Frontiers in Neuroendocrinology

Frontiers in Neuroendocrinology 28 (2007) 115–141 www.elsevier.com/locate/yfrne Review Regulation of anxiety during the postpartum period

Joseph S. Lonstein *

Neuroscience Program & Department of Psychology, Giltner Hall, Michigan State University, East Lansing, MI 48824, USA

Available online 2 June 2007

Abstract

Healthy mother–infant interactions are critical for the physical, cognitive, and psychological development of offspring. Such interac- tions rely on numerous factors, including a positive maternal emotional state. However, many postpartum women experience emotional dysregulation, often involving elevated anxiety. Neuroendocrine factors contributing to the onset of postpartum anxiety symptoms are mostly unknown, but irregularities in hypothalamic–pituitary–adrenal axis function, reduced prolactin and oxytocin signaling, or par- turitional withdrawal of ovarian, placental and neural steroids could contribute to anxiety in susceptible women. Although the causes of initial onset are unclear, postpartum anxiety can be mitigated by recent contact with infants. Numerous neurochemical systems, includ- ing oxytocin, prolactin, GABA, and norepinephrine mediate this anxiolytic effect of infant contact. Insight into the etiology of postpar- tum anxiety disorders, and how contact with infants helps counter existing anxiety dysregulation, will surely facilitate the diagnosis and treatment of postpartum women at risk for, or experiencing, an anxiety disorder. Ó 2007 Elsevier Inc. All rights reserved.

Keywords: Anxiety disorder; Breastfeeding; Hormones; Lactation; Maternal behavior; Neuropeptides; Nursing; Postpartum depression; Psychopathol- ogy; Stress; Suckling

1. Introduction are normal, but for some women lead to a postpartum mood disorder that often involves elevated anxiety. The prospect of becoming a mother for the first time, or The goals of this review are to provide an overview of re-experiencing the joys of a newborn baby, elicits pleasant the literature on the neural, endocrine, and neuroendocrine anticipation and great exhilaration in many women. factors influencing postpartum anxiety in women and lab- Indeed, becoming a mother is considered by some to be oratory rodents. The neurochemical events precipitating the most significant and rewarding of human experiences, increased anxiety after parturition are virtually unknown, and most women show stable or increased levels of positive although there are many likely contributors. Nonetheless, mood during late pregnancy and the early postpartum per- females are provided a natural stimulus that can help pre- iod. In many cases, this positive change in mood includes vent such increases—the infant. Contact with infants is decreased anxiety [12,54,94,128,152,170,227,234,241,386, anxiolytic in both women and laboratory rats, and under- 396,451]. This same life event, however, has tremendous standing the biological factors contributing to this phe- potential to be physically and psychologically distressing nomenon is a primary goal of our research. [209]. Issues regarding personal appearance and health, This review will focus on postpartum anxiety, with the health of the fetus and infant, increased demands on time realization that there is greater colloquial acknowledge- and energy, maintenance of interpersonal relationships, ment of postpartum depression, even though postpartum and the ability to adequately care for the neonate are fre- women are more likely to be anxious than depressed quent concerns [151,214,149,208,300,316]. Such concerns [465]. Even while considering postpartum depression, it is critical to recognize that it is rarely a unidimensional disor- der and is frequently associated with elevated anxiety * Fax: +1 517 432 2744. [29,31,36,201,369,412,465]. In fact, peripartum anxiety is E-mail address: [email protected]. a very strong predictor of later postpartum depression

0091-3022/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.yfrne.2007.05.002 116 J.S. Lonstein / Frontiers in Neuroendocrinology 28 (2007) 115–141

[36,204,371,412,426,427], and anxiety accounts for much of effects on their children. Anxiety is higher in mothers at the variance on the widely used Edinburgh Postnatal risk for or already abusing their infants [103,320,466], Depression Scale [63,369,426,427]. It is reasonable to and is associated with reduced likelihood of breastfeeding believe that a better understanding of postpartum anxiety [31,84,108,156,164,397], delayed physical growth [31,334], could help prevent a trajectory toward postpartum depres- delayed cognitive [86,165] and social development [165], sion for some women. Readers specifically interested in the reduced touching and speaking to the infant [485], irregu- etiology and treatment of postpartum depression, and how larities in mother–child interactions and attachment it is influenced by infant contact and lactation, are referred [5,31,282,314,444,477], and increased propensity for anxi- to other recent sources [43,106–108,153,195,222,223,235, ety and other psychiatric disorders in the children of moth- 291,295,296,346,353,366,385,470,488]. ers with elevated anxiety [32,207,294,335,476]. Given the high incidence rate of postpartum anxiety and its negative 2. Frequency and effects of postpartum anxiety dysregulation effects on child development, many researchers have con- cluded that increased attention to this type of postpartum Accurately determining the rate of anxiety disorders in emotional disorder is desperately needed [201,288,370, postpartum women is problematic. Numerous studies indi- 391,465,485]. cate that anxiety disorders afflict parturient women at a rate quite similar to the one-month or one-year incidence 3. Neurochemical contributions to high postpartum anxiety found for non-parturient women (5–12%) [16,29,85,92, 255,288,318,360,367,369,370,412,449]. Furthermore, high The neurobiology underlying why millions of women postpartum anxiety can often be predicted by a woman’s experience elevated anxiety after giving birth is poorly prepartum history of anxiety disorders, low psychological understood. Although it is only broad indication, a litera- resiliency, and socioeconomic disadvantage [54,62,204, ture search of Medline-indexed, non-review articles on 449,465]. These factors also predict anxiety in non-postpar- humans published over the past 38 years using the keyword tum people [see 62,263], so one might conclude that there ‘‘anxiety’’ with either ‘‘postpartum’’ or ‘‘lactation’’ reveals are no triggers for anxiety dysregulation specific to the only approximately 500 articles. In contrast, the number of postpartum period. That is, a woman’s predisposition for articles indexed on Medline with the keywords ‘‘anxiety’’ high trait anxiety and low resiliency leads to increased like- and ‘‘men’’ exceed 41,000. The rodent literature is even lihood of high anxiety whenever life stress is high, as is typ- more scant, with fewer than 55 Medline-indexed articles ically the case when caring for an infant. In this scenario, using the keywords ‘‘anxiety’’ and ‘‘rat’’ with either ‘‘post- anxiety disorders during the postpartum period might have partum’’ or ‘‘lactation’’. Nonetheless, some possibly unique similar biological underpinnings as anxiety disorders dur- neuroendocrine contributors to elevated anxiety during the ing any other time of a woman’s life. peripartum period are proposed below. The relative impor- This view of postpartum anxiety is probably incorrect. tance or degree of independence among them are not sug- Numerous studies report the onset of some types of anxiety gested, as a psychological phenomenon as complex as disorders during the postpartum period in women with no postpartum anxiety dysregulation surely has a large num- previous history of such disorders [11,62,204,279,370,391, ber of interacting and overlapping determinants. 