with either bGH or oLH five times from days 11–13. Controls were infused bilaterally with vehicle. Behavioral testing began after the 1000 h infusions on day 12 and continued through day 17. Brains were analyzed for cannula placements at the end of the study.
Exp 3: effects of the frequency of rPRL and rPL-I central
administration on the induction of maternal behavior on steroid-primed,
bromocriptine-treated, nulliparous rats.
The objective of the
third experiment was to evaluate the effectiveness of rPRL relative to
rPL-I in stimulating the onset of maternal behavior in steroid-primed
nulliparous rats. This study also sought to determine whether fewer
infusions, i.e. one or three, of either rPRL or rPL-I were
able to stimulate maternal behavior as rapidly as previously found for
the full complement of five infusions. We chose to compare the effects
of rPL-I with rPRL rather than rPL-II because rPL-I was more readily
available and appears to be more stable than rPL-II (16). The
biological potencies of rPL-I and rPRL in the Nb2 lymphoma
cell bioassay indicate that rPL-I is about twice as active as oPRL (NIH
PS-14) and 5 times as active as rPRL (NIH B-5) (16). The mol wt of
rPL-I and rPRL are approximately 30,000 and 20,000, respectively.
Animals were ovx, cannulated, and treated with the steroid (P plus E2) regimen previously described. Rats were then assigned to one of five groups. Groups of females received either vehicle (control) or one (day 11, 1000 h) or three (day 11, 1000 and 1600 h; day 12, 1000 h) infusions of rPRL or rPL-I. Half of the vehicle animals received a single infusion, whereas the remainder of vehicle-infused controls were administered vehicle three times. Behavioral testing was conducted from days 12–17, and brains were processed to verify infusion sites, as described above.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and 2. A
Kruskal-Wallis ANOVA among the four groups revealed significant
differences in latencies to retrieve a pup, crouch over the test young,
and display full maternal behavior (P < 0.002 for all
behaviors). Animals primed with both P and E2 exhibited the
shortest latencies for each behavior. Median latencies to retrieve,
crouch, and display full maternal behavior for the P plus
E2 group ranged from 1.75–2.1 days. In contrast, latencies
for the P only, E2 only, and nonsteroid-primed groups
ranged from 5.7–6.0 days. Statistical comparisons between groups for
each behavioral end point revealed that the P plus E2 group
retrieved a pup, crouched over the test young, and became fully
maternal significantly faster than the P only and nonsteroid-primed
groups (P < 0.05). Likewise, the P plus E2
group crouched over the pups and displayed full maternal behavior
significantly faster than the E2 only group
(P < 0.05 and P = 0.05, respectively),
but did not differ in their latencies to first retrieve a test pup. No
statistical differences were found among the E2 only, P
only, and nonsteroid-treated, rPRL-infused groups.
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). These
differences persisted from test days 3–6. A similar series of
statistical differences was found between the P plus E2 and
E2 only-primed rats over the 6 test days. More of the P
plus E2 animals were fully maternal on test days 5 and 6
(P < 0.05); this difference also approached
statistical significance on test days 3 and 4 (P =
0.053 and 0.062, respectively). No differences were found in
comparisons among the E2 only, P only, and
nonsteroid-primed groups infused centrally with rPRL.
PRL infusion sites within the MPOA are shown in Fig. 3.
The percentage of infusion sites in what appears to be the more
sensitive hormonal stimulation region of the MPOA from 7.8–8.2 AP (17)
did not differ among the treatment groups and, therefore, probably did
not confound the interpretation of the results. The percentages of
animals with infusion sites in this region were 78% for P plus
E2 rats, 83% for P only rats, 75% for E only rats, and
62.5% for blank animals.
