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Author's personal copy Frontiers in Neuroendocrinology 30 (2009) 46–64 Contents lists available at ScienceDirect Frontiers in Neuroendocrinology journal homepage: www.elsevier.com/locate/yfrne Review Medial preoptic area interactions with dopamine neural systems in the control of the onset and maintenance of maternal behavior in rats Michael Numan *, Danielle S. Stolzenberg Department of Psychology, Boston College, McGuinn Hall, 140 Commonwealth Avenue, Chestnut Hill, MA 02467, USA a r t i c l e i n f o Article History Available online 5 November 2008 Keywords: Maternal behavior Dopamine Medial preoptic area Estradiol Prolactin Oxytocin Brain development Neural plasticity a b s t r a c t The medial preoptic area (MPOA) and dopamine (DA) neural systems interact to regulate maternal behavior in rats. Two DA systems are involved: the mesolimbic DA system and the incerto-hypothalamic DA system. The hormonally primed MPOA regulates the appetitive aspects of maternal behavior by activating mesolimbic DA input to the shell region of the nucleus accumbens (NAs). DA action on MPOA via the incerto-hypothalamic system may interact with steroid and peptide hormone effects so that MPOA output to the mesolimbic DA system is facilitated. Neural oxytocin facilitates the onset of maternal behavior by actions at critical nodes in this circuitry. DA–D1 receptor agonist action on either the MPOA or NAs can substitute for the effects of estradiol in stimulating the onset of maternal behavior, suggesting an overlap in underlying cellular mechanisms between estradiol and DA. Maternal memory involves the neural plasticity effects of mesolimbic DA activity. Finally, early life stressors may affect the development of MPOA–DA interactions and maternal behavior. Ó 2008 Elsevier Inc. All rights reserved. 1. Introduction This paper will review the evidence that the medial preoptic area (MPOA) of the rostral hypothalamus interacts with dopamine (DA) neural systems in the regulation of both the onset and maintenance of maternal behavior in rats. The question arises as to whether such work is relevant to the neural control of maternal behavior in other mammals, including humans. Since maternal behavior is a defining characteristic of mammals, one should expect that evolutionarily conserved neural circuits exist which regulate maternal behavior across mammalian species. A theoretical framework which guides a research program that is aimed at uncovering forebrain neural circuits which control goal-directed maternal responses to infant stimuli should be able to tap into this core neural circuitry. Analysis of the limited research done on other mammalian species will support this contention. This paper will conclude with a discussion of how the reviewed research might help us understand the neural underpinnings of pathological conditions associated with the maternal condition in humans (the display of child abuse and neglect by mothers). The four major components of maternal behavior in rats are retrieval or transport behavior, nest building, nursing behavior, and pup licking/grooming [114]. Retrieval behavior (where the mother carries the altricial pup in her mouth, moving it from one location to another) serves to either transport displaced pups back to the nest site or to move pups to a new nest site. Nest building serves * Corresponding author. Fax: +1 617 552 0523. E-mail address: [email protected] (M. Numan). 0091-3022/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.yfrne.2008.10.002 to insulate the poikilothermic pups, keeping them warm in the mother’s absence. Licking/grooming of the pups cleans them and aids in pup defecation and urination; it is also an important source of tactile stimulation for the young. Finally, nursing behavior, where the mother crouches over the young pups to expose her mammary region, provides milk to the suckling pups. It is important to make a distinction between retrieval behavior and nursing behavior in terms of their characteristics and potential underlying neural regulation. Because retrieval behavior is initiated by the mother, Terkel et al. [174] classified it as an active maternal response; in contrast, they referred to nursing behavior as a passive maternal response since it is primarily initiated by nuzzling and suckling stimulation of the mother’s ventral surface by the young. Similar distinctions have been made by Hansen et al. [58] and Stern [167], who refer to retrieval behavior as either an appetitive or pronurturant response and to nursing as a consummatory or nurturant response. Indeed, one can conceive of nursing behavior as the final goal of a maternal–pup interaction bout, while retrieval behavior can be considered as a flexible appetitive approach response that transports pups to an adequate nest site so that nursing behavior can occur. [Of course, if the pups are already located in an adequate nest, then the return of the mother to the nest after a period of absence can also be considered an appetitive approach response.] Therefore, we would like to categorize pup-seeking and retrieval behaviors as voluntary proactive maternal responses which are likely to be highly dependent on forebrain neural activity for their normal occurrence. In contrast, nursing behavior is conceived of as primarily a reflexive or automatic maternal response elicited by proximal pup stimulation of Author's personal copy 47 M. Numan, D.S. Stolzenberg / Frontiers in Neuroendocrinology 30 (2009) 46–64 2. Hormonal basis of the onset of maternal behavior in primiparous female rats and the nonhormonal maintenance of the behavior after its initiation As already noted, virgin female rats do not show maternal behavior upon initial exposure to pups; they actively avoid pups that are presented to them [43,44]. However, if one cohabitates a virgin female with pups over a series of days, some major behavioral changes occur [43]. Initially the nulliparous female avoids the young pups, but after a period of 3–4 days she tolerates their proximity, and then, beginning about 7 days from the time of the initial exposure, she begins to care for them: she builds a nest, retrieves the pups to the nest, licks/grooms the pups, and hovers over them in a nursing posture even though she is unable to lactate. This induction of maternal behavior in virgin females through pup exposure has been called sensitized maternal behavior, and the process has been referred to as sensitization. The number of days of pup exposure required for maternal behavior to occur is designated as the female’s sensitization latency. It is as if prolonged stimulation from pups allows the virgin female to adopt the pups as her own. One interpretation of these results is that novel pup stimuli arouse fear-related processes and avoidance responses in virgins, but after a period of continuous exposure the female habituates to the fear-arousing properties of the young, which allows proximal contact to occur. At this point, additional stimuli from the pups, for example tactile inputs, begin to promote an increase in maternal responsiveness, which eventually leads to the occurrence of full maternal behavior. Based on this analysis, several investigators (see [147]) have proposed that maternal behavior occurs when the tendency to approach infant stimuli, remain with pups, and engage in maternal behavior is greater than the tendency to avoid or withdraw from infant stimuli. Please note that this interpretation suggests that the process of sensitization is actually a dual process in which a period of habituation is followed by a period of sensitization. Since this ‘sensitization’ process occurs in virgin female rats that have either been ovariectomized or hypophysectomized, it appears to have a nonhormonal basis [145]. In other words, there appears to be a basic neural substrate regulating maternal behavior which can ultimately be activated by pup-related stimuli without hormonal intervention, although in the naïve virgin rat this process takes some time to occur. In contrast to the virgin female, the parturient primiparous rat is immediately responsive to pups, and does not require a period of cohabitation, because her brain has been affected by the endocrine events associated with pregnancy and pregnancy termination. The critical endocrine events are rising levels of placental lactogens, pituitary prolactin, and estradiol, superimposed on a dramatic fall in blood levels of progesterone which occur near the end of a 22-day pregnancy [114]. Importantly, as shown by Moltz et al. [101] and by Bridges and his colleagues [15,19], if one treats ovariectomized virgin female rats with a systemic hormone regimen which simulates these endocrine changes, one can reduce sensitization latencies from the typical 7 days shown by control females to 1–2 days in the hormone-treated virgins. Rosenblatt’s group [148,149,159] has developed the pregnancy termination model to explore the endocrine basis of maternal behavior in rats and a proper understanding of this model will be important for the interpretation of data which will be presented in subsequent sections of this paper. Primigravid female rats that are presented with pups on day 17 of a 22-day pregnancy are generally not maternally responsive to young pups. When primigravid females are hysterectomized (removal of uterus, placentas, and pups) on day 15 of pregnancy (15H group) and presented with pups 2 days later (which would have been day 17 of pregnancy), they show sensitization latencies of about 1 day. Maternal behavior is stimulated in these females because the hysterectomy prematurely activates those endocrine events which would normally occur nearer to the time of parturition (declining progesterone, rising estradiol and prolactin: see [114] for mechanistic details). Importantly, if females are hysterectomized and ovariectomized on day 15 (15HO group) with pup presentation beginning 48 h later, sensitization latencies of 2–3 days are observed. These results suggest the importance of the estradiol rise after hysterectomy, which is confirmed by the following: Primigravid females that are 15HO but also receive 20 lg/kg of estradiol benzoate (administered sc in oil) on day 15 immediately following the surgery (15HO + E group) show immediate maternal behavior (0 day latencies) when presented with pups 48 h later. Some of these results are shown in Fig. 1, and we want to indicate that the 15HO females show an intermediate level of maternal responsiveness: their sensitization latencies are significantly shorter than that of naïve vigins but significantly longer than those of 15HO + E females. This suggests that in 15HO females the neural mechanisms underlying maternal behavior are partially or suboptimally primed. As will be a 7 Average sensitization latencies (days) the female’s ventral surface and is probably regulated to a large degree by brainstem–spinal mechanisms. Significantly, Stern [166] has shown that male rats, who normally do not show parental responses on their first exposure to pups, will show the reflexive nursing posture in response to nuzzling pups if the males are immobilized through drug treatment and placed over the pups. At the time of parturition, the primiparous female rat initiates the complete complex of maternal responses on her first exposure to her own or to foster pups [114]. Unlike species with precocial young, such as sheep, parturient rats do not form selective attachments to their particular pups, and will care for all young pups. In sharp contrast, the naïve nulliparous estrous cycling virgin female rat will not care for foster pups upon her initial exposure to them and will usually avoid the pups, but may sometimes attack them [114]. The distinction between the responsiveness of the parturient and virgin female rat to pup-related stimuli is an important one and shows that pup stimuli do not elicit maternal responses in all female rats. Critical internal changes occur in the primiparous parturient female which increase her maternal responsiveness or maternal motivation, indicating that the function of particular brain circuits in the primiparous mother is different from those operating in the naïve virgin female rat. b 2 c 0 Naïve virgins 15HO 15HO+E Fig. 1. Average sensitization latencies for female rats exposed to different treatments. 15HO = primigravid female rats that were hysterectomized and ovariectomized on day 15 of pregnancy and presented with pups 2 days later. 