393,465]. Furthermore, the rate of anxiety dysregulation at clinical or sub-clinical levels in postpartum women is 3.1. Prolactin and oxytocin probably much higher than the general population because the likelihood of detecting elevated anxiety in postpartum High prolactinergic or oxytocinergic activity is stress women is very low [85]. Additionally, elevated anxiety is relieving and anxiolytic in non-postpartum animals and particularly prevalent in women who experienced preg- humans [14,28,117,158,199,284,293,364,435,447,472,473]. nancy complications, gave birth prematurely, delivered a Considering that one of the hallmarks of lactation is low birthweight infant, or are caring for an infant with a increased pituitary gland release of the peptides prolactin birth defect [61,135,205,231,249,350,469,485]. These (PRL) and oxytocin (OT), which are necessary for milk women may not only be less willing to participate in studies production and letdown, it is not unexpected that numer- of postpartum emotional regulation, but are sometimes ous studies have attempted to correlate levels of these pep- purposely excluded from them. They give birth to approxi- tides with anxiety in parturient women. Indeed, low plasma mately 10% of the 4 million infants born each year in the PRL [21,182,330,464] and OT [330,448; although see 200] United States [100,286], further indicating that the reported titers are associated with higher anxiety in lactating and rate of elevated anxiety or diagnosable anxiety disorders in even non-lactating women, as is irregularity in peptide syn- postpartum women is significantly underestimated. In fact, thesis and breakdown [275]. the actual rate may be greater than 20–25% [61,85,275]. A potential problem interpreting these and other data Understanding the factors underlying postpartum anxi- correlating plasma peptide levels with anxiety is only ety is critical because increased anxiety in mothers, even at between 1% and 5% of many peptides circulating in blood sub-clinical levels and independent of comorbidity for plasma cross the blood–brain-barrier [130,131]. Plasma depression, has highly detrimental and long-term [166] PRL enters the central nervous system via transporter J.S. Lonstein / Frontiers in Neuroendocrinology 28 (2007) 115–141 117 proteins [136,460], resulting in cerebrospinal fluid levels on the HPA axis [20,225]. Even if this was possible, CRH that are positively correlated with plasma levels antagonists do not universally inhibit anxiety-related [9,22,23,285; however, see 349]. Levels found in individual behaviors in laboratory rats, and CRH effects on anxiety brain sites, however, are neither correlated with plasma lev- may be specific to the intensity, context, and innately anx- els nor affected by hypophysectomy, at least in laboratory iogenic properties of a stimulus [303]. If the same is true for rats [127,433]. Oxytocin does not readily cross into the women, postpartum anxiety disorders associated with par- brain [130,131] and, needless to say, blood levels often do ticular triggering stimuli or experiences—such as phobias, not correlate well with brain levels [9,13,15,422]. There is panic, or post-traumatic stress disorder—might be the no evidence that the blood–brain-barrier is weakened by most affected by intracerebral CRH activity [365]. pregnancy and lactation [341,421], so measuring peripheral PRL and OT, and probably most other peptides, may not 3.3. Estrogens, progestins, and neurosteroids readily contribute to our understanding of how peptides affect the neural networks regulating anxiety. Ovarian and placental steroids fluctuate dramatically PRL and OT are released not only from the pituitary during the peripartum period in women, with estrogens gland into the general circulation, but also intracerebrally and progestins high during late pregnancy, and then pre- from PRL- and OT-synthesizing neurons of the hypothal- cipitously falling at parturition [264,402]. Steroid hormones amus that project to widespread areas of the brain of peripheral origin readily enter the brain and have the [82,163,347,392,401,418,487]. Activity of these central pro- capacity to affect postpartum mood by directly affecting jections is probably far more important for anxiety than cellular activity and function [161,178,437,455], and indi- peripheral peptide release. Central PRL or OT levels in rectly by influencing neurotransmitters systems modulating postpartum women are unknown, but CSF measures of anxiety, including serotonin, norepinephrine, dopamine, OT do not differ between late-pregnant and non-pregnant and GABA [e.g., 17,37,38112,133,206,244,343]. women [9,421], while PRL is elevated during late preg- Surprisingly, there is little evidence for the involvement nancy [9]. In any case, unless samples are taken both before of ovarian hormones in the etiology of persistent postpar- and after the onset of postpartum anxiety symptoms, it tum anxiety. Progesterone has been reported to be inver- would be very difficult to ascertain whether low basal levels sely related to anxiety [464], but many other studies of OT or PRL could be a cause or effect of womens’ anxi- report no significant correlations between circulating pro- ety. It is also reasonable to consider that abnormal peripar- gesterone or estrogens and either anxiety or other mood tum fluctuations in PRL or OT, rather than only basal states after the first few postpartum days [21,65,194,197, levels of these peptides, could be responsible for elevated 201,331,337,338,371]. Steroid hormones readily cross the anxiety. blood–brain-barrier, but similar to peripheral peptides, plasma levels do not necessarily reflect what is bioavailable 3.2. Hypothalamic–pituitary–adrenal hormones to the central nervous system. Steroid hormone binding proteins in plasma and cerebrospinal fluid render steroids Hypo- or hyper-activity of the hypothalamic–pituitary– inactive, and these binding proteins are influenced by adrenal (HPA) axis has received considerable attention for reproductive state in human and non-human primates, a causitive role in emotional dysregulation in peripartum with levels of the estrogen-sequestering a-fetoprotein and and non-peripartum women [76,210,222,287,295,324, other steroid-binding proteins particularly high during late 325,365]. Women’s HPA axis response to stressors is sup- pregnancy and at parturition [230,237,240,446]. Further- pressed during late pregnancy [111,222], which is partly more, steroid hormone binding protein levels are lower in due to high placental release of corticotropin-releasing hor- CSF than plasma [134], so even if total hormone levels were mone (CRH) dampening maternal CRH release [287]. This similar in each compartment, bioactive hormone levels suppression may continue during the early postpartum per- might not. Correlations between unbound levels in plasma iod [277], but the lack of such HPA suppression could lead and cerebrospinal fluid also depend on womens’ reproduc- to postpartum hyperarousal and anxiety [3,20,441]. Fur- tive state, at least for progesterone [99]. It seems that mea- ther hyperarousal could result from HPA activation reduc- suring total levels of peripheral hormones, rather than ing the anxiolytic effects of other neurochemicals, such as unbound levels, and correlating them with mood states ovarian steroids [454]. across different reproductive states in women is limiting Studies exploring the association between peripheral [337,338]. measures of HPA responsiveness and anxiety symptoms Rather than basal hormone levels, the magnitude of in