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Brain Research 1025 (2004) 51 – 58 www.elsevier.com/locate/brainres Research report Disinhibition of maternal behavior following neurotoxic lesions of the hypothalamus in primigravid rats Phyllis E. Mann*, Jessica A. Babb Department of Biomedical Sciences, Tufts University School of Veterinary Medicine, 200 Westboro Rd., N. Grafton, MA 01536, United States Accepted 31 July 2004 Available online 11 September 2004 Abstract Virgin female rats do not respond maternally to foster pups due to an endogenous neural circuit that actively inhibits the display of maternal behavior. Once pregnant, primigravid rats will continue to avoid foster pups until just prior to or at parturition. Anosmia or lesions of the olfactory tract, medial amygdala, and areas of the hypothalamus will stimulate virgin females to display maternal behavior rapidly, but little is known of the effect of these lesions in primigravid rats. The objective of the present study was to determine if neurotoxic lesions of the dorsomedial (DMH) and ventromedial nuclei (VMH) of the hypothalamus will advance the onset of maternal behavior in primigravid rats. Nulliparous Sprague–Dawley female rats were mated and then on day 8 of gestation bilaterally infused with N-methyl-d-aspartic acid (NMDA; 8 Ag/0.2 Al/side) or vehicle directed toward either the DMH or VMH. Beginning on day 15 of gestation until parturition, females were tested daily for maternal responsiveness. DMH and VMH lesions significantly advanced the onset of maternal behavior (5–6 days vs. 0– 1 day before parturition) in first-time pregnant rats. These results indicate that the DMH and VMH are involved in the regulation of maternal behavior and may be part of an endogenous neural circuit that inhibits maternal behavior during pregnancy. D 2004 Elsevier B.V. All rights reserved. Theme: Neural basis of behavior Topic: Hormonal control of reproductive behavior Keywords: Pregnancy; Neurotoxin; NMDA; Ventromedial nucleus of the hypothalamus; Dorsomedial nucleus of the hypothalamus 1. Introduction Adult, reproductively inexperienced female rats (whether virgin or primigravid) are not spontaneously maternal. However, if they are housed with young pups for several days, they can be induced or bsensitizedQ to show maternal behavior having an average latency of 5–7 days [19,49]. Primigravid rats, if not exposed to foster pups, will display spontaneous maternal behavior only at or around parturition [50,60]. As the virgin female makes the transition from nulliparous (when she is nonmaternal) to pregnant to parous (when she is immediately maternal), many changes occur in the brain as a response to mating and the hormones of * Corresponding author. Tel.: +1 508 887 4911; fax: +1 508 839 7091. E-mail address: email@example.com (P.E. Mann). 0006-8993/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2004.07.064 pregnancy and parturition. These hormones, the gonadal steroids (estrogen and progesterone) and the lactogenic hormones (prolactin and the placental lactogens) facilitate the rapid onset of maternal behavior at parturition [37,41]. A number of studies suggest that the stimulatory activities of the medial preoptic area (MPOA) and the adjacent bed nucleus of the stria terminalis (BnST) are altered by these hormones, thereby contributing to the rapid onset of maternal behavior at parturition . Interestingly, there is also evidence for the existence of a neural circuit that inhibits the display of maternal behavior in virgin and primigravid rats. Early studies have shown that rendering the virgin female anosmic shortens the latencies to become maternal to 2–3 days [20,39]. Further studies demonstrated that both the main and accessory olfactory (vomeronasal) systems [21,23] are involved in maternal behavior inhibition, as well as the corticomedial amygdala 52 P.E. Mann, J.A. Babb / Brain Research 1025 (2004) 51–58 [22,46,56]. Evidences from our laboratory and others indicate that the hypothalamus also contributes to the regulation of maternal behavior. However, unlike the MPOA, which stimulates maternal behavior, areas of the hypothalamus inhibit its display [8,55]. Lesioning the anterior area of the hypothalamus (AH), the dorsomedial (DMH) and ventromedial (VMH) nuclei of the hypothalamus decreases the latency to display maternal behavior in steroid-primed, ovariectomized, virgin rats [3,8]. The