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). Behavioral latencies ranged from a median of
2.9 to 5.0 days for each group. Statistical analyses did not reveal
differences among or between any of the three treatment groups on any
behavioral measure. In general, less than 30% of the rats in each
group responded by the third test day, whereas about 50% of the
females were fully maternal through day 5 of testing. The median
latencies to retrieve a pup in the three groups ranged from 2.9–4.0
days, whereas crouching latencies ranged from 3.0–5.0 days. Females
treated with oLH tended to have longer latencies, although their
responses were not statistically different from those of either
controls or bGH-infused rats. These data, therefore, indicate that the
central stimulatory actions of PRL do not appear to be shared by a
nonlactogenic member of the PRL gene family, i.e. bGH, or by
a nonlactogenic pituitary hormone unrelated to the PRL gene family,
i.e. oLH.
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Exp 3: effects of the frequency of rPRL and rPL-I central
administration on the induction of maternal behavior on steroid-primed,
bromocriptine-treated, nulliparous rats
The effects of 1 and 3 bilateral infusions of rPRL and rPL-I on
the induction of maternal responsiveness in ovx, steroid-primed,
bromocriptine-treated, nulliparous rats are shown in Figs. 5 and 6. No overall statistical
differences were found after analysis of the behavioral responses of
the 5 groups. However, when groups were combined based on either
the number of infusions or the hormone treatment, some differences
emerged. First, rats given 3 infusions of either rPRL or rPL-I
responded faster than vehicle-infused controls. Although this effect
was not as robust a stimulation as that typically found in females
given 5 infusions (4, 5), by day 3 of testing significantly more rats
given either 3 infusions of rPRL or rPL-I were maternal compared with
vehicle controls (7 of 18 compared with 0 of 10 vehicle animals;
2 = 5.59; P < 0.02). A single set of
bilateral infusions (40 ng/side) of either lactogen failed to stimulate
any aspect of maternal care on a given test day (see Fig. 6).
Comparisons of the incidences of full maternal responsiveness between
the treatment groups on specified test days revealed that significantly
more animals given 3 infusions of rPRL responded maternally on test
days 2 and 3 than did vehicle-infused controls (P <
0.05). Similarly, on day 3 the number of rPL-I-infused rats given a
single infusion on treatment day 11 that responded maternally compared
with the number of maternal vehicle-infused animals approached
significance (P = 0.08). In addition, on test day 5
significantly more animals given a single infusion of rPL-I were fully
maternal compared with rats given a single set of rPRL infusions
(P < 0.05; 6 of 9 vs. 1 of 8).
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). When the MPOA
coordinates of the infusion sites are plotted as a function of the test
day on which maternal behavior was first displayed for individual test
animals, a significant positive correlation was found (r = 0.36;
P = 0.03). Lactogen-treated rats with infusion sites
located more anteriorly, e.g. anterior or equal to 7.8 AP),
tended to respond faster than females with sites located posterior to
this neural plane.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The results of the first study indicate that the central stimulatory actions of PRL are dependent upon the presence of sufficient P and E2 priming. The inability of PRL treatment alone to induce maternal behavior is consistent with previous studies which found that PRL-secreting pituitary grafts placed under the renal capsule (18) or intracerebroventricular infusions of oPRL alone (4) fail to affect the rate of induction of maternal behavior in nulliparous rats. Steroid priming alone also fails to stimulate maternal care in nulliparous rats in which endogenous PRL is suppressed with bromocriptine (13). Therefore, it appears that the combination of steroid priming with PRL (or PLs) is needed to bring about the rapid onset of maternal care in the female. How the steroids and lactogens interact to stimulate maternal behavior is not known. It is possible, on the one hand, that the steroids and lactogens act together on a similar neural substrate to stimulate the onset of maternal behavior, i.e. the steroids could directly potentiate PRL/PL action by increasing neural PRL receptor concentrations. Alternatively, the steroids and lactogens could act independently to stimulate maternal care.