lactating and non-lactating postpartum women have change in ovarian hormones across late pregnancy and been inconsistent, though [8,60,115,123,182]. There are the early postpartum period may instead be crucial for also discrepancies in whether the HPA axis during the early mothers’ anxiety [193,331,337,338]. Some women are postpartum period is suppressed [198,200,443]. It would be particularly susceptible to the mood-altering effects of more insightful, but clearly more difficult in humans, to hormone fluctuations across the menstrual cycle [42], evaluate CRH projections that could directly influencing and Rubinow and Schmidt suggest that their suscep- neural sites medating anxiety, independent of an influence tibility could be due to differences in the expression in 118 J.S. Lonstein / Frontiers in Neuroendocrinology 28 (2007) 115–141 polymorphisms for genes controlling steroid hormone It is unexpected, then, that the drop in allopregnanolone receptor expression and function [374]. Whether this is in parturient women is unrelated to of their emotional state directly relevant to recently parturient women is unknown [129], and that parturition increases depressive-like behav- because they experience months of elevated progesterone iors [162], but not anxiety-like behaviors in rats. The appar- and estradiol followed by their decline, compared to the ent lack of effects of neurosteroid withdrawal on anxiety in relatively short duration of high steroid levels and declines women may be because they all experience the withdrawal, across a menstrual cycle. In any case, a relationship but only some are susceptible to its effects on mood. between the magnitude of steroid hormone change across In parturient rats, Kellogg and Barratt [226] hypothe- the peripartum period and womens’ depressive symptom sized that anxiety-related behaviors do not increase in par- has sometimes been found [169,331,337,338,380], but as turient rats because suckling by pups elicits high far as I am aware, a relationship with their anxiety has progesterone release in mothers [183,425,432], thereby pro- not. tecting them from the anxiogenic effects of withdrawal of Even if the magnitude of change in ovarian hormones progesterone and its neuroactive metabolites. This is incon- across the peripartum period is found to intensify anxiety, sistent with the reduction in anxiety during lactation, how- using a naturally pregnant and parturient rat model to ever, because anxiety is highest during late lactation when study its cellular or molecular causes would be problematic maternal plasma progesterone is also at its highest because the endocrine profile of parturient rats differs from [265,352]. It is also inconsistent with Kellogg and Barratt’s that of parturient women. Unlike women, rats undergo a findings that conversion of progesterone into its reduced postpartum estrus, during which previously low estradiol metabolities was lower in lactating rats compared to levels sharply rise [91]. To avoid this surge in estadiol, virgins, that levels of reduced progesterone metabolites which itself is anxiolytic [161,437], some laboratories have did not correlate well with anxiety behaviors, and that examined anxiety after withdrawal of hormones from ste- administration of a 5a-reductase inhibitor further reduced roid-treated virgin rats or after ovariectomizing pseudo- anxiety in lactating females instead of increased it. pregnant females [41,399,472]. Another endocrine Conversely, 5a-reductase inhibition does increase anxiety- dissimilarity between postpartum women and rats is that related behaviors in pregnant rats [283], hinting at differ- progesterone levels remain low in parturient women for ences between virgin, pregnant, and lactating rats in how weeks or months, particularly if the infant is regularly progesterone and its metabolites influence anxiety. breastfeeding [298], whereas suckling by rat pups increases Nonetheless, studies examining anxiety in non-parturi- maternal progesterone within 3 days after parturition to ent models reveal that terminating pseudopregnancy in rats levels as high as those found during late pregnancy by ovariectomy increases anxiety-related behaviors in the [183,425,432]. Because ovariectomy soon after parturition elevated plus-maze [41,399]. This is due to the rapid with- virtually eliminates circulating progesterone, but does not drawal of progesterone’s reduced metabolites acting on alter anxiety in female rats [188,265], this particular endo- the GABAA receptor, as well as changes in GABAA recep- crinological difference may not be as problematic. tor subunit configuration that render the receptor less sen- Steroid hormones released from peripheral endocrine sitive to positive modulators [40,167,399]. As noted above, glands are not the only source of steroids that could even- estradiol levels sharply increase to produce a postpartum tually be found to contribute to the onset of postpartum estrus in naturally parturient rats, and as discussed in detail anxiety disorders. Steroids synthesized within the brain below, interactions with pups release many non-steroidal either de novo or from peripheral substrates (i.e., neuroster- neurochemicals that reduce anxiety. Withdrawal of neuros- oids) have been implicated in numerous psychiatric disor- teroids after pregnancy or pseudopregnancy has the poten- ders, including some types of anxiety disorders [for tial to increase anxiety in rats, but this is apparently reviews see 35,118,411] and in womens’ perimenstrual counteracted by the anxiolytic effects of dams’ rising estra- mood swings [159,175,313,358,416,461; however, 381]. diol levels and the physical contact dams have with infants Plasma, hippocampal, and cortical levels of 3a-hydroxy- during and after parturition. 5a-pregnan-20-one (3a,5a-THP or alloprenanolone), a Even if neurosteroid levels are not associated with post- reduced metabolite of progesterone and a positive allosteric partum anxiety in susceptible women, some cell-surface modulator of the GABAA receptor, dramatically drops receptors affected by neurosteroids, including those for within 3 days after parturition in rats [90,162], and plasma GABA [89,280], NMDA [2,184], dopamine [25], and opi- levels in women remain low for at least 6 months after giv- oids [114,186,187], are upregulated or downregulated ing birth [129]. Plasma and cortical levels of another across pregnancy and lactation. Peripartum modulation reduced metabolite of progesterone, 3a,21-dihydroxy-5a- at the receptor level could contribute to heightened or pregnan-20-one (allotetrahydrodeoxycorticosterone, blunted neurosteroid sensitivity. Data from pregnant and THDOC), also fall at parturition in rats [90]. Sudden with- early postpartum rats indicate no such changes in GABAA drawal of neurosteroids, and subsequent absence of their receptor sensitivity to 5a-reduced steroids, at least in the enhancement of GABAA receptor function, could dramat- cortex [226]. ically increase neural excitability and lead to hyperarousal In sum, sufficient data do not yet exist to confidently and anxiety. support a role for neurosteroids in mediating the onset of J.S. Lonstein / Frontiers in Neuroendocrinology 28 (2007) 115–141 119 postpartum anxiety. There is ample evidence from non- reduced fear or anxiety, but instead, reduced attention to postpartum models, however, suggesting that some partu- or perception of the startle stimulus because dams were dis- rient women could be more susceptible to the anxiogenic tracted while they interacted with the pups. Other studies effects of abnormal basal levels of neurosteroids [52], fluc- where pups are present in the apparatus during testing tuations in these levels across the peripartum period, or might be open to similar interpretations [140,141,188, reproductive state-specific changes in neurosteroid affinity 346], but alternatively, could reveal how dams might at the level of their receptors [389]. respond when the litter is also directly under threat [109,474]. 