15HO + E = 15HO females treated with estradiol immediately following the HO procedure. Groups with different letters differ significantly. The evidence upon which this figure is based can be found in Numan and Insel [114]. Author's personal copy M. Numan, D.S. Stolzenberg / Frontiers in Neuroendocrinology 30 (2009) 46–64 shown later, this model has been used by us to explore whether manipulations of DA neural systems can facilitate maternal behavior. The fact that the hormones associated with pregnancy and pregnancy termination promote immediate maternal responsiveness toward pups upon the primiparous female’s initial exposure to infant-related stimuli has important motivational implications. It suggests that hormonal action on the brain alters the phenotype of essential neural circuits so that avoidance, rejection, and defensive circuits that would respond to novel infant stimuli in naïve virgins are downregulated, while neural circuits regulating approach tendencies, acceptance, and maternal responses are upregulated and respond strongly to infant-related stimuli [124]. One final point to note is that although the immediate onset or initiation of maternal behavior in the parturient primiparous female rat is under hormonal control, its continuance or maintenance after its establishment is no longer tied to hormonal mediation [114]. Most significantly, females who are hypophysectomized after their maternal behavior has become established continue to show maternal behavior during the postpartum period even though they are no longer capable of lactating. It is as if the hormonal events associated with pregnancy termination set up neural circuits such that the first-time mother is immediately responsive to pup-related stimuli, but that once maternal interaction with pups occurs these neural circuits are further modified so that maternal behavior can continue long after the initial hormonal stimuli have occured [113,146]. We will have more to say about this mechanism when we explore the processes underlying the maternal experience effect or what has been called maternal memory. Ó Springer-Verlag with the kind permission of Springer Science and Business Media 2003 48 3. Medial preoptic area and maternal behavior in rats There is strong evidence that the medial preoptic area (MPOA) in the rostral hypothalamus and the adjoining ventral bed nucleus of the stria terminalis (vBST; a telencephalic structure) are essential for both the onset and maintenance of maternal behavior in rats. 1. Electrical lesions of MPOA/vBST, knife cuts which sever the lateral connections of the MPOA/vBST, or excitotoxic amino acid lesions of this critical brain area, which destroy MPOA/vBST neurons while sparing axons of passage through this region, have all been found to disrupt maternal behavior in rats [66,80,104,110,112,115,118,123,174]. It should be noted that MPOA damage disrupts the onset of the behavior when the lesions are performed prior to parturition [80,110] and the maintenance of the established behavior when the lesions are performed during the postpartum period [104,112,115, 118,174]. In addition, such lesions also disrupt sensitized maternal behavior in virgin female rats [66,123]. Finally, MPOA damage must be bilateral to cause a severe disruption in maternal behavior. Unilateral damage is either ineffective or causes only minimal and transient deficits [121,125,165]. In important studies, as shown in Fig. 2, Numan and Callahan [110] and Numan et al. [115] showed that knife cuts which destroyed the dorsolateral connections of the MPOA/vBST region selectively disrupted maternal behavior in postpartum rats (also see Terkel et al. [174]). In contrast, knife cuts which sever the ventrolateral MPOA connections or the dorsal, anterior, or posterior connections of MPOA/vBST do not selectively and specifically disrupt maternal behavior. These findings, along with the fact that excitotoxic amino acid lesions of MPOA/vBST cell bodies disrupt Fig. 2. (A) Frontal section through the medial preoptic area of the rat brain showing knife cuts (dashed lines) severing the lateral connections of the medial preoptic area and adjoining ventral bed nucleus of the stria terminalis. Full cuts, which travel from the level of the anterior commissure to the base of the brain selectively disrupt maternal behavior. The black dots separate the lateral cuts into dorsal and ventral parts. Dorsolateral cuts, but not ventrolateral cuts, also disrupt maternal behavior. (B) A frontal section showing a knife cut (dashed line) severing the dorsal connections of the medial preopitc area. (C) Sagittal section showing the placement of a knife cut severing the anterior connections of the medial preopitc area (dashed line between DB and MPOA) and a knife cut severing the posterior connections of the medial preoptic area (dashed line posterior to MPOA). Abbreviations: AC, anterior commissure; AH, anterior hypothalamic nucleus; CC, corpus callosum; CG, central gray (periaqueductal gray); CP, caudate-putamen; DB, nucleus of the diagonal band of Broca; DM, dorsomedial hypothalamic nucleus; GP, globus pallidus; H, hippocampus; LPOA, lateral preoptic area; LS, lateral septum; LSi, intermediate nucleus of lateral septum; LSv, ventral nucleus of lateral septum; M, mammillary bodies; MPOA, medial preoptic area; NA, nucleus accumbens; OB, olfactory bulb; PVN, paraventricular hypothalamic nucleus; SC, superior colliculus; TH, thalamus; vBST, ventral bed nucleus of stria terminalis; VM, ventromedial hypothalamic nucleus; VP, ventral pallidum; VTA, ventral tegmental area. Brain sections are adapted from Swanson’s [171] rat brain atlas. Reproduced from M. Numan and T.R. Insel [114] (Fig. 5.8, p. 132). maternal behavior, suggest the critical importance of MPOA/vBST efferents which exit this region dorsolaterally. [In Fig. 2, note the locations of the following nuclei for later reference: Nucleus accumbens (NA); ventral pallidum (VP); paraventricular nucleus of hypothalamus (PVN); ventral tegmental area (VTA).] Although all components of maternal behavior are disrupted by MPOA/vBST damage, retrieving behavior is virtually eliminated, as is nest building, while nursing behavior is reduced in duration but is not eliminated. Licking/grooming of pups is also depressed by MPOA lesions. These facts indicate that an intact MPOA/vBST is most essential for the occurrence of proactive voluntary or appeti- Author's personal copy 49 M. Numan, D.S. Stolzenberg / Frontiers in Neuroendocrinology 30 (2009) 46–64 tive maternal responses and that reflexive/consummatory nursing postures can occur in preoptic damaged females in response to proximal tactile pup stimulation of the female’s ventrum. Finally, note that the effects of preoptic damage on maternal behavior in rats are relatively specific see [114]: such females, who do not properly care for their offspring, exhibit normal body weight regulation, open field activity, sexual receptivity (as measured by the lordosis quotient), and hoarding behavior. The occurrence of hoarding behavior is important because it shows that the retrieval deficit is not caused by a more general oral motor deficit. 2. Many studies have shown that hormones act on the MPOA region to stimulate the onset of maternal behavior in rats. MPOA neurons contain prolactin receptors [5], progesterone receptors [122], and estrogen receptors [157]. Most importantly, discrete implants into the MPOA of either estradiol [41,42,123] or lactogenic hormones (pituitary prolactin or placental lactogens [17,18]) stimulate the onset of maternal behavior in rats that have been systemically primed with the other critical hormones that are necessary for maternal behavior onset. For the estradiol evidence, Numan et al. [123] employed the pregnancy termination model. Primigravid rats were hysterectomized and ovariectomized on day 15 of pregnancy and presented with pups 48 h later (day 0 of testing). As shown in Fig. 3, most females with estradiol benzoate (EB) implants into MPOA (a unilateral cannula containing pure crystalline EB was inserted into the MPOA on day 15 of pregnancy and left in place until just before the time of pup presentation on day 0 of testing) showed maternal behavior on their first day of pup exposure (median sensitization latency of 0 days), while females that received cholesterol implants into MPOA or EB implants into the posterior hypothalamus showed a delayed onset of maternal behavior, with sensitization latencies averaging around 2 days, which is typical of 15HO females that are not treated with estradiol. Oxytocin (OT), a hormone that is released from the pituitary gland, is closely tied to the physiological events of parturition and milk-ejection, but it has poor penetrance across the blood– brain barrier and therefore, as a hormone, it is unlikely to influence maternal behavior (see [106,107,114]). However, OT also serves as a neuromodulator or neurotransmitter within central neural circuits (the origin of such circuits is likely the parvocellular neurons of the PVN), and in this role OT has been found to facilitate the onset of maternal behavior in rats and other species [113]. For exam- 3. A final line of evidence indicating the involvement of MPOA/ vBST neurons for maternal behavior is that Fos proteins (cFos and Fos B) are expressed at high levels in these nuclei when pups are presented to females who engage in maternal behavior [45,67,116,117]. In contrast, a variety of control stimuli that do not evoke maternal behavior do not have this effect. Importantly, the hormonal events of pregnancy which activate maternal behavior have been shown to activate Fos expression in MPOA in the absence of pup presentation. For example, 15HO females injected (sc) with 20 lg/kg of EB exhibit high levels of cFos expression in MPOA 48 h later, while control 15HO females injected with the oil vehicle solution do not [156]. Since Fos proteins serve as transcription factors, it can be suggested that the hormonal events of late pregnancy alter the phenotype of MPOA neurons and that Fos proteins may be one of the mediators of this effect. The alteration of MPOA phenotype may include increases in the neurotransmitter/neuromodulator content of ‘maternal’ MPOA neurons as well as modifications in the expression of select neurotransmitter or neuromodulator receptors, such as OTRs, on MPOA neurons. This change in the phenotype of MPOA neurons may allow such neurons to be activated by pup-related stimuli which are likely to include perioral tactile and olfactory inputs from pups [114]. Once maternal behavior becomes established, pup stimuli alone may regulate the altered phenotype of MPOA neurons, maintaining their functional integrity and allowing maternal behavior to continue in the absence of hormonal mediation. Fos proteins also appear MPOA OT Chol-MPOA 80 EB-PH 60 40 20 0 1 2 3 Days of Testing 4 5 Ó American Psychological Association 1997 EB-MPOA 100 Cumulative % Maternal ple, although 15HO pregnancy-terminated female rats that are injected (sc) with EB at the time of HO show sensitization latencies of 0 days when presented with pups 48 h post HO, Fahrbach et al. [39] were able to block this immediate onset of maternal behavior by intracerebroventricular (ICV) injections of an oxytocin receptor antagonist (OTA) at the time of pup presentation. Importantly, the MPOA is one of the sites where neural OT acts to stimulate the onset of maternal behavior, since Pedersen et al. [138] found that direct injections of OTA into the MPOA disrupted the natural onset of maternal behavior in parturient rats. It is worth noting that one of the functions of estradiol within MPOA is to induce the expression of oxytocin receptors (OTRs: [27,138]. Therefore, as shown in Fig. 4, one function of estradiol within MPOA appears to be that it allows MPOA neurons to become responsive to OT. Fig. 3. Cumulative percentage of pregnancy-terminated female rats showing full maternal behavior on each test day after application of either estradiol benzoate (EB) or cholesterol (Chol) to various brain sites. MPOA, medial preoptic area; PH, posterior hypothalamus. Adapted with the permission of the American Psychological Association, from Numan et al. [123]. OTR E-ER E Maternal Behavior Fig. 4. Diagrammatic representation showing that one mechanism through which estradiol (E) affects the medial preoptic area (MPOA) function and maternal behavior is through the induction of oxytocin receptor (OTR) expression, which increases the responsiveness of MPOA to oxytocin (OT). E is shown as entering an MPOA neuron and binding to the intracellular estrogen receptor (ER), upon which it affects intracellular and transcription processes which lead to increased OTR synthesis and expression. Author's personal copy 50 M. Numan, D.S. Stolzenberg / Frontiers in Neuroendocrinology 30 (2009) 46–64 to be involved in this latter effect [164]. 5. Mesolimbic DA system Most of the work on the involvement of the MPOA/vBST in maternal behavior has been done on rats. However, other work exists showing the importance of MPOA neurons for parental behavior in mice, hamsters, ring doves, and sheep [21,79,114,141]. For example, Perrin et al. [141] reported that temporary inactivation of the MPOA with a local anesthetic disrupted maternal behavior in postpartum ewes. Furthermore, in an fMRI study, Lorberbaum et al. [86] recorded an increased BOLD response in BST and hypothalamus of human mothers who were attending to infant stimuli. 