Rapid Onset Of Maternal Behavior Research Articles

NMDA lesions in the prefrontal cortex delay the onset of maternal, but not infanticidal behavior in pup-naïve adult mice (C57BL/6).

While most pup-naïve adult female mice can display, or be induced (by repeated exposure to pups) to display parental behavior rapidly, adult males are infanticidal or nonparental. The medial prefrontal cortex (mPFC) participates in attentional selection, decision-making, behavioral flexibility, and planning that may be critical in the rapid display of parental or infanticidal behavior. We investigated if NMDA-induced lesions in the mPFC (targeting prelimbic cortex) inhibited maternal or infanticidal behavior in pup-naïve adult female and male mice (C57BL/6), respectively. All Control females displayed full maternal behavior at the first encounter with pups. Lesioned female groups were partially maternal (50%) or nonmaternal (50%). Five repeated exposures of 60-min to pups were needed to induce full maternal behavior in female NMDA-lesioned groups. Control and lesioned males did not show significant differences. Control males displayed nonparental (17%) or infanticidal (83%) behavior, while all lesioned males were infanticidal. There was no difference in general locomotor and exploratory activity (i.e., peripheral crosses, rearings, immobility time) in female or male groups. Nevertheless, females and males of lesioned groups showed a reduction in the number of central crosses and time in the central area of an open field respectively, suggesting an increase in anxiety. Our results show that the mPFC is engaged in the rapid onset of maternal behavior in females, contributing with the motivation and planning of its rapid execution, or reducing the anxiety to the first encounter with pups. In contrast, infanticidal behavior, likely a more impulsive behavior, might require less planning from the mPFC. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Distinct Effects of Estrogen on Mouse Maternal Behavior: The Contribution of Estrogen Synthesis in the Brain.

Estrogen surge following progesterone withdrawal at parturition plays an important role in initiating maternal behavior in various rodent species. Systemic estrogen treatment shortens the latency to onset of maternal behavior in nulliparous female rats that have not experienced parturition. In contrast, nulliparous laboratory mice show rapid onset of maternal behavior without estrogen treatment, and the role of estrogen still remains unclear. Here the effect of systemic estrogen treatment (for 2 h, 1 day, 3 days, and 7 days) after progesterone withdrawal was examined on maternal behavior of C57BL/6 mice. This estrogen regimen led to different effects on nursing, pup retrieval, and nest building behaviors. Latency to nursing was shortened by estrogen treatment within 2 h. Moreover, pup retrieval and nest building were decreased. mRNA expression was also investigated for estrogen receptor α (ERα) and for genes involved in regulating maternal behavior, specifically, the oxytocin receptor (OTR) and vasopressin receptor in the medial amygdala (MeA) and medial preoptic area (MPOA). Estrogen treatment led to decreased ERα mRNA in both regions. Although OTR mRNA was increased in the MeA, OTR and vasopressin receptor mRNA were reduced in the MPOA, showing region-dependent transcription regulation. To determine the mechanisms for the actions of estrogen treatment, the contribution of estrogen synthesis in the brain was examined. Blockade of estrogen synthesis in the brain by systemic letrozole treatment in ovariectomized mice interfered with pup retrieval and nest building but not nursing behavior, indicating different contributions of estrogen synthesis to maternal behavior. Furthermore, letrozole treatment led to an increase in ERα mRNA in the MeA but not in the MPOA, suggesting that involvement of estrogen synthesis is brain region dependent. Altogether, these results suggest that region-dependent estrogen synthesis leads to differential transcriptional activation due to exogenous estrogen treatment, and thereby results in different effects on maternal behavior.

Male pheromones initiate prolactin-induced neurogenesis and advance maternal behavior in female mice

Prolactin is required for rapid onset of maternal behavior after parturition, inducing adaptive changes in the maternal brain including enhanced neurogenesis in the subventricular zone during pregnancy. The resultant increase in olfactory interneurons may be required for altered processing of olfactory cues during the establishment of maternal behavior. Pheromones act through olfactory pathways to exert powerful effects on behavior in rodents and also affect prolactin secretion. Hence, this study aimed to investigate the effect of male pheromones on neurogenesis and maternal behavior in female mice. Virgin female mice were housed individually or in split-cages where they had pheromonal but not physical contact with a male. Maternal behavior was assessed in a foster pup retrieval paradigm. Some mice were injected with bromodeoxyuridine, and the labeled cells visualized using immunohistochemistry. The data show that exposure to male pheromones, for a duration equivalent to a murine pregnancy, advanced maternal behavior in both virgin and postpartum female mice. The pheromone action was dependent on prolactin and ovarian steroids, and was associated with increased cell proliferation in the subventricular zone and subsequent increases in new neurons in the olfactory bulb. Moreover, the effect of pheromones on both cell proliferation and maternal behavior could be induced solely through administration of exogenous prolactin to mimic the pheromone-induced changes in prolactin secretion. The data suggest that male pheromones induce a prolactin-mediated increase in neurogenesis in female mice, resulting in advanced maternal behavior.