4. Animal models of postpartum anxiety Maternal motivation and perception of the anxiogenic stimuli could be important factors contributing to mothers’ Given the detrimental effects of postpartum anxiety on anxiety state, but postpartum rats and mice are also less mothers and their children, understanding the underlying anxious than virgins in many paradigms even when pups neurobiology in an animal model would be greatly benefi- are not present during testing. These include acoustic star- cial. Similar to the reduced anxiety experienced by the tle [438], the open field [150,438], elevated plus-maze majority of postpartum women, most postpartum rats also [39,226,265], defensive burying of a electrified probe show decreased anxiety compared to non-parturient [352], punished drinking [140], and the light–dark box con- females. Also similar to women, reduced anxiety in post- flict test [276,308]. It is important to point out that numer- partum rats has been proposed to affect their ability to care ous studies have not found reduced fear or anxiety in for their offspring [150,192], and differences in the maternal lactating rats [44,138–140,326,328,345,352,394,405,482, behaviors displayed by presumed low-anxiety and high- 489]. Most, but not necessarily all, of these discrepancies anxiety mother rats have dramatic effects on the later phys- are probably due to procedural details. For example, our iology and behavior of offspring [71,73,80]. At least two laboratory has found that the amount of ambient light is complimentary and mutually informative paths of investi- critical for detecting the effects of reproductive state on gation have contributed to our understanding of postpar- behavior in the light–dark box. Differences between lactat- tum anxiety states in laboratory rodents. First, studying ing and diestrous females are found only under medium or the neurobiology responsible for why anxiety is reduced high-light conditions (600–1400 lux in white chamber), in most postpartum rats can provide insight into what but not under lower light conditions (15 lux in white could be awry in cases of elevated postpartum anxiety. Sec- chamber). This seems to be because diestrous females find ond, it has also proven useful to study cases of aberrantly the white chamber aversive only when it is intensely illumi- high-anxiety in rats, which one could do by comparing nated, while lactating rats do not find it aversive under any behavior and neurochemistry of the most anxious and least of our light conditions [308]. Other discrepancies probably anxious subjects within a larger sample of animals, or by result because different behavioral paradigms reveal differ- selectively breeding for high and low anxiety [47,327]. ent aspects of anxiety [307,345], some of which may be One of the first reports suggesting reduced anxiety in more sensitive than others to the effects of reproductive postpartum rats demonstrated that parturient females state. The timing of testing is also critical, as anxiety is would traverse an unfamiliar T-maze to retrieve pups, not reduced throughout all of lactation in rats, but only but that virgin females induced to act maternally due to within the first few days or weeks [265,352]. Another continuous exposure to pups (i.e., maternally sensitized) important issue is whether dams had recent contact with would not [57,59]. Although this could suggest that lactat- pups before testing, as removal of the litter prior to testing ing rats were less anxious or fearful of the T-maze, it could increases anxiety [265,325]. It is hopefully clear that, even alternatively suggest that they were simply more responsive though numerous studies have not been able to demon- than virgins to the sensory cues emanating from pups that strate that postpartum state reduces anxiety, changes in elicit retrieval. Indeed, sensitized virgins are as likely as lac- emotional state might be more readily observed when par- tating rats to leave the home cage and enter the T-maze ticular methodological details are considered. [407], but are less likely to then examine the two terminal In addition to current motherhood reducing anxiety, arms that may contain pups [59,407]. Degree of maternal there are long-term effects of parity on anxiety-related motivation is not only critical for how females respond to behaviors in rats. Females are less anxious in an elevated pups [see 267], but also how they respond to anxiogenic plus-maze and open field after giving birth and weaning a stimuli, as the presence of pups can override the effects of litter compared to inexperienced, virgin females [69,463]. an anxiogenic stimulus if mothers are sufficiently motivated Interestingly, these effects in the plus-maze were only found to contact infants [351]. A similar complication arises for when young, experienced females were tested during proes- interpreting the now ‘‘classic’’ study of postpartum anxiety trus, when ovarian hormones levels are relatively high by Hard and Hansen [192], in which they reported that lac- [69,70]. Age of the females is also a factor, because older, tating rats showed less freezing than virgins in response to primiparous, experienced females in constant estrous are a sudden acoustic stimulus. In this study, lactating rats more anxious than older, nulliparous ones [69], although only showed less freezing if their pups were also in the star- the opposite effect of age has also been reported [271].In tle chamber. This leads one to wonder if this result reflects the latter study, aged females were repeatedly tested in 120 J.S. Lonstein / Frontiers in Neuroendocrinology 28 (2007) 115–141 the elevated plus-maze, which may explain this discrepancy examine both the rats’ latency to escape after being placed because different trials in this paradigm measure different on the open arm, suggested to model panic, and their emotional states [147]. In any case, the effects of prior par- avoidance of the open arms after repeatedly being placed ity and motherhood on anxiety are due to ovarian hor- into closed arms, suggested to model generalized anxiety mones because they are eliminated by ovariectomy [69]. [181]. Stage of the estrous cycle affects female rats’ general- Given that ovarian hormones can be anxiolytic [161,437], ized anxiety-like behaviors (but not panic-like behaviors) in this result is surprising because these hormones are lower the elevated T-maze [180], demonstrating that this para- in young reproductively experienced females, not higher digm is sensitive enough to detect endocrine and neuroen- [58,69]. Even in light of lower circulating ovarian hor- docrine factors influencing anxiety, but it has yet to be mones, neural anxiety networks could be more sensitive utilized with postpartum rats. because of increased steroid hormone receptor expression [58], thereby leading to reduced anxiety in reproductively 5. Infant contact reduces anxiety in mothers experienced females. The diversity of behavioral paradigms detecting anxiety Given the importance of infant contact on almost all differences between mother and virgin rats greatly strength- aspects of postpartum physiology and behavior in mam- ens the validity of the anxiolytic effects of motherhood, and mals, it seems intuitive that infants would be intimately helps justify the use of laboratory rats as a model to study involved in regulating their mother’s anxiety. The human its underlying biology. It seems unclear, however, how