4. Neural-motivational model If the output of the MPOA is essential for the regulation of maternal motivation, through what mechanism might it exert its effects? Fig. 5 shows the organization of an hypothetical neuralmotivational model which would be consistent with approachavoidance models of maternal behavior [108,109,124,147]. It shows the MPOA as a maternal motivational region which, when primed and stimulated by hormones, OT, and pup stimuli, functions to increase a mother’s responsiveness to infant-related stimuli. It is proposed that MPOA efferents have this effect by depressing neural circuits which regulate rejection, withdrawal, and avoidance responses to infant-related stimuli while at the same time activating those neural circuits which regulate positive maternal responses, particularly voluntary proactive maternal responses to young. If these MPOA output circuits were not operative in rats, which is presumed to be the case in naïve virgin females, then pup stimuli would not be translated into maternal responses, but instead would cause avoidance behavior and other defensive responses. The focus of the remainder of this review is to present the evidence that MPOA/vBST interactions with the mesolimbic DA system is the mechanism through which the MPOA regulates proactive voluntary maternal responses. For an analysis of MPOA involvement in the inhibition of the defensive circuit, the reader is referred to Numan [108,109]. E Prol OT Pup stimuli MPOA Pup stimuli Defensive circuit Avoidance Behavior Pup stimuli Approach interaction circuit Maternal Behavior Fig. 5. Hypothetical model of medial preoptic area (MPOA) function with respect to maternal motivation. Estradiol (E), prolactin (Prol) and oxytocin (OT) are shown as acting on the MPOA to increase its responsiveness to pup stimuli. The activated MPOA sends out two separate pathways, one of which inhibits a defensive/ avoidance neural circuit and another which excites a neural system mediating approach and positive interactions with pups. Axons ending in a bar indicate inhibition and those ending in an arrow signify excitation. The mesolimbic DA system originates from DA cell bodies located in the midbrain VTA and ascending projections from this system terminate in many subcortical telencephalic regions [170]. Our focus will be on VTA–DA projections to the NA. This critical DA pathway serves general functions which have been described as either related to reinforcement processes or to the regulation of appetitive goal-directed (motivated) behaviors [70]. Emphasizing the latter, we share the view of many investigators that DA action on NA modulates an organism’s responsiveness to biologically significant stimuli that have been processed through the limbic system [10]. Indeed, Mogenson [100] referred to the NA as being a critical component of what he called the limbic motor system. Mogenson noted that a major output of NA consisted of a GABAergic inhibitory projection to VP. The VP, in turn, projects to forebrain and brainstem motor control regions. Mogenson suggested that DA action on NA depresses the GABAergic output from NA to VP, and this disinhibitory process then allows VP output to promote behavioral reactivity. It should be noted that both NA and VP receive glutamatergic inputs from the basolateral amygdala (BLA) and from the prefrontal cortex (PFC), and these are presumably two of the avenues through which processed sensory input can reach each of these structures [20,91,142,184]. Although Mogenson’s idea that DA functions to depress NA GABAergic output to VP is controversial [103,108,140], this working model fits with the data that we have collected with respect to the involvement of the mesolimbic DA system in the regulation of maternal responsiveness to pup-related stimuli. As reviewed in detail elsewhere [108], alternative models of mesolimbic DA function propose that the neural output of NA is essential for the expression of goal-directed behaviors. We will show below that this is not the case for goal-directed maternal responses. In addition, as predicted by Mogenson’s model, we will show that the output of VP is essential for maternal responsiveness. As we have done before [108,109,120,126], we will present a simplified hypothetical neural model through which MPOA/vBST interactions with the mesolimbic DA system might be involved in regulating proactive voluntary maternal responses to pup-related stimuli. We will then present the evidence from which the model was derived. In Fig. 6, we show that when MPOA/vBST is appropriately primed and/or stimulated by hormones and OT it is rendered capable of responding to pup-related stimuli which are presumably tactile and olfactory in nature. The activated MPOA/vBST in turn excites VTA–DA projections to NA, and following Mogenson’s [100] model, we suggest that DA serves to depress the responsiveness of NA to the excitatory inputs it receives from BLA/PFC. This process disinhibits VP, allowing it to respond to excitatory BLA/PFC inputs. BLA/PFC is shown as relaying sensory inputs to NA and VP, which would include pup-related stimuli. With respect to this model, note that pup stimuli enter the system at two levels: MPOA/vBST and NA–VP. If the MPOA/vBST is not appropriately primed it will not respond strongly to pup stimuli, the VTA will not be activated, and a gate will not open to allow the VP to respond strongly to pup stimuli. That is, when MPOA/vBST neurons are not functionally set up to respond to pup stimuli then both the NA and VP receive input from pup-related stimuli. Activation of the NA GABAergic projection to VP depresses the ability of the VP to respond strongly to pup stimuli and maternal reactivity is depressed. Note that in this model MPOA/vBST neurons do not organize maternal responses. An active MPOA/vBST simply serves as a trigger mechanism which allows the limbic motor system to process pup-related stimuli through the VP so that proactive voluntary maternal responses occur. The mechanisms Author's personal copy E Pup stimuli OT Prol MPOA vBST NA BLA DA VTA GABA VP Maternal responsiveness PFC Pup stimuli Ó American Psychological Association 2005 M. Numan, D.S. Stolzenberg / Frontiers in Neuroendocrinology 30 (2009) 46–64 Fig. 6. A neural model showing how an hormonally primed medial preoptic area and adjoining ventral bed nucleus of the stria terminalis (MPOA/vBST) might influence the proactive components of maternal behavior by interacting with the mesolimbic dopamine (DA) system. MPOA/vBST efferents activate ventral tegmental area (VTA) DA input to nucleus accumbens (NA). DA action on NA depresses the responsiveness of NA to afferent inputs from the basolateral amygdala and prefrontal cortex (BLA/PFC). These latter regions are shown as relaying pup-related sensory inputs to both NA and ventral pallidum (VP). Depression of NA responsiveness releases the VP from GABAergic inhibition derived from NA which opens a gate that allows VP to fully respond to BLA/PFC input. A fully active VP is proposed to be necessary for the occurrence of proactive voluntary maternal responses. Axons ending in an arrow indicate excitation and those ending in a bar indicate inhibition. E, estradiol; OT, oxytocin; Prol, prolactin. Adapted with the permission of the American Psychological Association, from Numan et al. [120]. through which the VP regulates this process remains to be determined. 6. Mesolimbic DA system and maternal behavior in postpartum rats Early studies showed that electrical lesions of the VTA disrupt maternal behavior in postpartum rats [49,125]. Since electrical lesions were used, these studies not only damaged VTA neurons but also axons of passage through the VTA. We [127, in preparation] have recently turned to the use of baclofen injections into the VTA in order the examine the effects of temporary inactivation of VTA neurons on the maternal behavior of postpartum rats. Baclofen is a GABA-B receptor agonist which will cause neural inhibition of neurons which contain GABA-B receptors (by increasing K+ conductance). Although baclofen will affect all neurons with such receptors, it is important that Westerink et al. [183] have provided evidence that VTA–DA neurons contain GABA-B receptors and that baclofen microinjections into VTA depress the release of DA into NA. Others have found that baclofen in VTA is highly effective in disrupting behaviors mediated by VTA–NA DA projections [186]. On day 14 of pregnancy, female rats were implanted with bilateral cannulas aimed at either the VTA or at the midbrain region 1.6 mm dorsal to VTA (DC: dorsal control). On days 3, 5, and 7 postpartum, 0, 10, or 15 ng of baclofen (dissolved in 0.3 ll of sterile saline) was injected (in a counterbalanced sequence) into either the VTA (Bac-VTA group) or DC region (Bac-DC group). On each test day, 20 min following the intracerebral injection, females were administered a 20 min retrieval test (the mother’s 8 pups were placed outside her nest and her retrieval responses were recorded). Following this test, all pups which were not retrieved to the female’s nest were placed back into the mother’s nest by the experimenter. Ten min later a 15 min nursing observation was conducted. Fig. 7 shows a typical VTA injection site and some of the data on retrieval behavior for the Bac-VTA group. Although all females under all conditions approached and sniffed the displaced pups with equal speed, the 10 and 15 ng baclofen injections into VTA, but not into the dorsal control site, depressed retrieval 51 behavior. Indeed, the mean number of pups retrieved after the 15 ng VTA injection was only 4 pups while the typical Bac-DC female receiving the 15 ng dose retrieved all 8 pups back to the nest. During the 20 min retrieval test, the Bac-VTA females either nursed the pups where they were placed by the experimenter without retrieving any pups to the nest, or they retrieved just a few pups and then began nursing. One interpretation of these results is that pup stimuli were less likely to evoke proactive voluntary retrieval responses after baclofen depression of VTA neural activity. [Note: Doses of baclofen higher than 15 ng completely eliminated retrieval behavior after injection into VTA.] Significantly, the 15 min nursing observation indicated that nursing behavior was not depressed in the Bac-VTA females, and in some cases it was even enhanced. It is important to emphasize that the disruption of retrieval behavior without a concomitant disruption of nursing behavior mirrors the effects of MPOA lesions, suggesting a functional link between MPOA and VTA in the regulation of the appetitive aspects of maternal responsiveness. Although the Bac-VTA data do not prove the involvement of VTA–DA neural projections to NA, other studies have clearly shown their involvement in maternal behavior. In microdialysis [56] and in vivo voltammetry research [28], evidence shows that extracellular DA levels in NA increase when a postpartum mother interacts with her young. Champagne et al. [28] show that when a female licked or groomed her pups, DA release occurred in NA, and that the increase in extracellular DA levels actually preceded the onset of a licking and grooming bout and could be used to predict the onset of such a bout. Significantly, the systemic administration of a DA uptake blocker to postpartum females increased both the extracellular DA signal in NA and the amount of licking or grooming of pups by the mother, suggesting that the increased postsynaptic availability of DA in NA fostered active pup-directed maternal behaviors. In a series of studies employing 6-hydroxydopamine (6-HD), a neurotoxin which destroys DA neurons, Hansen et al. [57,58] showed that 6-HD injections into either the VTA or NA (which destroyed VTA–DA neurons as a result of its uptake by DA terminal axons in NA; DA cell bodies are not present in NA) disrupted retrieval behavior in postpartum rats without affecting nursing behavior. Finally, Keer and Stern [69] showed that the microinjection of flupenthixol into the shell region of NA (NAs) disrupted retrieval behavior and licking/grooming of pups but actually enhanced nursing behavior in postpartum rats. There are two major types of DA receptors, denoted as D1 and D2 receptors. Flupenthixol is a mixed D1/D2 receptor antagonist, meaning that it blocks both DA receptor types. These results, taken as a whole, suggest that VTA–DA input to NA is essential for the more active components of maternal behavior. Nursing behavior is either not affected, or is enhanced following disruption of the mesolimbic DA system. The fact that nursing may be enhanced suggests a reciprocal relationship between appetitive and consummatory aspects of maternal behavior: when the appetitive aspects are depressed, consummatory nursing may increase. Importantly, since the MPOA is also essential for appetitive maternal responses, it may be linked with the mesolimbic DA system in controlling such responses. These studies on the mesolimbic DA system do not distinguish between the involvement of the different DA receptors in NA for maternal behavior control. D1 and D2 receptors are typically located on different neurons in NA and in the general case D1 receptors are positively linked to the cAMP-PKA intracellular signaling cascade while D2 receptors are negatively linked to this second messenger system [88,99]. In a recent study, we set out to determine the relative importance of D1 and D2 receptors in NAs for the occurrence of proactive voluntary maternal responses in post- Author's personal copy M. Numan, D.S. Stolzenberg / Frontiers in Neuroendocrinology 30 (2009) 46–64 c a 8 1200 a b 6 900 b 4 600 a 300 2 0 10 Latency to retrieve all to nest (sec) – Meaan (+SE) # pups retrieved 52 15 Baclofen doses (ng/0.3ul) Fig. 7. A baclofen injection site into the ventral tegmental area (left) and the effects of such injections on retrieval behavior in postpartum rats (right). Data are shown as Means + standard