Induction of maternal behavior in adult female rats following chronic morphine exposure during puberty.

The peripubertal period in the female rat is the time when the stimulatory effects of opioids on prolactin (PRL) secretion develop. In the adult rat, the administration of chronic high-dose morphine has been shown to attenuate the ability of opiates to stimulate PRL secretion. One function of PRL in adult virgin rats is the induction of maternal behavior. The present study examined whether chronic high-dose morphine exposure during the peripubertal period alters PRL-mediated induction of maternal behavior in adult female rats. Two groups of juvenile female rats were administered increasing doses of morphine or vehicle (s.c.) from age 30 to 50 days. As adults, these females either remained intact, or were ovariectomized and treated with a PRL-dependent, steroid hormone regimen that stimulates a rapid onset of maternal behavior. All females were then exposed daily to rat foster pups to determine whether peripubertal morphine exposure affected their latencies to induce maternal behavior. Morphine treatment resulted in a delay in vaginal opening and a temporary reduction in the rate of weight gain; however, the rate of onset of maternal behavior was unaffected by peripubertal morphine treatment. Thus, chronic morphine exposure in the pubertal female did not impact the expression of pup-induced maternal care.

Central Infusions of the Recombinant Human Prolactin Receptor Antagonist, S179D-PRL, Delay the Onset of Maternal Behavior in Steroid-Primed, Nulliparous Female Rats**This work was supported by USPHS Grants R01-HD-19789 and K05-MH-01374 (to R.S.B.) and funds provided by the Cancer Federation and Sensus Drug Development Corp. (to A.M.W.).

The expression of maternal behavior in the newly parturient rat is under endocrine regulation. Blocking endogenous PRL secretion with bromocriptine delays the normal rapid expression of maternal care shown toward foster young in steroid-primed virgin female rats. The recent development of the PRL receptor antagonist S179D-PRL, a mutant of human PRL in which the serine residue at the 179 position is replaced with aspartate, provides a potentially useful tool to examine the role of PRL in neural processing. In the present report, three experiments were conducted that examined the effects of this PRL antagonist on the induction of maternal behavior. In each experiment, ovariectomized, nulliparous rats were treated sequentially with SILASTIC capsules implanted sc with progesterone (days 1-11) and estradiol (days 11-17), a treatment that stimulates a rapid onset of maternal behavior in virgin rats. On day 11, females were implanted with Alzet miniosmotic pumps connected to cannulae directed unilaterally at the lateral ventricle (Exp 1) or bilaterally at the medial preoptic area (MPOA; Exp 2 and 3). Pumps contained either doses of S179D-PRL (0.115 or 1.15 mg/ml; Exp 1 and 2), wild-type human PRL (1.15 mg/ml; Exp 3), or the saline vehicle (Exp 1-3). Testing for maternal behavior began on day 12, a day after pump insertion, and animals were tested daily for 6 days. Latencies to contact, retrieve, and group foster test young were recorded. Administration of both the high and low doses of S179D-PRL infused into the lateral ventricle (Exp 1) or MPOA (Exp 2) significantly delayed the onset of maternal behavior. In contrast, MPOA infusions of the control hormone, wild-type human PRL, in Exp 3 did not delay the onset of maternal behavior. These findings support the concept that the effects of S179D-PRL are caused by its actions as a PRL receptor antagonist rather than by a nonspecific effect of the protein. Overall, these results demonstrate the effectiveness of S179D-PRL acting at the level of the central nervous system (and, more specifically, within the MPOA) to regulate maternal behavior, a PRL-mediated response.