ani- literature suggests that breastfeeding reduces anxiety and mal behavior in these paradigms corresponds to human increases positive mood in recently parturient women anxiety disorders. As noted in a recent discussion of this [4,182,196,200,305,448,452], implicitly or explicitly impli- issue [388], most animal models of anxiety involve conflict cating suckling and its hormonal and other neurochemical or threat, which has high face validity for almost all types concomitants in this reduction. Interpreting this literature of anxiety disorders in humans. Mapping animal models can be problematic for numerous reasons. First, not all onto specific symptoms particular to different types of studies consistently report a relationship between breast- human anxiety disorders, though, can be more difficult feeding and anxiety [7,10,224,309,447,464,465,467],even [388]. Postpartum women are most likely to experience if breastfeeding affects other measures of mood. Second, symptoms of obsessive–compulsive disorder (OCD; 20% some studies do not include a postpartum, but non-breast- of postpartum women), panic disorder (10% of postpar- feeding, control group that would really be necessary to tum women), and generalized anxiety disorder (6% of make such a claim; they instead use non-mothers as con- postpartum women) [370]. Paradigms that model aspects trols [196,304,448]. It cannot be determined if giving birth of these disorders in animals could be the most valuable and caring for an infant, rather than breastfeeding and lac- for understanding anxiety in postpartum women. tation, are the critical factors in these studies. One often- Numerous animal models of obsessive–compulsive dis- cited study that does include a non-breastfeeding control order have been developed, and include animals with group reports only marginally significant effects of breast- genetically or pharmacologically altered dopaminergic or feeding on anxiety, possibly due to very high variability serotonergic activity, and several behavioral models [for in bottlefeeding group [452]. Lastly, breastfeeding involves review see 220]. One simple behavioral model used is rats’ both skin-to-skin contact with the infant and suckling repetitive burying of innocuous marbles placed in the home inputs to the nipples. Bottlefeeding typically involves nei- cage, which is sensitive to pharmacological agents known ther. Without a control group controlling for the recent to treat general anxiety or OCD. Another model is the sig- physical contact with the infant, the relative importance nal attenuation model, in which rats are first trained to bar- of physical contact versus infant suckling remains press for food in the presence of a specific stimulus. After unknown. This is an important consideration, as both this training, the stimulus is repeatedly presented without suckling and non-suckling tactile stimulation from infants the opportunity for rats to barpress to obtain food. When increase neuropeptide and hormone release in women the levers and signaling stimulus are presented together [289,299]. In fact, one study that did include mothers again, but still without the possibility of obtaining food, who simply held their infants on their laps before anxiety rats will compulsively barpress. According to Joel [220], testing reported that their anxiety was similar to mothers this model has high face, construct, and predictive ability who just breastfed their infants [200]. Another problematic for OCD. Neither the marble-burying nor the signal atten- issue is that anxious women are less likely to breastfeed uation paradigms seem to have been used with lactating [88,344], leading one to wonder if higher anxiety in some rodents. bottlefeeding women is a cause or effect of their feeding The elevated T-maze paradigm is designed to address method. specific symptoms of human panic and generalized anxiety Using a clever design, two studies examined mood in disorders. The elevated T-maze is similar to an elevated women who were both bottlefeeding and breastfeeding, plus-maze, with the exception that there is one closed during or after these women fed their infant using one of arm and two open arms, instead of two arms of each type the methods. Modahl and Newton [309] reported that anx- [181]. The advantage of this paradigm is that one can iety was the same when these women breastfed as when J.S. Lonstein / Frontiers in Neuroendocrinology 28 (2007) 115–141 121 they had not recently fed their infant, but that anxiety in holeboard tests. Also in apparent support of a role for both cases was non-significantly lower than non-postpar- pup suckling in their mother’s anxiety, dams did not show tum women. Mezzakappa and Katkin [305] found that a reduced anxiety if, for the 4 h before testing, their pups bout of breastfeeding decreased negative mood (as mea- were encased in a wire mesh box that allowed transmission sured with the Positive and Negative Affect Scale; of just olfactory, visual, and auditory cues. Only if dams PANAS), but had no effect on positive mood, while bottle- could physically contact the pups did they show reduced feeding decreased positive mood, but did not affect nega- anxiety. tive mood. It remains unknown if the decrease in A critical experiment was necessary before we could negative mood after breastfeeding is specifically related to appropriately interpret these results. We needed to examine decreased anxiety or other dimensions of negative mood the effects of physical contact with pups in the absence of detected by the PANAS (e.g., depression). suckling. Surgical removal of the 12 teats (i.e., thelectomy) It seems that, although many studies report that most is a relatively non-invasive procedure that eliminates suck- new mothers are less anxious than non-mothers, the sen- ling by infants, but not other ventral somatosensory inputs sory underpinnings and cause-and-effect relationships they provide. Thelectomy had previously been used to remain unclear. Our laboratory has recently been investi- demonstrate that physical contact with pups, but not suck- gating the fundamental sensory determinants of reduced ling, can maintain essentially normal maternal behavior anxiety during lactation in laboratory rats [265]. Given and maternal aggression in lactating rats [290,406].We the gist of the human literature, we originally hypothesized found that thelectomy 24 h prior to testing, or even prior that suckling and consequent pituitary and ovarian hor- to mating, had no effect on elevated plus-maze behavior mone release were necessary for reduced anxiety in post- in postpartum dams [265, Fig. 2]. This conclusively demon- partum rats. We found that this was not the case. As strated that recent physical contact with pups was neces- assessed with an elevated plus-maze, one of the most fre- sary for reduced anxiety in mother rats, but suckling was quently used and pharmacologically reliable paradigms to not. This differs notably from the reduced responsiveness examine anxiety in rodents, we found that postpartum of the hypothalamic–pituitary–adrenal (HPA) axis to mothers did not show reduced anxiety throughout all of stressors during lactation [200], which clearly requires suck- lactation, but only during the first week after giving birth. ling by infants [442]. We do not yet know what types of By day 14 postpartum, their anxiety-related behaviors were non-suckling somatosensory inputs are required for similar to diestrous virgins [265]. Lactation and continual reduced anxiety in postpartum rats. Rooting in their dam’s suckling by pups, therefore, seemed to be insufficient for ventrum while searching for a nipple does have physiolog- reduced anxiety. We also found that dams separated from ical consequences for the mother [269,270,310,408], but their pups for as little as 4 h before testing showed greatly perioral stimulation that dams receive during interactions elevated anxiety [Fig. 1], indicating that the anxiolytic with pups may also be sufficient to reduce anxiety [315]. effects of infant contact are relatively transient. This was This series of experiments lead us to conclude that suck- consistent with data from the Neumann laboratory [noted ling was not the critical sensory factor reducing anxiety in in 325] indicating that separation from pups for 2 h before postpartum rats. Instead, physical interaction with infants testing increased anxiety in the elevated plus-maze and alone was sufficient to produce a temporary anxiolytic effect in mother rats. Our data are consistent with studies