errors. For each retrieval measure, groups with different letters differ significantly. SN, substantia nigra; IP, interpeduncular nucleus. partum rats [120]. We made use of a standard D1 receptor antagonist, SCH 23390, and a standard D2 antagonist, eticlopride. Pregnant rats were implanted with bilateral cannulas aimed at NAs and on days 3, 5, and 7 postpartum various doses (0, 1, 3 lg) of either the D1 or the D2 antagonist were microinjected and the effects on maternal behavior were examined. In this study, retrieval tests were 2 h long and a 15 min nursing observation occurred during this period between 45 and 60 min after the start of the retrieval test. The results indicated that eticlopride microinjections into NAs had no effect on either retrieval behavior or nursing behavior. These females typically retrieved all six of their pups back to their nests in less than 5 min and then began nursing the litter after retrieval completion. In contrast, compared to females receiving the 0 lg dose, both the 1 and 3 lg dose of SCH 23390 into NAs disrupted retrieval behavior without affecting total nursing duration. Females treated with the 1 lg dose completed retrieval of all their pups in about 45–60 min while females that received 3 lg completed retrieval in about 2 h. These females behaved like the females that received baclofen in the VTA: they would approach the displaced pups and either nurse them outside the nest without retrieving them, or they would retrieve one or two pups to the nest and then begin nursing for long durations after which they might return to the displaced pups and retrieve additional pups to the nest and then nurse again before coming back out to retrieve more pups. This similarity with the Bac-VTA data supports the proposal that baclofen was depressing retrieval behavior (but not nursing) by interfering with VTA–DA projections to NAs. These results indicate that DA action on D1 receptors in NAs is essential for appropriate retrieval behavior. Although DA action on D2 receptors in NAs does not seem essential for effective pup retrieval in postpartum females, it is certainly possible that higher doses might have been effective (see [120]). In this regard, it has been reported that injection of pimozide, another D2 antagonist, into NA disrupts maternal behavior in postpartum rats [160]. This latter study is difficult to interpret because the pimozide and control injections were not administered in a counterbalanced order. In addition, pimozide has other neural effects that are independent of its effects on D2 receptors (see [120]). The neural model presented in Fig. 6 includes the MPOA and VP. In this regard, note that NA, VP, and MPOA are spatially located close to one another. In addition, the VP receives a DA input from VTA [72], and the MPOA gets diencephalic DA input from the incerto-hypothalamic DA system [161,181]. We [120] wanted to show that microinjection of SCH 23390 into NAs disrupted retrieval behavior because of action on NAs and not because of spread to either VP or MPOA. We found that injection of 1 and 3 lg of SCH 23390 into VP had no effect on maternal behavior. In comparing NAs with MPOA, it was found that while 1 and 2 lg of the D1 antagonist into NAs disrupted retrieval behavior, these doses had no effect when applied to MPOA. A 3 lg dose of SCH 23390 in NAs caused a major disruption of retrieval behavior, while the same dose, when applied to the MPOA, caused a slight disruption in retrieval. These latter results are shown in Fig. 8. Overall, these findings indicate that NAs is a major site where SCH 23390 acts to disrupt the proactive voluntary components of maternal behavior. In accord with our findings, Miller and Lonstein [97] have reported that microinjection of a 1-lg dose of SCH 23390 into MPOA does not disrupt maternal behavior in postpartum rats. These authors also found that a 5-lg dose into MPOA caused a significant disruption of retrieval behavior without interfering with nursing. These results suggest that in postpartum females small doses of a D1 antagonist in NA effectively disrupt maternal behavior, while higher doses are needed at the level of the MPOA to disrupt retrieval behavior. However, we cannot rule out the possibility that the disruptive effects on retrieval behavior of high dose SCH 23390 injection into MPOA might be due to spread of the drug to NAs. We will return to this issue later when we explore the facilitatory effects of a D1 receptor agonist on the onset of maternal behavior. Our results indicate that DA action on D1 receptors in NAs is necessary for effective maternal responsiveness in postpartum rats. The model in Fig. 6 proposes that DA action on NA functions to depress NA output to VP, in this way facilitating VP activity through a process of disinhibition. What is the evidence for this view? The central point is that our model proposes that VP output, rather than NA output, is needed for effective maternal behavior. In support of this perspective, we have found [121] that either electrical lesions of NAs or microinjections of muscimol into NAs do not interfere with normal maternal behavior in postpartum rats. Muscimol is a GABA-A receptor agonist which would cause a temporary inactivation of NA neurons, which are known to contain GABA-A receptors [153]. Therefore, although DA action on D1 receptors in NA is important for maternal behavior, the evidence just described indicates that DA is not acting to facilitate NA output and is consistent with the idea that DA is depressing NA output. In support of the view that DA action on NA releases the VP from NA inhibition, we have found that an intact VP is necessary for normal postpartum maternal behavior in rats. Either excitotoxic amino acid lesions of VP or muscimol injections into VP disrupt maternal behavior, and the primary effect is on retrieval behavior [112,121]. With respect to the relationships between DA, NA, and VP in the regulation of maternal behavior, our data lend support to the model shown in Fig. 6. However, this model is certainly an oversimplification since the anatomy of the internal circuitry and efferent projections of NA are much more complex than indicated in the figure (see Section 11). If the model were a completely accurate reflection of the regulation of maternal behavior, one would expect to be able to facilitate maternal behavior after inactivation of NA. Let’s examine this issue more closely. In our study [121] neither Author's personal copy 53 Ó American Psychological Association 2005 M. Numan, D.S. Stolzenberg / Frontiers in Neuroendocrinology 30 (2009) 46–64 Fig. 8. Cumulative mean (+SE) number of pups retrieved to the nest at different time points during a 2-h retrieval test for postpartum females that received 3 lg of the D1 dopamine receptor antagonist SCH 23390 into either the medial preoptic area (MPOA) or nucleus accumbens (NA). Asterisks indicate a significant difference (t-test) from the corresponding MPOA group. Reproduced with the permission of the American Psychological Association, from Numan et al. [120]. electrical lesions nor muscimol injections into NAs affected maternal behavior in postpartum rats. Maternal behavior in this case may not have been facilitated because of a ceiling effect. Interestingly, Li and Fleming [84] have presented data that appear to be in conflict with the model shown in Fig. 6. They found that NAs electrical lesions slightly disrupted retrieval behavior in postpartum rats, suggesting that the output of NA is essential for completely normal retrieval behavior. In particular, they found that while control females retrieved all their pups to their nests in about 2 min, NAs-lesioned females took about 10 min to do so. This very mild deficit should be contrasted with the retrieval deficits observed after SCH 23390 injection into NAs, where females can take over an hour to complete retrieval. As already mentioned, SCH 23390-treated females tend to retrieve some pups and then ignore the rest while engaging in nursing behavior. In contrast, in the Li and Fleming study, the females with NAs lesions would retrieve some pups but then get distracted by other stimuli and would engage in rearing, sniffing, and feeding. This distraction effect, where many stimuli become salient, slightly lengthened retrieval latencies. One conclusion is that NAs-lesioned females are too reactive to a wide range of external stimuli, whereas SCH 23390-treated females are less reactive, and such an analysis generally fits with the model shown in Fig. 6. If inactivation of NA does increase behavioral reactivity to a wide range of external stimuli, it might be possible to show that such inactivation would stimulate maternal behavior if the proper animal model were employed. For example, perhaps muscimol application to NAs would facilitate the onset of maternal behavior in suboptimally hormone primed female rats, such as the 15HO female. This particular experiment has not been performed, but related work is presented in Section 8 of this paper. Please note, however, that lesions or muscimol application to NAs are likely to depress all NA neurons, but in order to facilitate maternal responsiveness, it may be necessary to selectively depress only those neurons which contain D1 receptors. 7. MPOA interaction with the mesolimbic DA system and the regulation of maternal responsiveness MPOA lesions, baclofen injections into VTA, and interference with DA action on D1 receptors in NAs all cause similar disruptions in maternal behavior: retrieval is disrupted while nursing behavior is relatively intact and may even be enhanced. These behavioral data suggest a functional link among these structures. We will now review the more substantive evidence linking MPOA output to the mesolimbic DA system in the control of maternal behavior. We will describe the anatomical evidence and the behavioral evidence supporting this linkage. The anatomical evidence can be outlined as follows: (1) Anterograde tract tracing studies have shown that iontophoretic application of PHAL (Phaseolus vulgaris leucoagglutinin) to MPOA/vBST labels a strong projection from this region to the VTA [51,118,163]. (2) In a double-labeling anatomical study, Numan and Numan [119] showed that MPOA/vBST neurons which express cFos during maternal behavior project to VTA. (3) Fahrbach et al. [40] showed that estradiol binding neurons in MPOA/vBST project to VTA. (4) Lonstein et al. [85] found that a significant proportion of neurons within MPOA/vBST which express cFos during postpartum maternal behavior in rats also contain intracellular estrogen receptors (estrogen receptor alpha). These results suggest that MPOA/vBST neurons whose phenotype is altered during maternal behavior and which are also responsive to estradiol (a steroid which acts on MPOA to stimulate the onset of maternal behavior) project strongly to VTA. A final important finding indicates a functional–anatomical linkage between MPOA output and mesolimbic activity during maternal behavior. It has been found that cFos is expressed in NAs during maternal behavior in postpartum rats [85,165]. When MPOA/vBST neurons are lesioned with an excitotoxic amino acid on only one side of the brain, maternal behavior continues normally in postpartum rats because bilateral lesions are necessary to substantially disrupt maternal behavior. However, these unilateral MPOA/vBST lesions completely eliminate the cFos response during maternal behavior in the ipsilateral NAs, while Fos activation is still present at high levels in NAs on the side of the brain contralateral to the MPOA/vBST lesion [165]. These results suggest that an active MPOA/vBST is necessary for the cFos expression in NAs that is associated with maternal behavior. Since DA action on D1 receptors in NA can cause cFos expression [61,102,144], these results are consistent with the view that MPOA/vBST output to VTA stimulates DA release into NAs with an action on D1 receptors. Although cFos expression has usually been conceived of as related to increases in neural activity, this is not necessarily the case [60]. Perhaps DA action on D1 receptors in NAs is exerting a neuromodulatory effect that is partially mediated by Fos expression and the subsequent altered phenotype of NAs neurons renders them less responsive to excitatory inputs derived from BLA and PFC see [108,126]. Two studies have provided important neurobehavioral evidence for an interaction between MPOA/vBST and aspects of the mesolimbic DA system in postpartum rats. In an early study, Numan and Smith [125] used an asymmetrical lesion design to present evidence for such an interaction. This study was based on the knowledge that bilateral damage to MPOA output circuits is needed to severely disrupt maternal behavior. Postpartum rats that received unilateral knife cuts severing the lateral connections of MPOA/vBST paired with contralateral electrical lesions of the VTA showed severe deficits in the proactive voluntary components of maternal Author's personal copy 54 M. Numan, D.S. Stolzenberg / Frontiers in Neuroendocrinology 30 (2009) 46–64 behavior (retrieving and nest building). Females with a variety of control lesions, including unilateral MPOA knife cuts paired with ipsilateral VTA lesions, showed relatively normal maternal behavior. The interpretation of these results is limited by the fact that nonspecific lesioning procedures were used that damaged both neuronal cell bodies and axons of passage through the critical regions. In a more recent study with an asymmetrical lesion design that employed excitotoxic amino acid lesions, Numan et al. [121] showed that when selective destruction of MPOA/vBST neurons on one side of the brain was paired with contralateral excitotoxic amino acid lesions of VP, retrieval behavior, but not nursing, was severely disrupted. Control females, which included females with ipsilateral lesions, showed relatively normal maternal behavior (see Fig. 9). Importantly, females with contralateral MPOA-VP cell body specific lesions showed normal hoarding behavior and general activity levels. Although these two studies did not selectively manipulate DA neuron activity, the findings, when taken in the context of the other work we have reviewed, adds excellent support for the view that MPOA/vBST interactions with the mesolimbic DA system is important for the appetitive aspects of maternal behavior. 