majority of the studies investigating the neural circuitry involved in the inhibition of maternal behavior used an adult virgin female model in which subjects were either intact (e.g., Ref. ) or ovariectomized and steroidprimed (e.g., Ref. ). Additional studies employed a variation of the pregnancy-terminated model  that involves hysterectomizing and ovariectomizing the females during pregnancy followed by estradiol priming . The objective of the current study was to examine whether neurotoxic lesions of the DMH and VMH would advance the onset of maternal care in intact pregnant rats. AP=À2.5; DV=À9.5; ML=F1.0) or the VMH (N=9–10; AP=À2.5; DV=À10.0; ML=F0.70), coordinates based on bregma . Eight micrograms of NMDA dissolved in 0.2 Al of vehicle or vehicle alone was infused into each side of the brain over a 2-min period. The infusion needle was then raised 0.2 mm and left for 5 min after each infusion to allow for diffusion of the solution into the tissue. 2.3. Behavioral testing Maternal behavior testing began on day 15 of gestation. Testing continued daily for 8–9 days until the rat exhibited full maternal behavior (FMB) or gave birth. Testing was conducted each day between 0900 and 1200 h. On each test day, three recently fed foster pups (3–8 days old) were placed in each of the three quadrants outside of the nest area. Test subjects were observed continuously for 15 min and then spot-checked at 15-min intervals for 1 h. Females were considered fully maternal if they retrieved, grouped, and crouched over all the pups within the hour test period for 2 consecutive days. Latencies to respond maternally were recorded as the first of two consecutive days before parturition that the female responded maternally, i.e., latencies would be different depending on whether an animal gave birth on day 22 or day 23 of gestation. The day following parturition, the body weight of the dam, the weight of each litter, and litter size were recorded. 2.4. Histology At the end of the experiment, subjects were anesthetized with CO2. Their brains were removed after decapitation and placed in 10% formalin (4 8C) until sectioned. Sections (40 Am) were stained with 0.1% formal thionin and checked for lesion placements. Only animals that had correct lesion placements were included in the study. 2.5. Statistical analysis Median latencies to respond maternally were analyzed using the Mann–Whitney Rank Sum U-test and the proportion (percentage) of rats maternal on each test day was analyzed using the Fisher Test for Exact Probability. Dam body weight data was analyzed using a two-way repeated measures ANOVA, while the litter data was analyzed using a t-test. Differences were considered significant if pb0.05. 2. Materials and methods 2.1. Subjects Nulliparous female Sprague–Dawley rats [Crl:CD(SD) BR] weighing 226–250 g were obtained from Charles River Breeding Laboratories (Kingston, NY, USA). Animals were housed in light (on 0500–1900 h)- and temperature (21–24 8C)-controlled rooms and were provided food and water ad libitum. One week after arrival, subjects were placed with stud males. The day that sperm were present in the lavage was considered day 1 of pregnancy. Females were individually housed in 45Â25Â20 cm opaque polypropylene test cages on day 8 of gestation after surgery. Oneinch-high Plexiglas dividers were placed in each cage 1 day prior to behavioral testing, in order to prevent the pups from crawling to the nest. All animals were maintained in accordance with the guidelines of the Division of Teaching and Research Resources at Tufts University School of Veterinary Medicine, which follows the procedures for animal care prepared by the Committee on the Care and Use of Laboratory Animal Resources, National Research Council. 2.2. Surgery and infusions N-methyl-d-aspartic acid (NMDA; Sigma, St. Louis, MO) or vehicle (0.9% saline) was administered to rats under ketamine/xylazine anesthesia on day 8 of gestation. NMDA is an axon-sparing excitotoxin which lesions specific neuronal populations . Infusions were administered using a 0.5-Al Hamilton syringe with a 25-gauge beveled tip attached to a microinjection unit (Kopf model 5000). The infusion needle was directed at either the DMH (N=4–5; 3. Results 3.1. Histology Histological placements for each animal in both the DMH and the VMH groups are shown in Fig. 1. Only unilateral lesions placements are shown for each animal. P.E. Mann, J.A. Babb / Brain Research 1025 (2004) 51–58 53 Fig. 1. Histological drawings of the DMH and VMH lesions of each animal. Each symbol refers to an individual subject and only unilateral lesion placements are indicated. Diagram is reconstructed from Paxinos and Watson . Section plane values are in relation to Bregma. The NMDA lesions (black circles) are indicated on the left side of each drawing, while the vehicle lesions (gray circles) are on the right. 