Fig. 1. A 4-h separation (Sep.) from the litter increases dams’ anxiety- Fig. 2. Thelectomy (removal of the teats) has no effect on anxiety-related related behaviors in the elevated plus-maze (i.e., reduces the percentage of behavior in dams. Thelectomized and sham-operated dams spend a time spent in the open arms of the maze) to levels found in diestrous similarly greater percentage of time in the open arms of the elevated plus- virgins. Different letters above bars indicates statistically significant maze compared to diestrous virgins. Different letters above bars indicates differences between groups (p < 0.05). Modified from [265]. significant differences between groups (p < 0.05). Modified from [265]. 122 J.S. Lonstein / Frontiers in Neuroendocrinology 28 (2007) 115–141 showing that virgin female rats induced to be maternal modulate anxiety [179,445], and are two of probably many through contact with pups are less anxious, even though brain areas where infant contact increases intracerebral they are neither parturient nor lactating [141,351; but see PRLergic and reduces anxiety. 407]. This is also conceptually similar to the study noted High central OTergic activity is also anxiolytic in labo- above where simply holding an infant was associated with ratory rats and mice [28,293,364,472,473]. The recently reduced anxiety in postpartum women [200], indicating developed OT-knockout mouse lends support for an that general somatosensory inputs from infants may be important role for OT in anxiety states, as virgin female an effective modulator of anxiety in many mammals. OT knockouts are more anxious than wild-type females, ‘‘Kangaroo care’’, which promotes holding neonates on an effect that can be reversed with intracerebral infusion the mother’s chest or regularly carrying older infants in a of OT [14,284]. Regulation at the level of the OT receptor harness on the mother’s chest (even if infants are not is also relevant, with virgin female rats with low-anxiety breastfed), increases skin-to-skin and non-skin-to-skin con- having higher OT receptor binding in the central amygdala tact between mothers and infants. It promotes mother– and bed nucleus of the stria terminalis (BST), areas of the infant bonding, infant physical development [18,81], and traditional fear and anxiety networks [459], compared to possibly reduces anxiety in new mothers [68,390]. It is inter- females with higher anxiety [158]. A negative relationship esting to note that the mother–infant dyad is not the only between plasma OT and anxiety is not always found in context where somatosensation reduces anxiety, and mas- female rats [326,327,329], reinforcing a more critical role sage is well-known to reduce anxiety in non-lactating for central, rather than peripheral, OT. humans [48,105,142–146,297]. The effects of OT on anxiety in male are less clear. Anx- iety is reduced after intranasal infusion of OT in men [199] 6. Infant contact modulates neurochemistry to reduce and after peripheral injection in male rats [447], but it is postpartum anxiety also reduced in male OT-knockout mice [284,475; although see 110]. Furthermore, plasma levels of OT and OT synthe- Many neurochemical systems mediate how recent phys- sis in the hypothalamus are not correlated with anxiety in ical contact with infants prevents high-anxiety in postpar- male rats [247,468]. This apparent sex difference in the tum rats. Many of these are the same as those indicated effects of OT on anxiety may be related the fact that OT above as possible precipitators of anxiety disorders in par- release and receptor expression in many sites are sensitive turient women, suggesting that perturbations of these sys- to circulating estradiol [292,355], which is typically greater tems could contribute to the onset of anxiety disorders, in females than males. but that contact with infants can retune maternal neuro- OT levels in the cerebrospinal fluid, preoptic area, and chemistry to help reduce her anxiety. BST are elevated when sheep and rats interact with their offspring [228,229,323], but this does not occur everywhere 6.1. Prolactin and oxytocin in the postpartum brain. Bosch and colleagues [45] found that basal OT levels do not differ between lactating and vir- Empirical data from laboratory rats support both PRL gin female rats in the PVN, central amygdala, or lateral and OT in how infants modulate their mother’s anxiety. septum. They also found [46] that rat dams selectively bred The critical source of these peptides must be from central to have high or low anxiety do not differ in their basal OT origin, as we found that surgical removal of the pituitary levels within the PVN and central amgydala, and that gland during late pregnancy does not affect the ability of highly anxious dams show greater OT release in these sites pups to later reduce mothers’ anxiety-related behaviors in when exposed to a stressful and anxiogenic aggressive the elevated plus-maze [265], similar to the lack of effects interaction than do low-anxiety dams. One might have of hypophysectomy on maternal behavior [132,251,265] expected low-anxiety dams to have greater OTergic tone and maternal aggression [132]. in these sites, but this could indicate that elevated OT As mentioned above, the anti-stress effects of PRL in receptor expression in these sites is more important than lactating and non-lactating rats have long been recognized the amount of OT released for females’ anxiety. However, [117,379], but PRL effects on anxiety-related behaviors virgin and early postpartum rats do not differ in their OT have been only recently examined. Torner and colleagues receptor expression in some sites traditionally involved in demonstrated that intracerebroventricular infusion of generating anxiety, including the ventromedial hypothala- PRL is anxiolytic in virgin female and male rats, while con- mus, central amygdala, and ventral subiculum versely, infusion of antisense oligonucleotides targeting the [157,215,216,483]. If examined very soon after parturition, long form of the PRL receptor was anxiogenic [435]. The though, OT receptor mRNA and binding levels are very anxiogenic effects of central administration of PRL recep- high in the ventromedial hypothalamus, lateral septum, tor antisense was later extended to lactating rats [434]. central amygdala, and dorsal BST [215,216,483]. Because Torner and colleagues also showed that interaction with OT receptor levels do not remain elevated throughout early pups increases PRL mRNA expression and release specifi- lactation, its relevance for reduced anxiety of mother rats is cally within the paraventricular nucleus of the hypothala- unclear, and it may instead be related to the onset of mater- mus (PVN) and preoptic area (POA) [433]. These sites nal behavior at parturition. Nevertheless, in the only study J.S. Lonstein / Frontiers in Neuroendocrinology 28 (2007) 115–141 123 to directly examine the