8. Activation of the mesolimbic DA system promotes the onset of maternal behavior in pregnancy-terminated rats We have shown that depression of MPOA output disrupts, while hormonal stimulation of the MPOA facilitates, maternal behavior. We have also shown that interference with the mesolimbic DA system or with MPOA interactions with VTA–NA–VP circuits disrupts maternal behavior. To strengthen the case we are trying to make, it would also be important to show that activation of the mesolimbic DA system is capable of promoting maternal responsiveness. To examine this issue, Stolzenberg et al. [168] employed the 15HO pregnancy termination model because the maternal responsiveness of these females is partially or suboptimally primed (see Fig. 1). Such females show sensitization latencies of 2–3 days instead of the typical 7 days observed in naïve virgin females. In Contralateral MPOA-VP Ipsilateral MPOA-VP MPOA MPOA MPOA MPOA VTA VTA VTA VTA NA NA NA NA VP VP VP VP Disrupted Retrieval Behavior Normal Retrieval Behavior Fig. 9. Diagrammatic representation of the neural pathways between medial preoptic area (MPOA) and ventral pallidum (VP) which shows that when unilateral MPOA damage is paired with contralateral VP damage, retrieving behavior is disrupted in postpartum rats. Ipsilateral damage to these two nuclear regions are ineffective. NA, nucleus accumbens; VTA, ventral tegmental area. Axons ending in an arrow signify excitation while those ending in a bar indicate inhibition. Based on data from Numan et al. [121]. our first experiment we examined whether microinjection of a D1–DA receptor agonist, SKF 38393, into NAs could reduce the sensitization latencies of 15HO females. Recall that our neural model proposes that the endocrine events of late pregnancy prime MPOA/vBST so that it becomes fully responsive to pup stimuli, which allows MPOA activation of VTA–DA input to NA. As shown in Fig. 10, in the 15HO female that is partially primed because estradiol is not administered at the time of HO, MPOA efferents to VTA may not be fully activated by pup-related stimuli. However, if we were to add D1 stimulation to NAs, we predicted that we would mimic a fully active MPOA and produce full maternal behavior. 15HO females were presented with pups 48 h following HO. On days 0, 1, and 2 of behavioral testing, females received microinjections into NAs of either 0, 0.2, or 0.5 lg (in 0.5 ll of sterile water) of SKF 38393. Freshly nourished pups were presented daily and full maternal behavior was recorded as having occurred if a female retrieved all pups to a common nest site, hovered/crouched over the pups, and groomed them on two consecutive days. Behavioral testing was terminated after 5 days for those females that did not show maternal behavior. Some of the results are shown in Fig. 11. The 0.5 lg injection of the D1 agonist into NAs clearly facilitated maternal behavior: 90% of such females were showing full maternal behavior by the second day of testing (after 24 h of pup exposure), while this was true for only about 33% of females receiving the 0 lg dose. Subsequent experiments in this series [168] showed that injection of quinpirole (a D2 agonist) into NAs did not facilitate maternal behavior in 15HO females, emphasizing the importance of D1 receptors, as did our postpartum work with DA antagonists. Importantly, we also provided evidence for the anatomical specificity of our results, since SKF 38393 microinjection into the caudate/putamen, which receives DA input from the substantia nigra, did not facilitate maternal behavior. With respect to the proposal presented in Fig. 10, it should be noted that once maternal behavior was initiated after D1 agonist application to NAs, the behavior continued normally or was maintained even when SKF 38393 application to NAs was terminated. Once a female begins to interact with her pups in a maternal fashion, it is possible that this experience reorganizes the MPOA so that it becomes fully responsive to pup stimulation, thus allowing it to effectively activate the VTA. It is then no longer necessary to apply SKF 38393 to NAs since the reorganized MPOA presumably allows for increases in endogenous DA release into NA. This perspective is likely related to the well known dichotomy between the onset and maintenance of maternal behavior in rats, where hormones promote the onset of the behavior but are not required for its maintenance. Once a female begins to show maternal behavior, neural mechanisms are modified so that pup stimuli can activate the relevant circuits in the absence of continued hormonal mediation. Because of the importance of the MPOA for maternal behavior, and because the MPOA contains DA terminals from the incertohypothalamic DA tract, and the periventricular preoptic area contains DA cell bodies [161], Stolzenberg et al. [168] explored the possibility that SKF 38393 might also act on MPOA D1 receptors to stimulate maternal behavior in 15HO females. We found that the 0.5 lg dose of the D1 agonist stimulated maternal behavior in a manner similar to that observed after the injection of that dose in NAs. Therefore, it is likely that DA action on D1 receptors in either NAs or MPOA can stimulate maternal behavior in 15HO females see (see [126]). However, it is also possible that the facilitatory effect observed after injection of SKF 38393 into MPOA was actually the result of the spread of the drug to NAs. More work needs to be done to resolve this issue. The fact that SKF 38393 injections into the dorsal striatum were ineffective in stimulating maternal behavior suggests that spread from the injection site Author's personal copy 55 M. Numan, D.S. Stolzenberg / Frontiers in Neuroendocrinology 30 (2009) 46–64 Full Hormone Regimen + Pups NA Partial Hormone Regimen + Pups MPOA MPOA NA VTA VTA Full maternal behavior with 0-1 day sensitization latencies Partial stimulation of maternal behavior with 2-3 sensitization latencies Partial Hormone Regimen + DA Agonist + Pups NA MPOA VTA Full maternal behavior with 0-1 day sensitization latencies Cumulative % maternal 100% 80% 60% vehicle 40% 0.2 20% 0.5 0% 0 1 3 2 Days 4 5 Ó American Psychological Association 2007 Fig. 10. Diagrammatic neural model representing how exogenous dopamine (DA) receptor agonist application to the nucleus accumbens (NA) might facilitate maternal behavior in females exposed to suboptimal hormone levels. The diagram on the left shows that when the medial preoptic area (MPOA) is fully primed with the relevant hormones, MPOA efferents to the ventral tegmental area (VTA) effectively activate endogenous DA release into NA so that full maternal behavior occurs. The center diagram shows the case where the female is suboptimally primed with hormones. Pup stimuli are less effective in activating MPOA efferents to VTA, less DA is released into NA, and maternal responsiveness is incomplete. However, as shown on the right, if the suboptimally primed females are also microinjected with a DA D1 receptor agonist into NA, it is predicted that they would show full maternal behavior. Fig. 11. Cumulative percentage of pregnancy-terminated female rats showing full maternal behavior on each test day. Females received bilateral microinjections of either 0, 0.2, or 0.5 lg of SKF 38393 (a dopamine D1 receptor agonist) into the nucleus accumbens on days 0, 1, and 2 of testing (indicated by arrows on the abscissa). Asterisk indicates a significant difference from the 0 lg group, Fisher exact probability test, p < .05. Reproduced with the permission of the American Psychological Association, from Stolzenberg et al. [168]. may not be an important concern. Some additional support for an action of SKF 38393 on MPOA in the facilitation of maternal behavior comes from Woodside’s group. In postpartum rats during the maintenance phase of maternal behavior, it was found that LNAME [a nitric oxide synthase (NOS) inhibitor that blocks the synthesis of the gaseous neuromodulator nitric oxide (NO)] injection into the MPOA disrupted retrieval behavior, but that this effect could be reversed by coinjection of SKF 38393 with L-NAME [154,155]. These results suggest that NO systems interact with DA action on D1 receptors within MPOA to regulate the occurrence of proactive voluntary retrieval responses in postpartum rats. As we will see in Section 9, evidence indicates that NO enhances the synaptic availability of DA within MPOA [37]. Therefore, based on the use of both D1 agonists and antagonists (see Section 6), the overall evidence suggests that DA action on D1 receptors in either the NAs or MPOA is involved in both the onset and maintenance of maternal behavior in rats [97,154,155,168]. To the extent that D1 agonists promote maternal behavior by an action on either MPOA or NA, it is likely that the intracellular and/ or intercellular mechanisms mediating these effects are different. MPOA output is essential for maternal behavior. In contrast, we have proposed that NA output must be depressed for active maternal responses to occur. Therefore, D1 agonists in MPOA should promote the activity of output neurons (to the VTA, for example), while D1 agonists in NAs should ultimately depress output to VP. These different outcomes could potentially arise from different sites and/or mechanisms of action within each region, for example, from a direct effect of DA on the output neurons in one of the regions and a direct effect of DA on local circuit neurons (interneurons) within the other region. 9. Relevance of D1 stimulation of the onset of maternal behavior for an understanding of estradiol stimulation of maternal behavior In reference to Fig. 1, note that 15HO females typically show sensitization latencies of 2 days. In contrast, if such females are injected (sc) with 20 lg/kg of EB in oil at the time of HO and presented with pups 48 h later, typical sensitization latencies are 0 days (most females are maternal on their first day of pup exposure). Interestingly, Fig. 11 indicates that if 15HO females are injected with SKF 38393 into NAs beginning 48 h after HO and 20 min prior to pup presentation, then such females show sensitization latencies of 0.5 days. In a subsequent study where the D1 agonist was injected into either NAs or MPOA, 0 day sensitization latencies were observed for both groups [168]. These results indicate that D1 agonist injection into either NAs or MPOA at the time of pup presentation can substitute for the stimulatory effects of EB, which is typically administered 48 h prior to pup presentation. In studies employing the pregnancy termination model, EB has always been administered at the time of HO. Such a procedure was most likely adopted because of the assumption that estradiol was exerting classical genomic transcription effects which would take some time to develop. Our results with D1 agonists, however, raise the possibility that EB injection at the time of HO may have been exerting some or all of its stimulatory effects at the time of pup presentation. Such a possibility, of course, depends on whether EB remained in the circulation for 48 or more hours. Another implication of the fact that D1 agonist injection can substitute for EB is Author's personal copy 56 M. Numan, D.S. Stolzenberg / Frontiers in Neuroendocrinology 30 (2009) 46–64 Cumulative % maternal that the underlying mechanisms through which estradiol stimulates maternal behavior onset may share some similarities with the mechanisms through which D1 agonists exert facilitatory effects. The following points suggest that EB injection (sc) at the time of HO may have been exerting some direct effects at the time of pup presentation. The use of EB (rather than free estradiol) in oil is likely to result in the long-term slow release of EB from the subcutaneous depot, so that physiological levels of the steroid would probably be present 48 h later [34]. Numan [105] and Numan et al. [123] showed that when 15HO females are injected subcutaneously with 20 lg/kg of EB at the time of HO, vaginal cytology indicated that an estrogenized pattern was observed up to 7 days post-injection. Finally, in MPOA implant studies, where application of either EB [123] or estradiol [41,42] facilitated maternal behavior in females, the estrogen implants