54 Table 1 Summary of pre- and postpartum data Lesion placement DMH VMH Group NMDA Vehicle NMDA Vehicle N 4 5 10 9 P.E. Mann, J.A. Babb / Brain Research 1025 (2004) 51–58 Body weight at surgery (g) 289.0 303.0 292.8 283.7 (F9.6) (F12.3) (F7.2) (F5.2) Body weight day after parturition 259.5 252.8 279.3 266.2 (F7.4) (F18.2) (F8.9) (F8.2) Litter size (no. of pups) 16.0 13.6 12.9 12.1 (F0.91) (F0.68) (F1.2) (F1.1) Total pup body weight 97.8 71.6 87.4 75.8 (F4.7) (F11.9) (F7.6) (F6.2) Data are given as means (FS.E.M.). There were no significant differences among groups of the same lesion placement. 3.2. Subject weight and litter size and weight DMH and VMH lesions did not affect the body weights of the females the day after parturition compared to the day of surgery ( pN0.05; Table 1). In addition, there were no differences in litter size or total body weight of the litter the day after parturition ( pN0.05). 3.3. Behavioral testing Pregnant rats that received NMDA infusions into the DMH displayed maternal behavior a median of 5.5 days before parturition compared to the vehicle-treated groups which displayed maternal behavior around parturition (median=0; Fig. 2). This difference did not reach statistical significance ( p=0.055), probably due to the low number of subjects in each group. The cumulative percentage maternal on each test day is shown in Fig. 3. Significantly more NMDA-treated rats were maternal on day 5 before parturition (75%) compared to vehicle-treated rats (0%; pb0.05). NMDA lesions of the VMH significantly shortened latencies to display maternal behavior in primigravid rats ( pb0.05; Fig. 4). NMDA-treated females were responsive to pups a median of 6 days before pregnancy, whereas a vehicle-treated animal was only likely to be maternal the day of or the day before parturition. There were no differences in the cumulative percentage maternal on each test day between the NMDA-lesioned animals and vehicle- treated animals, although the difference approached significance 6 days prior to parturition ( pb0.08; Fig. 5). 4. Discussion The VMH is recognized as a key area in the control of energy metabolism, hormone release, and reproduction, specifically female sexual behavior [28–30,35]. The present findings indicate that the DMH/VMH are also important areas in the regulation of another aspect of reproduction: maternal behavior. Specifically, neurotoxic lesioning of the DMH/VMH advances the onset of maternal behavior in primigravid rats. These results contribute to the growing evidence that the DMH/VMH may be part of an endogenous maternal behavior inhibitory neural circuit [3,8,55,56]. The development of maternal behavior during pregnancy has been well-characterized. An intact primigravid rat will not spontaneously respond maternally to foster pups until the periparturitional period [50,60]. If, on the other hand, pregnant rats are constantly exposed to foster pups (bsensitizedQ), their maternal behavior latencies are similar to virgin rats, i.e., approximately 5 days [5,50]. The only way to shorten the latencies from 5 to 1–2 days is to terminate the pregnancy either by caesearean section  or hysterectomy [50,52], or to ovariectomize and/or hysterectomize the rat during the second half of pregnancy [5,7]. Fig. 2. Median days prepartum to display full maternal behavior in primigravid rats following DMH lesions. Fig. 3. Cumulative percentage of females displaying maternal behavior on each test day following DMH lesions in primigravid rats. *pb0.05 compared to vehicle group. P.E. Mann, J.A. Babb / Brain Research 1025 (2004) 51–58 55 Fig. 4. Median days prepartum to display full maternal behavior in primigravid rats following VMH lesions. *pb0.05 compared to vehicle group. These procedures (casesarean section, hysterectomy plus ovariectomy) drastically reduce the amount of circulating progesterone within 6 h . Since progesterone alone normally inhibits the display of maternal behavior , its removal prepartum potentiates a rapid onset of the behavior. Procedures that stimulate short-latency maternal behavior in virgins, such as nasal zinc sulfate administration, bulbectomy, and medial amygdaloid lesions, have not been performed during the physiological state of pregnancy with the goal of determining their effect on prepartum maternal behavior. The results presented here demonstrate that the onset of maternal behavior during a first pregnancy can be advanced by lesioning hypothalamic nuclei involved in the endogenous maternal behavior inhibitory circuit. Since studies have shown that progesterone can be used to inhibit maternal behavior following pregnancy termination , future experiments will examine whether progesterone is involved in the disinhibition of maternal behavior following DMH/VMH hypothalamic lesions. What is the mechanism that underlies the involvement of the VMH in maternal behavior? When virgin or primigravid rats first come in contact with foster pups they either avoid them or cannibalize them. Part of the initial reluctance of the female to behave maternally may be neophobia or an aversion to the odor of pups . In fact, researchers have used biphasic motivational factors, such as approach and avoidance, in order to explain the initial reluctance of primigravid rats to behave maternally and then the immediate onset of maternal responsiveness at parturition [42,51]. When the olfactory stimulus is eliminated, either by rendering the animal anosmic or by lesioning the main and/or accessory olfactory tracts, the aversive quality of the pups is reduced and the approach aspect appears allowing short-latency maternal behavior . In addition, when areas of the brain involved with fear and anxiety are lesioned (e.g., the amygdala and bed nucleus of the stria terminalis ), latencies to respond maternally are shortened [22,46]. Studies indicate that the VMH is also involved in stress and anxiety [1,25,36], and receives afferent projections from the amygdala [17,56]. It is possible that the VMH is also involved in the initial avoidance of pups and exerts a chronic inhibitory influence via its projections to the MPOA , thereby suppressing the initiation of maternal behavior. Therefore, constant exposure to pups in a virgin rat (sensitization) or prolonged exposure from the hormones of pregnancy followed by progesterone withdrawal in a primigravid rat may inactivate the endogenous maternal behavior inhibitory (avoidance) circuit and stimulate maternal behavior. The present data indicate that the DMH also has a role in the maternal behavior inhibitory circuit. Previous work established the DMH as part of a Qhypothalamic defenseQ area [16,53]. Injection of excitatory amino acids into the DMH produces stress-like responses including tachycardia, increased respiratory rate and escape behavior . In addition, GABAA receptor antagonists enhance avoidance stress responses and produce experimental ddanxietyTT in a social interaction test . GABAA agonists, on the other hand, when injected into the DMH, reduce physiological signs of stress . These data indicate that the DMH is involved in the activation of the hypothalamic-pituitaryadrenal (HPA) axis during stress. Since lesioning the DMH stimulates fast-latency maternal behavior, these data support the concept that the DMH is part of the neural substrate that underlies the initial aversion/avoidance of the pups by primigravid rats. Evidences from Fos immunocytochemical studies have demonstrated areas of the brain that respond to the stimulation [33,47] or inhibition of maternal behavior [55,56]. An increase in the number of Fos-immunoreactive cells in the MPOA [34,63] and ventral BnST [44,62] is associated with ongoing maternal care. In contrast, virgin animals exposed to pups that do not display maternal Fig. 5. Cumulative percentage of females displaying maternal behavior on each test day following VMH lesions in primigravid rats. 56 P.E. Mann, J.A. Babb / Brain Research 1025 (2004) 51–58 behavior demonstrate increases in Fos immunoreactivity in several neural areas, including the DMH and VMH . The fact that the presence of pups in non-maternal animals activates Fos in these areas supports the involvement of the DMH and VMH in an inhibitory circuit and that those cells project to the MPOA and vBnST to actively inhibit the behavior. The neuroanatomical circuit underlying the endogenous