The inability of PRL to stimulate maternal behavior in P only-treated rats in the first study is consistent with some (3, 4, 8, 13), but not all, previous reports (19). Specifically, it was previously found that ectopic pituitary grafts together with very high levels of P (six sc implants) reduced the maternal latencies of the nulliparous female rats from 6 to 1.5 days (19). It is possible, therefore, that under certain experimental conditions, e.g. highly elevated titers of P and prolonged exposure to elevated levels of PRL and GH (19, 20), PRL may interact with P to stimulate maternal care. Further studies, however, are needed to identify how P, E2, and lactogenic hormones interact to stimulate maternal behavior.
The central actions of PRL in Exp 1 in stimulating the onset of maternal behavior in the P- plus E2-treated rats are rapid; only an acute exposure to PRL is needed to stimulate maternal care. The P plus E2 and bromocriptine preparation that employs the acute administration of PRL or rPL was used because it provides a reliable behavioral preparation for elucidating the possible roles of central acting hormones such as PRL and rPL. However, under the physiological conditions of pregnancy, prolonged exposure to PRL as well as to rPLs may also play an important role in stimulating maternal care. Earlier work using hypophysectomized rats found that long term exposure to oPRL in combination with P plus E2 stimulated full maternal care, whereas shorter term exposure to oPRL only stimulated retrieval behavior (21). Based upon these findings, it has been proposed that during pregnancy, PRL and rPLs prime the maternal brain over a prolonged period (22). This priming action appears to complement the more acute regulatory actions of the neuropeptides, oxytocin and ß-endorphin (22). Thus, the temporal dynamics and actions of the lactogenic hormones that stimulate maternal behavior are important factors in evaluating the hormonal regulation of maternal behavior.
The findings of the present study together with those of earlier investigations (3, 4, 5) indicate that the central stimulation of maternal behavior by PRL is shared by other lactogenic hormones, but not by nonlactogenic hormones. Central MPOA infusions of bGH failed to facilitate a rapid onset of maternal behavior relative to that in vehicle-infused controls. Likewise, central infusions of oLH, a pituitary glycoprotein hormone unrelated to the PRL gene family, was unable to affect the expression of maternal care in steroid-primed nulliparous females. However, these negative findings do not totally exclude a possible stimulatory role for some nonlactogenic members of the PRL/GH/PL family. In an earlier study using hypophysectomized, steroid-primed rats, it was found that systemic injections of oGH, a nonlactogenic molecule, also reduced the latencies of females to display maternal care (20). Additional studies are needed to determine the specific molecular sequence and conformation responsible for the induction of maternal care. These stimulatory molecules could have a common sequence that activates central lactogenic receptors and induces the onset of maternal behavior.
The mechanism of lactogenic stimulation of maternal behavior presumably involves the binding of the lactogens to lactogenic receptors. Autoradiographic studies indicate that radiolabeled rPL-I, like PRL (23, 24), binds to cells of the choroid plexus and hypothalamus (25, 26). This binding most likely involves a form of the PRL receptor, although the receptor to which rPLs bind in the brain has not been characterized. More recent studies have localized messenger RNA for the long form of the PRL receptor within the brain and MPOA of female rats (27, 28). In fact, the density of cells expressing messenger RNA for the long form of the PRL receptor increases significantly in the MPOA prepartum (28). It is not known whether this receptor binds lactogenic molecules apart from PRL or whether there exists a distinct pool of receptors that bind the PLs. In vitro studies indicate that the PRL receptor binds PLs, but has no or low affinity for other placental hormones, such as PRL-like protein A (29).