Opioid stimulation in the ventral tegmental area facilitates the onset of maternal behavior in rats

This research investigated the effect of an increase or decrease in opioid activity in the ventral tegmental area (VTA) on the onset of maternal behavior in rats. In Experiment 1, the latency to show maternal behavior toward foster rat pups (sensitization latency) was determined in maternally naive female rats given either nothing or a unilateral intra-VTA injection of morphine sulfate (MS) (0.0, 0.01, 0.03, 0.1 or 0.3 μg), on the first three days of a 10-day period of constant exposure to pups. Rats treated with 0.03 μg MS had significantly shorter sensitization latencies than did rats treated with 0.0 μg MS, 0.01 μg MS, or receiving no treatment (higher doses of morphine produced intermediate results). The facilitating effect of intra-VTA MS on the onset of maternal behavior was blocked by pretreatment with naltrexone hydrochloride and was found to have a specific site of action in the VTA (MS injections dorsal to the VTA were ineffective). In Experiment 2, sensitization latencies were determined in periparturitional rats given a bilateral intra-VTA injection of either the opioid antagonist naltrexone methobromide (quaternary naltrexone), its vehicle, a sham injection, or left untreated 40 min after delivery of the last pup. The mothers' own pups were removed at delivery; mothers were nonmaternal at the time of testing. Quaternary naltrexone treatment produced significantly slower sensitization to foster pups than did control conditions. Total activity and pup-directed activity did not differ significantly with treatment. The results demonstrate that increased opioid activity in the VTA facilitates the onset of maternal behavior in inexperienced nonpregnant female rats, and decreased opioid activity in the VTA disrupts the rapid onset of maternal behavior at parturition.

Central prolactin infusions stimulate maternal behavior in steroid-treated, nulliparous female rats.

A series of experiments were conducted to determine whether and under what conditions central prolactin (PRL) administration would stimulate the onset of maternal behavior in female rats and to identify possible neural sites of PRL action. In each experiment ovariectomized, nulliparous rats whose endogenous PRL levels were suppressed with bromocriptine were tested for maternal behavior toward foster young. In experiments 1, 2, and 4, females were also exposed to pregnancy-like levels of progesterone (days 1-11) followed by estradiol (days 11-17). In experiment 1 infusions (days 11-13) of four doses of ovine PRL (400 ng, 2 micrograms, 10 micrograms, or 50 micrograms, but not 80 ng) into the lateral ventricle resulted in a rapid onset of maternal behavior (behavioral testing, days 12-17). The stimulatory action of these doses of PRL appears to be central, since subcutaneous injections of 50 micrograms of ovine PRL failed to affect maternal responsiveness (experiment 2). Experiment 3 indicated that the stimulatory effect of intracerebroventricularly administered PRL is steroid dependent. Infusions of either 10 micrograms of ovine PRL or 10 micrograms of rat PRL failed to induce maternal behavior in nonsteroid-treated animals. In the final experiment (no. 4) bilateral infusions of 40 ng of ovine PRL into the medial preoptic area of steroid-treated rats resulted in a pronounced stimulation of maternal behavior. These findings demonstrate a central site of PRL action in the stimulation of maternal responsiveness and point to the medial preoptic area as a key neural site for PRL regulation of maternal behavior.

Growth hormone is secreted by ectopic pituitary grafts and stimulates maternal behavior in rats

The onset of maternal behavior at parturition in rats is hormonally regulated. Recently, we reported that treatment of behaviorally inexperienced, hypophysectomized (hypox), ovariectomized (ovx) rats with a sequential steroid treatment of progesterone (P) and estradiol (E 2), and either ectopic anterior pituitary grafts or prolactin (PRL), stimulated maternal responsiveness toward foster young. That growth hormone (GH) has a number of PRL-like activities led us to ask whether the actions of PRL on maternal behavior were specific to PRL or might be shared by other PRL-like protein hormones, i.e., GH. In Experiment 1 we quantified plasma concentrations of GH and PRL by RIA in groups of hypox female rats that were ovariectomized and treated with a combination of ectopic pituitary grafts (Days 1–23) and Silastic capsules filled with P (Days 1–11) and E 2 (Days 11–23). Blood samples were collected from Days 1 to 23 of treatment. Both plasma PRL and GH levels increased after grafting, initially rising 10- to 60-fold by Day 4 and gradually declining throughout the remainder of the 23-day sampling period. Throughout the 3-week period after grafting plasma GH levels were as high or higher than those of PRL. In Experiment 2 the behavioral effects of exogenously administered ovine (o)-GH were measured in groups of hypox, ovx rats that were treated with P and E 2 as in Experiment 1. Experimental rats were injected twice daily with 0.25 mg oGH beginning on Day 1. Testing for maternal behavior toward foster young was conducted daily from Day 12 to Day 22. In steroid-treated rats, GH treatment stimulated a more rapid onset of maternal behavior (latencies of 3 vs > 10 days for vehicle-injected controls). These data indicate that GH, like PRL, is secreted by ectopic pituitary grafts and is capable of stimulating maternal behavior.