relationship between OT and the postpartum performance of anxiety-related behaviors, Neumann and colleagues [328] demonstrated that intracer- ebroventricular infusion of a highly specific OT receptor antagonist decreased the percentage of time spent in the open arms of an elevated plus-maze, indicating increased anxiety, without affecting general activity. In contrast, OT receptor antagonism had no effects on elevated plus- maze behavior in virgin females. Areas of the brain where disruption of OT receptor activity produces anxiogenic effects in lactating rats are probably widespread. Work in our laboratory has impli- cated the midbrain periaqueductal gray (PAG) as one such site. The PAG is necessary for a myriad of behavioral and physiological processes [30]. It receives descending projec- tions from many sites involved in anxiety, and acts as a supraspinal ‘‘final common pathway’’ for anxiety- and Fig. 3. Infusion of an OT receptor antagonist (OTA, courtesy of Dr. Maurice Manning; 125 ng/side), but not saline (SAL), into dams’ cPAGv fear-related behaviors in animals [53]. Electrical stimula- reduces the percentage of time spent in the open arms of the elevated plus- tion of the PAG elicits feelings of anxiety and panic in maze to levels found in diestrous virgins. Different letters above bars rodents and humans [217,319,378], and functional MRI indicates significant differences between groups (p < 0.05). [Figueira, reveals that the PAG is activated when people feel anxious Peabody, and Lonstein, in preparation]. [120]. Conversely, lesions of the PAG are anxiolytic [232,253,450] and manipulating a number of neurochemi- There may also be transient upregulation of OT receptor cal systems in the PAG reduces anxiety [53,302]. The expression in the cPAGv when mothers are with their PAG contains OTergic terminals [66], expresses OT recep- infants, as changes in OT receptor content can occur rela- tors [481], and exhibits electrophysiological responses to tively quickly [87,382]. The source of OTergic input to the iontophoretically applied OT [336]. cPAGv is unknown, as no retrograde-tracing studies from In lactating female rats, the ventrocaudal PAG (cPAGv) the cPAGv have been performed in conjunction with dual is uniquely sensitive to somatosensory inputs from pups labeling for OT. One would expect that it arises from intra- [269,270]. Lonstein and Stern found that this sensitivity cerebrally projecting parvocellular OTergic cells of the was relevant for dams’ nursing behavior [269,270], and also medial paraventricular nucleus. Interactions with pups dur- their anxiety. When the cPAGv was lesioned, there was a ing the early postpartum period elicits immediate early further decrease in anxiety-related behavior in lactating gene expression in some magnocellular OTergic cells rats [268]. At least part of the cPAGv’s function in modu- [260,261], and perhaps also in parvocellular OTergic cells. lating anxiety in dams is medated through OTergic mecha- Novel populations of OT-immunoreactive cells are found, nisms. Similar to the demonstration by Neumann et al. however, in areas outside the PVN during lactation [219]. [328] that OT receptor antagonism increases anxiety in lac- These might be unique sources of OTergic input to the tating rats when infused ICV, we found that infusion of cPAGv and elsewhere to regulate anxiety and other behav- this same highly specific antagonist directly into the cPAGv iors during lactation. Indeed, excitotoxic lesions encom- (but not the dorsal cPAG) also increases anxiety in dams to passing much of the parvocellular PVN affect neither the levels typically found in virgin females [Figueira, Pea- exploration or defecation in a novel chamber, nor freezing body and Lonstein, in preparation; Fig. 3]. Midbrain infu- in response to an acoustic startle stimulus [339]. This could sions that missed the cPAGv did not affect anxiety. mean that the source of OT modulating dams’ anxiety is Importantly, infusion of the OT antagonist into the cPAGv not the PVN, or that there are redundencies in the neural of diestrous virgin females had no effects on plus-maze systems modulating anxiety, such that infant contact suffi- behavior, suggesting that OT’s effects are specific to mother ciently affects other systems to be anxiolytic even without a rats. Conversely, we have also found that in mothers that contribution from the parvocellular PVN. were more anxious because their pups were taken from them before testing, infusion of OT itself into the cPAGv reduced anxiety back to low levels. This was also specific 6.2. Corticotropin-releasing hormone to postpartum state, as OT infused into the cPAGv of dies- trous virgins did not reduce their anxiety. High central CRH signaling is anxiogenic, and its reduc- Possibly analogous to the rooting and probing that pups tion anxiolytic, in non-lactating rats [27,210,246,381]. do in their dam’s ventrum, repeated stroking-like somato- Some CRH systems are downregulated during lactation sensory stimulation of the ventrum increases OT content in rats [96,97,148,436,456,457,471,473], and this downre- in the PAG of male rats [274], and this increase might also gulation is necessary for milk letdown [6], maternal aggres- occur in lactating females while they interact with pups. sion [168], and hyporesponsiveness to stress [116,258,324, 124 J.S. Lonstein / Frontiers in Neuroendocrinology 28 (2007) 115–141

456]. Similar to the downregulation discussed above that of estradiol are more anxious than females tested at other might help prevent the onset of postpartum anxiety, con- times of the reproductive cycle when hormone levels are tinued downregulation of CRH systems in response to lower [326,489]. Second, administering exogenous hor- infants might help maintain decreased anxiety. mones or inducing pseudopregnancy to mimic the hor- At the moment, however, there does not seem to be suf- monal patterns of pregnancy do not reduce anxiety in ficient data supporting this. Only one study directly sug- female rats [41,409], unless females interact with pups dur- gests this to be the case in lactating rats, with CRH ing or after treatment [57,189,407]. Third, the greatest unable to enhance their startle responding, as it does in vir- reduction in anxiety is found during early lactation gins [436]. Because this was examined in dams on day 14 [265,352], when ovarian hormone levels are relatively low postpartum, when anxiety as measured in the elevated in rats nursing a full litter of pups [183,425,432]. Finally, plus-maze and defensive burying has reverted back to vir- and most importantly, postpartum ovariectomy has no gin levels [265,353], it is unknown if downregulation of effect on dams’ elevated plus-maze behavior [265] or pun- CRH systems contributes to the decrease in anxiety during ished drinking [188]. These results are not completely unex- early lactation. It may not, because CRH mRNA is highest pected, because even ovariectomized virgin female rats in PVN, POA, and central amgydala during the first few induced to be maternal just through contact with pups days postpartum when anxiety is at its lowest [97,109]. show somewhat reduced anxiety [141,351], suggesting that Additionally, basal CRH-1 receptor mRNA expression, some of the anxiolytic effects of infant contact do not at least in the PVN, is not affected by reproductive state require prior or current exposure to ovarian hormones. [97]. Corticosterone feeding back onto the brain also does Even if ovarian steroids are not responsible for how litter not seem critical, as adrenalectomy does not prevent high contact reduces anxiety, neurosteroids remain a possibility. rates of punished drinking in dams [188]. Even in maternal rats that are not naturally