maternal behavior inhibitory neural circuit appears to include the main and accessory olfactory bulbs, that project to the medial amygdala and, based on the present results and others, extend to the DMH/VMH [8,55]. The VMH and possibly DMH, in turn, likely send inhibitory projections to the MPOA. During late pregnancy, the DMH/VMH to MPOA projections may become inactivated, presumably by the hormones of pregnancy, allowing the female to be fully maternal at parturition. The neurotransmitter systems involved in this maternal circuit are just beginning to be identified. Sheehan and Numan  proposed a role for the tachykinin, neuropeptide K, since tachykininergic neurons project from the medial amygdala to the VMH, and the administration of neuropeptide K into the VMH significantly delays the onset of maternal behavior in pregnancy-terminated, estradiol-treated rats. The neurotransmitter system(s) involved in the presumed inhibitory projection from the DMH/VMH to the MPOA is unknown. The amino acid derivative, g-aminobutyric acid (GABA) is one possible candidate. During pregnancy, GABA levels in the brain decrease in the mouse  and GABAA receptor concentrations and affinity are altered in a site-specific manner [24,32,59]. In fact, the levels of GABAA receptors in certain areas of the brain are regulated by both progesterone and its metabolites , which are increased in the brain during most of pregnancy (highest levels on days 14 and 15) and are low on day 21 [12–14,24]. These neuroactive steroids enhance the inhibitory actions of GABAA receptors in the brain until the periparturitional period . The known changes in supraoptic nucleus (SON) oxytocin neurons during pregnancy may be a possible model for (or mimic) the changes that occur in the MPOA that subserve maternal behavior. The electrical activity of oxytocin magnocellular neurons in the SON radically changes across pregnancy and lactation [10,24]. At first, SON oxytocin neurons fire at low levels during most of pregnancy due to a tonic inhibition of SON cells by high levels of progesterone and/or allopregnanolone. These progestins enhance GABAA receptor inhibitory activity by slowing the rate of ion channel closure or preventing recovery [26,27,66]. At the end of pregnancy, there is an abrupt transition to elevated firing levels and periodic synchronous bursts . In addition, the sensitivity of GABAA receptors to allopregnanolone declines . This abrupt transition appears to be mediated by the precipitous prepartum decline in progesterone. Thus, progesterone and/ or allopregnanolone acting via the GABAA receptor are bbrakesQ on the neurons that secrete oxytocin until the end of gestation when it is essential for parturition. It is possible that a similar mechanism occurs in the MPOA in the regulation of maternal behavior, such that progesterone and/or allopregnanolone act via GABAA receptors in the MPOA to tonically inhibit MPOA neurons involved in the stimulation of maternal behavior. The fall in prepartum progesterone disinhibits the MPOA, so that maternal behavior can be displayed at parturition. Taken together, these data indicate a possible role for GABA and the GABAA receptor in the inhibition of maternal behavior in virgin and primigravid rats and in the disinhibition of maternal behavior at parturition. Experiments are being performed in our laboratory investigating this hypothesis. The question arises as to the evolutionary advantage of having maternal behavior tonically inhibited in adult, virgin rats, especially since the behavior is present in juvenile females [4,9,38,65]. One possible evolutionary advantage for maternal behavior to be inhibited while the female is nulliparous is to ensure that energy and resources are devoted to finding mates. In addition, the adult, virgin, female rat can not lactate, and therefore, she would be expending energy needlessly by taking care of pups in which she has less of a genetic investment. In summary, neurotoxic lesions to the DMH and VMH advance the onset of maternal responsiveness in intact primigravid rats. These data support the existence of an endogenous maternal behavior inhibitory circuit that includes the DMH and VMH as part of the underlying neural substrate. Acknowledgement This research was supported by National Institutes of Health HD39668. References  S.J. Aou, J.Y. Ma, T. Hori, N. 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