Peridural anesthesia disturbs maternal behavior in primiparous and multiparous parturient ewes

Several experiments were carried out to study the effects of peridural anesthesia (Sylvocaine, 6 ml between sacrum and 1st caudal vertebra) performed either at the first signs of birth (early peridural: EP), or little before expulsion (late peridural: LP). When performed late, peridural anesthesia altered maternal behavior only slightly when compared with controls. By contrast severe deficits were observed in the case of EP. Seven out of 8 primiparae failed to show interest for their lamb within 30 min of the birth of the young (vs. 1 9 in LP group, p<0.01). In multiparae these proportions were 8 27 and 0 22 respectively ( p<0.01). Within the EP group the effects of the peridural were more marked in primiparous than in multiparous mothers ( p<0.05). Even in EP multiparous ewes becoming maternal within 5 min after giving birth a reduction in duration of licking was noted, when compared with the LP group ( p<0.05). On the other hand, these same ewes established normally a selective bond within 2 hours after giving birth, as did the LP or control ewes. These results confirm the importance of genital stimulation for the rapid onset of maternal behavior in parturient ewes. They fail however to clarify the role played by genital stimulation in the establishment of a selective maternal bond.

Maternal behavior in cyclic and androgenized female rats: Role of ovarian hormones

A comparative study on the induction of maternal behavior (MB) in response to pups was carried out in cyclic and androgenized rats. Moreover, the effects of exposure to ovarian hormones on the induction of MB in response to pups were studied in cyclic and androgenized rats. A high percentage of androgenized and proestrus rats displayed MB after 48 hr of exposure to pups (87.9% and 87.5% respectively). Diestrus day-1 rats were significantly less maternal (37.5%). Ovariectomy did not impair MB in androgenized rats. High serum progesterone levels induced in androgenized rats by treatment with 10 I.U. of HCG (40 hours before pup presentation) or with progesterone silastic implants prevented the onset of MB. Ovariectomy performed 8 hours before HCG administration restored MB. When behavioral testing began 72 hours after HCG treatment, 75% of the rats were maternal 12 hr after exposure to pups. This rapid onset of MB in proestrus and androgenized rats appeared to be estrogen dependent. The presence of progesterone inhibited the maternal response of androgenized rats.

Pregnancy termination by prostaglandin F 2α stimulates maternal behavior in the rat

Treatment with PGF 2α resulted in the termination of pregnancy in 16- and 19-day pregnant rats, but not in 10- or 13-day pregnant rats. Rats that aborted displayed a rapid onset of maternal behavior when tested with foster pups. Aborted rats also displayed sexual receptivity and ovulation: these phenomena resemble the sequence of events following hysterectomy on the same days of pregnancy. Both can be related to the events surrounding normal parturition in the rat. The results are interpreted as due to a pregnancy-induced deactivation of the factor in the uterus that prevents estrogen from stimulating maternal behavior in nonpregnant females. In the absence of this factor, the PGF 2α-induced rise in estrogen secretion facilitates maternal behavior and sexual behavior and induces ovulation.

The quality of hormonally stimulated maternal behavior in ovariectomized rats

Maternal behavior was induced in ovariectomized female rats through injections of estradiol, progesterone, and prolactin followed by continuous pup exposure. This behavior was compared with that of pup-exposed, vehicle-injected, ovariectomized females and of parturient females on a wide variety of measures. The hormone injections did not significantly reduce retrieval latency. However, the performance of hormone-injected females on other measures, especially measures of pup-directed behaviors and of nest building, was markedly superior to that of ovariectomized females and similar to that of parturient animals. These results suggest that the hormonal factors which normally facilitate rapid onset of maternal behavior may not be identical to those affecting the quality of the behavior displayed.

Retention of rapid onset of maternal behavior during pregnancy in primiparous rats

Possible inhibitory effects of pregnancy upon the retention of maternal responsiveness in primiparous rats were examined by measuring behavioral latencies to respond to foster young in pregnant primiparous, nonpregnant primiparous, and virgin female rats. While high serum titers of progesterone associated with pregnancy are reported to inhibit rapid onset of maternal behavior in primigravid rats, findings in the present study demonstrate that the physiological state associated with a second pregnancy did not disrupt rapid reestablishment of maternal behavior. Specifically, 30–36 days after last exposure to their own young the median latencies to respond maternally to foster young ranged from 0.43 to 1.25 days for pregnant and nonpregnant primiparous rats. In contrast, virgin female rats with no prior maternal experience responded maternally significantly slower (median latencies: 4.33–4.75 days) than did primiparous females. These data suggest that after hormonal activation maternal responsiveness is retained independent of hormonal state.