were in place in MPOA up to the time of pup presentation. In order to test the hypothesis that estradiol may be acting on the brain at the time of pup presentation, we have undertaken the following study [169]. Female rats were HO on day 15 of pregnancy. Pups were presented to these females beginning 48 h post HO. On days 0 and 1 of testing, 1 h prior to pup presentation, females were injected subcutaneously with either 0, 20, or 100 lg/ kg of a water soluble form of 17-b-estradiol in a cyclodextrin/physiological saline vehicle solution [34,177]. This estradiol is likely to be cleared from plasma within 24 h of each injection see [34]. We found that both the 20 and 100 lg/kg dose of estradiol facilitated maternal behavior, and that the higher dose was more effective. Subsequent findings from this series of experiments showed that a single injection of 100 lg/kg of 17-b-estradiol on day 0 of testing was just as effective as when the estradiol was administered on both days 0 and 1. These data are shown in Fig. 12, which indicates the cumulative percentage of females showing maternal behavior across test days in the 0 and 100 lg/kg groups. In comparing Figs. 11 and 12, it can be seen that there is a remarkable similarity in the facilitation of maternal behavior that is observed in 15HO females after either SKF 38393 application to NAs or subcutaneous estradiol injection, with both compounds being administered at the time of pup presentation, rather than on day 15. Importantly, we found that when virgin female rats were HO and presented with pups beginning 48 h post-HO, the 100 lg/kg dose of the water soluble form of estradiol was not effective in stimulating maternal behavior when injected on day 0 of behavioral testing (48 h post-HO). These results suggest that prior expo- * 100 80 60 40 20 0 1 2 3 4 5 Days Fig. 12. Cumulative percentage of pregnancy-terminated female rats showing full maternal behavior on each test day. Females received a subcutaneous injection of either 100 lg/kg of a water soluble form of 17-b-estradiol (dashed line) or the cyclodextrin-physiological saline vehicle solution (solid line) on day 0 of testing, 1 h before pup presentation. Asterisk indicates a significant difference from the vehicle group, Fisher exact probability test, p < .01. sure of the brain to the hormones of pregnancy, which would include progesterone withdrawal, is necessary for estradiol to exert acute stimulatory effects on the onset of maternal behavior when it is administered at the time of pup presentation. Finally, when either 100 or 20 lg/kg of the water soluble form of estradiol was administered (sc) on day 15 of pregnancy, it was ineffective in stimulating maternal behavior. Under this schedule the estradiol was most likely cleared from the system by the time of pup presentation, emphasizing the need for estradiol action at that time for the development of a rapid onset of maternal behavior. Several important reviews have been written which describe the various ways in which estradiol has been found to exert its cellular effects [8,11,33,71,90,96,179]. The classical model is for estradiol to bind to intracellular estrogen receptors (ERs: ERa or ERb) which then exert transcriptional genomic effects through the binding of the estradiol-ER complex to the estrogen response element (ERE) in the promoter region of various target genes. This classical genomic model is conceived as producing changes in cellular phenotype which take some time to develop (several hours). However, researchers have also observed rapid cellular effects of estradiol which occur within minutes after exposure of a neuron to estradiol; these effects might be the result of the binding of estradiol to either a membrane bound ER or to an intracellular ER that is linked to second messenger cascades. It is likely that some of the ERs that mediate the rapid effects of estradiol on neuronal phenotype are chemically distinct from ERa or ERb. Importantly, the rapid nongenomic effects of estradiol may, in turn cause genomic/ transcriptional modifications through non-classical mechanisms. For example, estradiol that is bound to either a membrane or intracellular receptor may activate intracellular second messenger cascades which can have a dual action: the activation of intracellular kinases could phosphorylate cytoplasmic proteins to produce rapid effects but might also phosphorylate the cAMP response element binding protein (CREB), which would then affect the transcriptional activity of genes which contain a calcium/cAMP response element (CRE) in their promoter regions. With this brief background, we would like to propose some possible models to describe how estradiol and DA activation of D1 receptors in either MPOA or NA may share some common mechanisms in stimulating the onset of maternal behavior in 15HO female rats. Some of these models are based on the typical response of a cell to D1 stimulation: activation of the cAMP-PKA second messenger cascade. There is good evidence that MPOA/vBST contains ERa or ERb, while scant evidence exists that such receptors are present in NA [157,158]. Therefore, if estradiol exerts effects on the onset of maternal behavior through an action on NAs, it is likely to do so via a mechanism that does not utilize ERa or ERb. Implant studies do suggest that the primary site of action of estradiol in stimulating maternal behavior is the MPOA. However, some of these studies did not utilize anatomical controls [41], and in the studies that did so [42,123], the control estradiol implant sites were in brain regions caudal to MPOA. Since NA is about 1 mm rostral to MPOA, it is possible that estradiol implants into MPOA which stimulated the onset of maternal behavior were at least in part effective because of diffusion of the estradiol to NA. No one has explored the effects of estradiol application to NAs on the onset of maternal behavior in 15HO females. The evidence already reviewed shows that SKF 38393 application to MPOA at the time of pup presentation and estradiol application to the MPOA, which may also be acting at the time of pup presentation, are capable of stimulating maternal behavior in 15HO females. We would like to outline some possibilities which suggest that these effects may share some common underlying mechanisms (also see [126]). These models are not mutually exclusive and estradiol and DA may be exerting multiple effects to fully promote maternal responsiveness. Author's personal copy M. Numan, D.S. Stolzenberg / Frontiers in Neuroendocrinology 30 (2009) 46–64 1. Gangolli et al. [50] have presented evidence for ligand-independent activation of the intracellular ER. Importantly, they show that D1 agonists can activate the ER through a cAMP-PKA phosphorylation cascade. It is interesting to speculate that either estradiol or DA release into MPOA may be capable of activating ERa, and that these two effects complement one another and may substitute for one another to facilitate the initiation of maternal behavior. 2. Opioid action on the l opioid receptor and GABA action on GABA-A or GABA-B receptors in MPOA inhibits maternal behavior in rats [4,16]. Lagrange et al. [75] and Qiu et al. [143] have shown that 17-b-estradiol can rapidly (<20 min) decrease the ability of l-opioids and GABA-B agonists to hyperpolarize hypothalamic neurons. The mechanisms through which estradiol exerts these effects include activation of the cAMP-PKA cascade. Perhaps D1 agonist application to MPOA can duplicate some of these possible estradiol effects on MPOA neurons, in this way reducing inhibition on MPOA neurons and therefore stimulating MPOA output (to VTA and other regions). Other studies have also shown that estradiol is capable of rapidly activating neurons via a cAMP cascade [54,98]. 3. Several studies have shown that estradiol is capable of rapidly (15–30 min) activating CREB phosphorylation in preoptic region neurons [1,55,187]. Perhaps D1 agonists can substitute for this effect and perhaps the genomic effects of CREB phosphorylation in MPOA/vBST contribute to the onset of maternal behavior in rats. The involvement of genomic effects is supported by an examination of the data in Fig. 12, where it can be seen that most 15HO females treated with estradiol at the time of pup presentation do not show maternal behavior until day 1 of testing. Of course, both genomic and nongenomic effects may influence maternal behavior onset. It should be noted that CREB knock-out mice show deficits in maternal behavior [63]. 4. A final possibility is suggested by the work of Dominguez and Hull [37] on male sexual behavior, and the findings of Service and Woodside [154,155] on maternal behavior. Through genomic and/or nongenomic mechanisms, estradiol may activate NOS (see [132]). Subsequent NO production in MPOA may enhance the synaptic availability of DA. In the absence of estradiol, direct application of D1 agonists to MPOA may substitute for estradiol’s ultimate effect and stimulate the onset of maternal behavior in 15HO rats. With respect to the fact that D1 agonist microinjection into NAs can also substitute for the effects of estradiol in stimulating the onset of maternal behavior in 15HO females, the most likely explanation is that outlined in Fig. 10: estradiol action on MPOA/vBST, through genomic and/or nongenomic mechanisms, stimulates MPOA output to VTA. In the absence of estrogen stimulation of MPOA output, D1 agonist injection into NAs replicates the estradiol-MPOA effect. However, we would also like to present some evidence which raises the possibility that estradiol and DA may both act on NAs to stimulate the onset of maternal behavior. First, note that there is evidence that estradiol can act directly on NA to influence reproductive behavior and motivational processes [48,182,185]. Second, direct application of estradiol to NA neurons can potentiate the release of DA into NA [175,176]. One model that has been offered is that estradiol in NA activates a second messenger cascade which dampens the effectiveness of the dopamine transporter, in this way potentiating the synaptic availability of DA. If this were the case with respect to maternal behavior, then D1 agonist application to NA could directly substitute for the missing estradiol effect. 57 10. Oxytocin, DA, and maternal behavior We have mapped out a neural circuit which regulates the onset and maintenance of proactive voluntary maternal behavior in rats. The purpose of this section is to show that neural oxytocin may act at critical nodes in this circuit to foster maternal responsiveness. The main source of oxytocinergic neural projections within the brain (rather than to the neurohypophysis) is from parvocellular parts of the PVN [36,76,172]. However, scattered OT neurons have also been found in MPOA [64,139]. The current view, with some qualifications, is that the release of oxytocin into the brain of the parturient female is essential for the initiation of maternal behavior in rats and other species, but once maternal behavior becomes established during the maintenance phase of maternal behavior, oxytocin neural systems are no longer essential [108,114]. For example, Insel and Harbaugh [62] showed that PVN lesions performed during pregnancy disrupted the onset of maternal behavior in rats while Numan and Corodimas [111] showed that similar lesions were without effect when performed during the postpartum maintenance phase of maternal behavior. Similarly, when OTR antagonists (OTA) are injected ICV, they eliminate the onset but not the maintenance of maternal behavior [38,137,139]. Finally, ICV injections of OT stimulate the onset of maternal behavior in estradiol-primed rats [38,135]. Similar effects of OT on the onset of maternal behavior have been observed in sheep (see [114]). Although OT neural systems are not essential for the continuance of maternal behavior during the maintenance phase of maternal behavior, recent studies have shown that during this period OT modulates or fine tunes the kinds of maternal behaviors, and their intensity, that occur in postpartum females: ICV injections of OTA decrease both the licking/grooming of pups and certain types nursing postures, although the total amount of time nursing pups is not affected [27,136]. Takayanagi et al. [173] produced a transgenic mouse line with a null mutation of the OTR gene. Parturient mice with this knock-out mutation showed deficits in retrieval behavior, but general nursing behavior appeared normal (the pups could not obtain milk because of the disruption of the milk-ejection reflex). Because of the retrieval deficit, although total nursing duration was not affected, the number of pups that were nursed was decreased. These effects are similar to that observed after MPOA lesions, suggesting that OT may interact with MPOA–VTA neural circuits to promote the onset of active maternal responses in parturient rats. Both the MPOA and the VTA contain OTRs and mRNA for the OTR, the PVN projects to both MPOA and VTA, and estradiol and the other endocrine events that occur near the time of parturition act to increase the expression of OTRs in these two critical brain regions [9,27,74,93,94,138,162,178]. Interestingly, Melis et al. [94] report that OT injection into VTA promotes DA release into NA and that this effect is blocked by concurrent