Whereas the relative affinities of PRL and rPLs for lactogenic receptors have not been determined, findings from Exp 3 suggest that once inside the brain, PRL and rPL-I are fairly equally effective in stimulating the induction of maternal behavior. No consistent differences in the behavioral potencies of rPRL and rPL-I were detected when the number of infusions into the MPOA was varied in the test animals. Modest effects were evident after three infusions of these lactogens; however, single infusions did not affect the expression of maternal behavior. It, therefore, appears that the most effective treatment regimen involves repeated infusions, ideally five, of the lactogens just before and after the start of behavioral testing (3, 4, 5). Although these data indicate that the behavioral potencies of these two lactogens are similar, they do not establish similar physiological potencies for rPRL and rPL-I. It is possible, for example, that one could detect differences in the neural sensitivity to these two hormones if higher doses were given for shorter periods or lower doses were given over multiple infusions. In attempting to evaluate the physiological importance of rPRL and rPL-I on the induction of maternal behavior at parturition, it is also important to consider the relative accessibility of these lactogens to the brain during pregnancy. Recent studies in our laboratories have shown that rPL-I and rPL-II are the predominant lactogens present in the cerebrospinal fluid (CSF) during the second half of gestation (5). Specifically, during late pregnancy on day 21 of gestation, the mitogenic activity in the CSF was almost completely neutralized with antibodies to rPL-II in the Nb2 lymphoma cell bioassay, but was unaffected by antibodies to rPRL. Thus, during late pregnancy when circulating levels of rPL-II and rPRL are high (6, 9, 10), transport of rPL-II across the blood-CSF barrier appears to be much greater than that of rPRL. Hence, although the central stimulatory potencies of rPRL and rPLs may be similar, during late pregnancy much more rPL gains access to the brain and, therefore, may have a greater role in stimulating the induction of maternal care.
Although rPRL and rPLs stimulate the induction of maternal behavior in behaviorally inexperienced, female rats when infused into the MPOA (4, 5), the site specificity of lactogenic stimulation within the brain has not been sufficiently explored. Histological analyses from these studies and an earlier one in which a stimulatory action of human PL was reported after MPOA infusions (17) indicate that the region of the MPOA from 7.8–8.2 AP is the most sensitive to hormonal stimulation. This region would be a likely area to examine the presence and abundance of lactogenic receptors. Another possible site of lactogenic action may be the ventromedial hypothalamus (VMH). In birds, infusions of oPRL into the VMH stimulate food intake (30). Likewise, in rats, bilateral infusions of rPRL into the VMH produce shortened latencies to display maternal care compared to those in vehicle-infused controls even though they are already fairly responsive due to the lowering of cannula through the brain into the VMH (3). Receptor studies demonstrate detectable levels of rPRL receptors in the MPOA, VMN, and amygdala (28, 31). These areas of the brain require further study to determine whether lactogens act at more than one region of the brain in regulating maternal care.
The neurochemical systems with which and through which lactogens act to stimulate maternal behavior have only recently begun to be explored. One line of research using knockout rats suggests a possible dopamine D2-receptor involvement in retrieval (32). As dopaminergic turnover is increased in hyperprolactinemic rats, these data indicate that one mode of lactogen action may involve an alteration of dopaminergic action. Other possible neural transmitters that might be affected by these lactogens and that have been shown to regulate maternal care include oxytocin and the endogenous opioids (33, 34, 35, 36). Further work, however, is needed to establish which neurochemical systems PRL and rPL influence and whether the transduction pathway affecting maternal care involves activation of the JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway (37) or immediate early gene activation, i.e. fosB (38).
In summary, the central stimulatory actions of PRL are dependent upon steroid priming and appear specific to lactogenic hormones of the PRL gene family. Moreover, although the behavioral potencies of rPRL and rPL-I are similar when infused directly into the brain, the rPLs appear to gain greater access to the CSF and brain during gestation (5) These findings support the concept that lactogenic hormones, specifically the rPLs, play an important role in stimulating the onset of maternal behavior at parturition. Although the commonality of hormonal stimulation across mammals is unknown, the presence of hPL in the CSF during gestation in women (39) provides a possible endocrine substrate for central lactogenic modulation of maternal behavior. Examinations of the possible behavioral actions of lactogenic hormones in humans and primates are merited and await study.
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Acknowledgments |
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Footnotes |
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Received July 22, 1996.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), P only
(
), E2 only (•), and P and E2 (
). All
placements were bilateral, but are only shown on one side of the brain
for clarity. One P only and one P and E2 animal had
bilateral placements within the MPOA at 7.4 AP (section not shown).