Inhibitory effects of various progestins and deoxycorticosterone on the rapid onset of maternal behavior induced by ovariectomy-hysterectomy during late pregnancy in rats

The inhibitory effects of progesterone (P), 5α-dihydroprogesterone (5α-DHP), 17α-hydroxyprogesterone (17-HP), and deoxycorticosterone (DOC) upon the rapid onset of maternal behavior induced during late pregnancy in primigravid rats by ovariectomy-hysterectomy (OH) were examined. Progesterone administration at a dosage of 5.0 mg in oil vehicle daily (beginning on Day 17 and ending when the subject responded maternally to foster pups) significantly delayed by about 1.5 to 2.0 days the onset of maternal behavior. In contrast, P at dosages of either 1.0 or 2.5 mg daily, 5α-DHP at 5.0 mg administered daily in either an oil or Tween-80 vehicle, 17-HP at 5.0 mg in oil daily, and DOC at dosages of either 5.0 or 10.0 mg in oil daily failed to affect the rapid onset of maternal behavior induced by ovariectomy-hysterectomy on Day 17 of pregnancy. These data suggest that during pregnancy the onset of maternal behavior is inhibited in a rather specific manner by progesterone.

Failure of pituitary transplants to facilitate the onset of maternal behavior in ovariectomized virgin rats

Ovariectomized virgin female rats received two pituitary glands grafted under a kidney capsule in an attempt to assess the effect of chronically increased plasma levels of prolactin on the onset of maternal behavior. When exposed to fresh foster pups on 6 consecutive days, only 5 out of 12 of these females and 2 out of 12 females in an ovariectomized control group displayed maternal behavior, whereas all 4 rats in an additional control group of lactating mothers were maternal throughout these tests. Ovariectomized animals which failed to become maternal then received subcutaneous injections of either 10 μg estradiol benzoate (EB) or oil on two consecutive days, and 1 day thereafter foster pups were again presented to these females for 18 hr. Significantly more EB-treated females displayed maternal behavior, regardless of whether or not they bore pituitary grafts, suggesting that estradiol and not prolactin may be essential for the rapid onset of maternal behavior in parturient rats.

Induction of maternal behaviors in primigravid rats by ovariectomy, hysterectomy, or ovariectomy plus hysterectomy: Effect of length of gestation

The effects of terminating pregnancy by means of ovariectomy (O), hysterectomy (H), or ovariectomy plus hysterectomy (OH) at different stages of gestation upon the latency to initiation of maternal behavior were examined in primigravid rats. O, H, or OH on either Day 13 or 17 of pregnancy resulted in an accelerated onset of maternal behaviors (median range = 1.0–2.0 day latency for O, H, or OH animals vs 4.0–5.0 day latency for sham-operated intacts). However, O and H on Day 8 of pregnancy were ineffective in inducing a rapid onset of maternal behavior, while OH on Day 8 of pregnancy only slightly facilitated the onset of maternal behavior when compared to animals sham-operated on Day 8 of pregnancy. O, H, and OH on either Day 13 or 17 of gestation were also significantly more effective in rapidly inducing maternal behaviors than the corresponding surgeries performed on Day 8 of pregnancy. These data suggest that the onset of maternal behavior in the pregnant rat can be rapidly induced after mid-pregnancy by surgical procedures that presumably result in a rapid decline in serum steroids of ovarian origin.

Hormonal basis of hysterectomy-induced maternal behavior during pregnancy in the rat

Hysterectomy during the last half of pregnancy (i.e., Day 10–19) induces a rapid onset of maternal behavior; ovariectomy in addition to hysterectomy, prevents this effect. Estradiol and progesterone were tested for their ability to restore short-latency maternal behavior in hysterectomized-ovariectomized (HO) females operated on the 10th, 13th, 16th and 19th days of pregnancy. A single injection of either 20 μg/kg or 100 μg/kg estradiol benzoate (EB) immediately following HO either alone or followed by 0.5 mg progesterone (P) 44 hr later restored short-latency maternal behavior similar to that observed following hysterectomy only. The lower dose of EB was found to be equally effective at all stages of pregnancy and P was unnecessary to induce maternal behavior. The effectiveness of EB in inducing maternal behavior was discussed in relation to the hormonal changes which follow hysterectomy during pregnancy and to those which are associated with the normal onset of maternal behavior around parturition.