injection of OTA into VTA. Most importantly, Pedersen et al. [138] showed that microinjection of OTA into either the MPOA or into the VTA was capable of disrupting the onset of maternal behavior in naturally parturient rats. In contrast, Pedersen et al. [139] found that similar injections into the VTA did not disrupt ongoing maternal behavior in postpartum rats during the maintenance phase of the behavior. Therefore, parturient events which stimulate the release of OT into the MPOA and VTA are likely to exert modulatory effects on the MPOA-toVTA circuit which, in the context of the other hormonal and neurochemical events that we have already described, promote the onset of proactive voluntary maternal responses toward infant stimuli. After a female interacts with her pups for a critical amount of time, it is proposed that the MPOA becomes reorganized in some way so that pup stimuli alone can now activate MPOA output to VTA with- Author's personal copy 58 M. Numan, D.S. Stolzenberg / Frontiers in Neuroendocrinology 30 (2009) 46–64 out the continued need for OT, estradiol, and prolactin effects. The only qualification is that OT action on MPOA may remain necessary for the occurrence of high levels of pup licking/grooming by the postpartum mother during the maintenance phase of maternal behavior [27]. D1 agonist injection into MPOA appears to promote the onset of maternal behavior in 15HO rats. To what extent are OT neural systems involved in this effect? Several possibilities come to mind. In the absence of estradiol, it is likely that OTR expression in MPOA is not at maximal levels, since estradiol activates OTR expression in MPOA [27]. Perhaps, as suggested by Chamapagne et al. [27], D1 agonists activate the ER in a ligand-independent manner [50] so that the expression of OTR in MPOA is increased in spite of the lack of estradiol administration. Another possibility along these lines also exists: the OTR gene contains a CRE and therefore a D1/ cAMP/PKA cascade may substitute for estradiol to activate OTR expression [6,7,59]. Another possibility should also be considered. Perhaps D1 agonist injection into MPOA is actually stimulating OT release. The anterior parvocellular PVN is located just caudal to MPOA. It has been reported that microinjection of D1, but not D2, agonists into this PVN region promote the release of OT from the neural lobe of the pituitary in lactating rats [35,134]. In the suboptimally hormone primed 15HO female, OT release within the brain may not be sufficient to promote the rapid onset of maternal behavior. Perhaps SKF 38393 microinjection into MPOA resulted in spread of the drug to the rostral PVN and caused OT release into MPOA and VTA, in this way stimulating the rapid onset of maternal behavior in the absence of estradiol treatment. Note that dual effects may be occurring here: SKF 38393 may increase OTR expression in MPOA as previously proposed and may also cause OT release into MPOA. A final study on prairie voles is important to mention [128,129]. In adult virgin prairie voles, about 50% of females are spontaneously maternal toward pups, while the remainder avoid pups. This difference was correlated with higher levels of OTR expression in NAs of the spontaneously maternal females. Importantly, when OTA was injected into NAs, none of the virgin females showed spontaneous maternal responses. These results indicate that OT acts on NAs to promote maternal responsiveness in prairie voles. These results may be relevant to rats, since OTRs are located in NAs of rats [129,180], raising the possibility that in addition to OT action at the level of MPOA and VTA, there may be a DA–OT interaction in NAs which regulates maternal responsiveness in rats. The fact that a D1/cAMP/PKA cascade can regulate OTR expression in certain brain regions [6] is also relevant to these considerations. 11. Consolidation of maternal responsiveness Although the hormonal events associated with the end of pregnancy are necessary for the rapid onset of maternal behavior at parturition in primiparous rats (as well as in parturient females of other species), once female rats have had a critical amount of postpartum maternal experience their future maternal responsiveness becomes less dependent upon hormonal stimulation even when they have been separated from young for long periods of time (for reviews, see [113,114]). The seminal studies describing this process were done by Bridges [12–14]. Primiparous rats were allowed 1 or 2 days of postpartum maternal experience with their pups and then the pups were removed for 25 days. When young pups were returned to these mothers after these 25 days, sensitization tests indicated onset latencies of 1–2 days. In contrast, if pups were removed from primiparous females at birth, so that the initial maternal experience was minimal, 25 days later sensitization tests indicated onset latencies of 5 days, which did not differ significantly from the sensitization latencies of naïve virgin females. Sub- sequent work by Orpen and Fleming [130] showed that this maternal experience effect was dependent upon proximal contact with young at the time of parturition; distal pup stimuli were ineffective in facilitating future maternal responsiveness. These results show that an initial maternal experience in primiparous rats partially emancipates their future maternal responsiveness from the control of pregnancy hormones. Full emancipation does not occur, as such females typically do not show immediate maternal behavior, but instead require 1 or 2 days of pup exposure before becoming maternal. This experiential influence on maternal responsiveness has been referred to as either maternal memory or the maternal experience effect. We will also refer to this process as the consolidation of maternal responsiveness. The consolidation of maternal responsiveness indicates that some kind of maternal experience-induced synaptic plasticity occurs within the neural circuits that underpin maternal behavior so that pup stimuli can more effectively activate these circuits in the absence of pregnancy hormone mediation. At first glance, this process appears similar to the fact that the onset, but not the maintenance, of maternal behavior is dependent upon hormones. A critical difference exists however. During the maintenance phase females remain in proximal contact with their pups, and as already reviewed, hormones are not needed for the display of the behavior during this period. However, the maternal memory work shows that one can separate females from their pups for long periods of time after a critical amount of maternal experience, and subsequent maternal responsiveness is still facilitated in the absence of pregnancy hormones. Although the neural modifications underlying the maintenance of maternal behavior may be the same as those which are involved in maternal memory (see [114]), there may also be some important differences. Pedersen et al. [139] showed that OTA injection into VTA did not disrupt maternal behavior in postpartum rats as long as the mothers remained in proximal contact with their young. However, similar injections into the VTA did disrupt the rapid re-emergence of maternal behavior if females were separated from pups for several days. These results suggest that alterations in the ability of pup stimuli to activate oxytocinergic input to VTA (and perhaps also MPOA) may be necessary for the expression of maternal memory, but is not necessary for the maintenance of maternal behavior. The results also indicate the involvement of the mesolimbic DA system in the expression of maternal memory, which should not be surprising since this system is critical for both the onset and maintenance of maternal behavior. What are the neural changes which mediate the maternal experience effect? Although many possibilities have been reviewed [114], we will emphasize the involvement of DA systems. In reference to Fig. 5, as a result of a prior maternal experience, there may be a downregulation of the withdrawal/avoidance system so that pup stimuli are less likely to activate avoidance behavior (see [114]). Alternatively, with respect to Fig. 6, there may be a permanent upregulation of MPOA sensitivity so that pup stimuli can more easily activate the MPOA-to-VTA circuit in the absence of pregnancy hormones, even after a long period of mother-pup separation. Perhaps OT input to the MPOA and VTA enables this activation. Afonso et al. [2] have provided some support for this latter possibility. Female rats either had prior maternal experience or were naïve virgins. Microdialysis probes were implanted into NAs and females were transferred from their home cages to a microdialysis chamber, where they were exposed to pups for a short period of time. Although none of the females showed maternal behavior in the chamber, the experienced females released more DA into NAs. One interpretation of these findings is that as a result of a prior maternal experience the MPOA is reorganized in some way so that it can be activated by pup stimuli without pregnancy hormone mediation, and the activated MPOA, in turn, Author's personal copy 59 M. Numan, D.S. Stolzenberg / Frontiers in Neuroendocrinology 30 (2009) 46–64 stimulates mesolimbic DA input to NAs. A complicating factor in this study was that although maternal behavior was not shown, the experienced females sniffed the stimulus pups more. Therefore, the increased DA release could have been due to the increased sniffing/investigatory behavior, which may not have been caused by MPOA stimulation of DA release. This study did not inform us as to whether the DA increase occurred prior to or after the sniffing responses, which would be important to know. A voltammetry analysis could have provided that kind of data [28]. A final possibility, which we will explore in some detail, is that the consolidation of maternal responsiveness occurs because of synaptic changes within some components of the mesolimbic DA system independent of any changes in MPOA; these changes would then allow the mesolimbic system to function effectively despite a decreased stimulation from MPOA efferents. Research from Fleming’s lab has shown that activation of NAs is necessary for the consolidation of maternal responsiveness [81,83]. Electrical lesions or sham lesions of either the NAs or the NA core (NAc: the NA region lateral to NAs) were performed during pregnancy and females were allowed to give birth and engage in maternal behavior with their pups for 12–24 h. All females showed normal maternal behavior at this point. After this maternal experience session, all females were separated from their pups; 10 days later young pups were reintroduced to these females and sensitization testing began. Females in the sham lesioned groups and in the NAc lesioned group showed evidence of a consolidation of maternal responsiveness with sensitization latencies of about 2 days. In contrast, females with lesions of NAs acted like naïve virgins and had sensitization latencies of about 7 days. In an additional experiment it was shown that when the NAs lesions were performed 24 h after a maternal experience the consolidation of maternal responsiveness occurred normally: such lesioned females had short sensitization latencies when tested 10 days after the initial maternal experience. These results indicate that although the NAs is necessary for the formation of maternal memory, the actual neural modifications which underlie this memory occur in a brain region outside NAs. In a final experiment [133], it was shown that both D1 and D2 DA receptors in NAs are involved in the establishment of maternal memory. Primiparous females gave birth and were allowed only 1 h of postpartum maternal experience. Immediately thereafter, they were microinjected into NAs with either SCH 23390 (D1 antagonist), sulpiride (D2 antagonist), flupenthixol (D1/D2 antagonist), or control injections. Females injected with either sulpiride or flupenthixol demonstrated an interference with the full consolidation of maternal responsiveness when sensitization tests were begun 10 days later, and the disruptive effect was greatest in those females injected with the mixed D1/D2 antagonist. Therefore, although D1 antagonism alone, at the dose and time administered, did not appear to disrupt the formation of maternal memory, it did enhance the disruptive effect caused by D2 antagonism. The neural model shown in Fig. 6, along with supporting evidence, suggests that NAs output neurons must be suppressed (to activate VP) in order for maternal behavior to occur. Some of the work reviewed above conforms with this view as NAs lesions did not interfere with the initial onset of maternal behavior when performed prior to parturition and did not interfere with a rapid onset of maternal behavior in experienced females if the lesions were performed 24 h after the maternal experience. Clearly, an intact NAs is not necessary for the performance of maternal behavior [121]. Yet the results from the Fleming group indicate that an active NAs is essential for the consolidation of maternal responsiveness in a neural region outside NA and that D1 and D2 receptors seem to act together to foster this consolidation effect. How can we account for these results? A simple neural model is presented in Fig. 13 in an attempt to show that the positive involvement of NAs output in the consolidation of maternal responsiveness can be consistent with the view that DA–D1 activity operates to depress NAs output so that maternal behavior can occur (for an alternate model, see [108]). The model is based on the following facts: (1) The output of the NA is complex and its efferents project to regions other than VP [140]; (2) The internal circuitry of the NA is complex and although most NA neurons are GABAergic output neurons, there is a significant population of inhibitory local circuit neurons which can exert strong and widespread inhibitory effects on the output neurons [73]; (3) DA action on D1 and D2 receptors is usually conceived as exerting opposite cellular effects, but the D1 and D2 receptors are also viewed as being located on different neurons in NA [52,88,144]; (4) Local circuit neurons as well as output neurons in NA contain DA receptors [3,25,68,151,152]. The simplified model should not be taken as a factual representation of NA involvement in maternal behavior; it is meant to present a possibility which would be consistent with the data we have reviewed. In this model we only show DA receptors on interneurons although such receptors are also located on the output neurons and on presynaptic terminals. In the model we show that when MPOA is activated by hormones and pup stimuli, it activates DA–D1 input to NAs, which stimulates inhibitory interneurons, which ultimately strongly disinhibit VP. In parallel, MPOA activated DA input into NA is shown to suppress the responsiveness of inhibitory interneurons via D2 receptors, which increases the activity of a population of output neurons which function to inhibit a hypothetical (and unknown) region which we have called a consolidation brake region. This braking region is shown as inhibiting VP. The proposal is that when the VP is disinhibited from both NA output (via D1 receptors) and from the consolidation brake via the action of DA on D2 receptors, the synapse relaying pup-related stimuli to the VP from BLA and/or PFC is strengthened. In the future, when the MPOA is not being affected by hormones and therefore may less effectively activate the VTA in response to pup stimuli, its smaller disinhibitory effect on VP is still effective because of the strengthened synapse. The mechanism of this model attempts to explain Hormones + Pup stimuli DA D2 NA D1 MPOA VTA Consolidation Brake Pup stimuli VP Maternal Behavior BLA PFC Fig. 13. A neural model which attempts to show how medial preoptic area (MPOA) stimulation of the mesolimbic dopamine (DA) system might be important for both the activation of proactive maternal responses and for the process referred to as maternal memory. The model also attempts to explain why nucleus accumbens (NA) lesions do not block maternal behavior but do interfere with the consolidation of maternal memory. MPOA efferents to the ventral tegmental area (VTA) are shown as activating two separate DA inputs to NA: one to a neural circuit containing D1 dopamine receptors (shown in black) and the other to a circuit containing D2 dopamine receptors (shown in white). In the model, DA receptors are only shown on NA interneurons, although in reality they also exist on NA output neurons. The synapse from the basolateral amygdala/prefrontal cortex (BLA/PFC) to the ventral pallidum (VP) which is encompassed by a dashed circle is the synapse that is proposed to be strengthened by a maternal experience of sufficient duration. Axons ending in an arrow = excitation; those ending in a bar = inhibition. See text for operational details. Author's personal copy 60 M. Numan, D.S. Stolzenberg / Frontiers in Neuroendocrinology 30 (2009) 46–64 why NAs lesions made prior to an initial maternal experience do not disrupt maternal behavior but do disrupt the consolidation of maternal memory. It is argued that under hormonal stimulation and during the maintenance phase, deactivation of NAs does not disrupt maternal behavior, possibly because of strong BLA/PFC input to VP under high motivational conditions and because of disinhibition of VP by the NA depression. However, after a long period of separation from pups, which may result in pup stimuli becoming less salient, a rapid onset of maternal behavior does not occur, although sensitization latencies consistent with that of naïve females do occur, because the indicated synapse has not been permanently strengthened. 12. Experiential factors and natural variations in the maternal behavior of mammals: possible effects on MPOA-to-VTA circuits and a window into the mechanisms which might contribute to maternal neglect in humans A final issue to discuss is the relevance of the work we have reviewed for the human condition. The neural model we have developed from rodents may be defining a core neural circuitry for maternal behavior in mammals. Species may differ in the degree to which pregnancy hormones stimulate maternal behavior and in the degree to which inexperienced females show avoidant responses toward infants (see [114]), but the neural circuits which regulate proactive voluntary maternal responses, which include MPOA, VTA, NA, and VP located in the phylogenetically older parts of the brain, are likely to contribute to maternal responsiveness in most mammals, including primates. A disruption in the operation of these circuits may be one of the factors which contributes to pathological disorders associated with maternity in humans. In this context, the concept of intergenerational continuity or transmission of maternal responsiveness in mammals is important to consider. With respect to child abuse or neglect by human mothers, evidence indicates that there is a cycle of violence and that those children who have been abused or neglected by their parents tend to become abusive or neglectful parents themselves (see [26,65,89,114]). Early primate research by Harlow’s group [150] showed that rhesus monkeys raised without their mothers showed poor maternal behavior toward their own young. Maestripieri [89] has found that infant abuse naturally presents itself in about 10% of normal populations of rhesus monkey mothers and that such abuse is a stable characteristic of the affected mothers and occurs with each birth. Significantly, the daughters of such abusive mothers are likely to also abuse their own offspring. To determine whether this familial pattern of maternal abuse in rhesus monkeys is due to genetic or experiential transmission, Maestripieri [89] conducted a cross-fostering study. The results showed that the exposure of infants to either a biological or foster abusive mother increased the probability that the exposed offspring would abuse their own young in adulthood. Importantly, infants born to known abusive mothers but cross-fostered to non-abusive mothers did not develop the abuse phenotype. These results [89,150] suggest that early adverse experiences, in these cases either maternal abuse or neglect (maternal deprivation), can act on the brain of the young primate to cause it to show poor maternal behavior in adulthood. Maternal deprivation studies in rodents have yielded similar, although less severe, effects [53,87,95]. Complete maternal deprivation of female rats during early life results in adult females who can raise their own young, although nursing and licking of pups is decreased to a large degree. Interestingly, the consolidation of maternal responsiveness does not occur in such females [82]. Early adverse social rearing conditions could undoubtedly disrupt adult maternal responsiveness by affecting the develop- ment of multiple neural mechanisms which might include: (1) an increase in the activity of neural regions regulating fearand anxiety-related behaviors [22–24]; (2) the development of a dysfunction in the mesolimbic DA system [92]; (3) a decrease in the activity in MPOA output circuits that regulate maternal behavior [26]. Our focus will primarily be on the last mechanism and will include a brief review of the rodent research from the laboratories of Meaney and Champagne which suggests that early experiences between an infant and its mother can modify the development of the infant’s hypothalamus, and in particular, the projections between the MPOA and the mesolimbic DA system. The Champagne and Meaney research does not examine the effects of early adverse experiences on the development of maternal behavior but, instead, examines the development and neural underpinnings of natural variations in normal maternal behavior in rodents. Rat mothers show individual differences in the intensity of their maternal behaviors [29]. In particular, some mothers, referred to as high licking and grooming (HLG) females, spend more time during the first postpartum week licking/grooming their offspring when compared to low licking and grooming (LLG) mothers. Although all mothers raise their young to weaning, one interpretation of these results is that HLG dams are more attentive to their young than are their LLG counterparts. Table 1 shows some of the neural correlates of these differences in maternal behavior: HLG dams have more ERs [31,32] and OTRs [27,30,46] in MPOA, greater release of DA into NA during maternal behavior [28], and more D1 DA receptors in NA [28] than do LLG females. These results fit with a view that HLG mothers are more attentive to their young because the greater number of ERs and OTs in MPOA has the ultimate effect of allowing pup stimuli to more effectively activate MPOA-to-VTA circuits. Since all HLG and LLG mothers care for their young and raise them to weaning, what is being described is variations in a neural circuit which could give rise to individual differences in maternal behavior. Table 2 shows that some of these individual differences in maternal behavior and neural organization are due to the type of maternal environment experienced by infant females. Infant females raised by HLG biological or foster mothers become HLG females in adulthood and they also have more ERs in MPOA, and the opposite occurs for females raised by biological or foster LLG mothers [29,31]. It is highly likely that a similar experiential effect influences the development of OTRs in MPOA [30]. In addition to experiential factors, genetic factors also contribute to variations in maternal behavior. The Flinders sensitive line (FSL) of rats has been used as a genetic model of depression [131]. In this context, note that postpartum depression in humans is associated with faulty maternal behavior (for review, (see [114]). Postpartum FSL rats show deficits in retrieval behavior, nursing behavior, and pup licking/grooming [47,77]. Interestingly, a microdialysis study found that in comparison to postpartum Sprague– Table 1 Individual differences in the intensity of rodent maternal behavior are correlated with individual differences in the neural circuitry of maternal behavior. Neural phenotype Type of mother High LG Low LG ERs in MPOA OTRs in MPOA DA release in NA D1 DARs in NA High High High High Low Low Low Low The data were derived from the following sources: [27,28,30–32,46]. Abbreviations: DA, dopamine; DARs, dopamine receptors; ERs, estrogen receptors; LG, licking/grooming; MPOA, medial preoptic area; NA, nucleus accumbens; OTRs, oxytocin receptors. Author's personal copy 61 M. Numan, D.S. Stolzenberg / Frontiers in Neuroendocrinology 30 (2009) 46–64 Table 2 Effect of maternal environment on the characteristics of adult rodent offspring. Phenotype of adult offspring Maternal environment Raised by biological mother Maternal behavior ER expression in MPOA OTR expression in MPOA Cross-fostered HiLG LoLG HiLG-to-LoLG LoLG-to-HiLG HiLG High High LoLG Low Low LoLG Low — HiLG High — The data were derived from the following sources: [29–31]. Abbreviations: ER, estrogen receptor; HiLG, a mother that licks and grooms her offspring at a high level; LoLG, a mother that licks and grooms her offspring at a low level; HiLG-to-LoLG, offspring born to HiLG moms but cross-fostered to LoLG moms on day 1 of life; LoLG-to-HiLG, offspring born to LoLG moms but cross-fostered to HiLG moms on day 1 of life; MPOA, medial preoptic area; OTR, oxytocin receptor. Note: Although the data on OTR expression in MPOA of cross-fostered young is not available, other evidence suggests that it should be modulated in the same direction as ER expression in MPOA. That is, since estradiol increases OTR expression, females with higher ER expression are expected to have higher OTR expression (also see [30]). Dawley control rats, FSL rats showed decreased release of DA into NA during maternal behavior [78]. The implication of these findings is that by studying the underlying mechanisms which cause variations in maternal behavior, one might gain insight into how extreme adverse early life events such as maternal abuse, neglect, and/or deprivation might affect the brain of offspring so that truly faulty maternal behavior develops. In humans, it is likely that gene-environment interactions are important, and it is possible that under certain genetic backgrounds one of the significant effects of exposure of a young infant to maternal abuse and neglect could be the severe disruption of MPOA output circuits and/or the mesolimbic DA system. 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