parturient, Data from our laboratory also suggest that CRH is not infant contact has neuroendocrine consequences [413,428], involved in how infant contact reduces anxiety during early and at least one other form of tactile input (vaginocervical lactation. We found that Fos expression within the dense stimulation, with last injection four hours before testing) populations of CRH-synthesizing cells of the PVN, dorsal leads to changes in neurosteroid levels in female rats BST, and central amgydala [420] does not differ between [160]. In an initial examination of this possibility, we subcu- dams that were separated or not separated from their pups taneously administered the steroidogenesis inhibitor, ami- before exposure to an elevated plus-maze [398]. That is, there noglutethimide, to dams twice per day during postpartum seems to be no ‘‘recruitment’’ of CRH-synthesizing cells days 5–7 (100 mg/injection, with last injection four hours when highly anxious dams who had their pups removed prior before testing), and found that it had no effect on their ele- to testing are exposed to an anxiogenic situation. Instead of vated plus-maze behavior [Cavanaugh and Lonstein, the number of cells being affected, it could be the amount of unpublished data]. This supports the work detailed above CRH produced or released is rapidly increased in anxious by Kellogg and Barrett [226], showing that inhibition of just dams, although this also may be unlikely because increased the 5a-reduced products of progesterone does not affect CRH signaling necessary for resumption of stress respon- dams’ anxiety. Nonetheless, the effect of more chronic treat- siveness after removal of the litter is not rapid, but rather, ments and additional doses of aminoglutethimide or other takes at least 24–72 h to occur [259,406,457]. I have previ- steroidogenesis inhibitors need to be examined before a role ously highlighted the numerous dissociations between activ- for neurosteroids in postpartum anxiety can be excluded. ity of the HPA axis and anxiety-related behaviors in lactating rats [266], but detailed and direct examination of how central 6.4. GABA CRH influences postpartum anxiety in a variety of behav- ioral paradigms is still required. Even if the central CRH sys- The postpartum period introduces an entire array of tems influencing the HPA axis and anxiety behaviors partly neurochemicals, including PRL and OT, which are released overlap, how the postpartum suppression of the HPA axis in in unique patterns and quantities to potentially influence rats pertains to postpartum women can be unclear because, anxiety. The relative degree that these unique factors con- as discussed above, the HPA axis in women does not seem tribute to postpartum anxiety state is unknown, but it to be chronically downregulated and its activity is also not makes sense that the fundamental neurochemistry regulat- consistently correlated with anxiety [8,10,200,224, 277,443]. ing anxiety in non-postpartum animals is still pertinent in postpartum ones. The inhibitory neurotransmitter, GABA, 6.3. Estradiol, progesterone, and neurosteroids is well-known to influence anxiety states in both humans and laboratory rodents. This is largely based on the anxio- Estradiol and progesterone, and activation of their lytic effects of GABA receptor activation, with the GABAA receptors, modulate anxiety in virgin female rodents receptor subtype particularly well studied [307,321]. Seda- [161,437,465]. Circulating levels of these hormones are tive and anxiolytic agents including benzodiazepines, bar- not responsible, however, for how infant contact reduces biturates, and steroids have binding sites on the GABAA anxiety in postpartum rats. First, late-pregnant rats with receptor and facilitate negative chloride ion influx and high circulating levels of progesterone and increasing levels hyperpolarization of neurons. Mice with genetic mutations J.S. Lonstein / Frontiers in Neuroendocrinology 28 (2007) 115–141 125 of the GABAA receptor show increased anxiety [93,272], and female rats with higher anxiety have lower benzodiaz- epine receptor expression in many areas of the brain [71]. In humans with some types of anxiety disorders, GABAA and benzodiazepine receptor expression are reduced [55,281]. The GABAB receptor subtype is not completely irrelevant, and mice with a genetic mutation leading to non-functional GABAB receptors are also more anxious [312]. Additionally, human panic disorder can be alleviated with baclofen, a GABAB-receptor agonist [56]. Given this, it is surprising that very few studies find a negative correlations between plasma or cerebrospinal fluid GABA with anxiety in humans [50], and most find no asso- ciation [176,177,212,363,372,373], or even a positive associ- ation [173]. CSF GABA levels also do not change after Fig. 4. Infusion of bicuculline (BIC; 2.5 ng/side) into dams’ cPAGv, but treatment with anxiolytics and alleviation of anxiety symp- not dorsal to the cPAGv, reduces the percentage of time spent in the open toms [363]. Instead of examining GABA levels in plasma or arms of the elevated plus-maze. Different letters above bars indicates CSF, examining it site-specifically in the brain may be more significant differences between groups (p < 0.05). [348, Miller, Peabody and Lonstein, in preparation]. fruitful [129,176], as would determining GABA’s effective- ness at its receptors [55,185,430]. Little is known about changes in central GABA systems include all of the sites one might expect, because infusion in postpartum women, but CSF levels are reduced during of bicuculline into either the ventromedial hypothalamus late pregnancy [9], increase during labor [383], and occipi- or amygdala does not increase the duration that dams tal cortex levels of GABA are reduced after giving birth freeze in response to an acoustic startle stimulus [190].In [129]. Other mammals show numerous changes in GABA fact, GABAA antagonism in the ventromedial hypothala- signaling that may be associated with reduced postpartum mus tends to further reduce dams’ freezing [190]. anxiety. Cerebrospinal fluid levels of GABA sharply Not only is the cPAGv susceptible to the anxiolytic increase in lactating rats and sheep when they interact with effects of OT, but it is also part of the network where their infants, but drop to very low levels when infants are GABA affects postpartum anxiety. As noted above, lesions removed [229,356]. One study in mice shows that GABA encompassing the cPAGv decrease the already low levels of concentrations in the cortex, cerebellum, thalamic region, anxiety displayed by lactating rats [268], indicating that striatum, and hippocampus do not differ between late-preg- similar to male rats, reducing cPAGv output by completely nant and recently parturient mice, but that GABA turn- destroying it reduces anxiety in postpartum rats. The over is actually somewhat reduced in the first three brain intrinsic circuitry of the PAG is characterized by a tonically sites after delivery [400]. It is not stated if dams in this active network of inhibitory interneurons [34,361], with at study were housed with their litters until the moment of least half of the neurons in the cPAGv synthesizing GABA, sacrifice, though, making interpretation difficult. These receiving GABAergic terminals, and/or expressing data, plus our results showing that ovariectomy, hypophy- GABAA receptors [361]. The cPAGv is highly responsive sectomy, nor inhibiting steroidogenesis alters anxiety in to somatosensory cues from pups [269], and these cues mother rats [188,256, Cavanaugh and Lonstein, unpub- may increase tonic inhibition of the cPAGv, thereby reduc- lished data], strongly suggest that the postpartum upregu- ing anxiety in dams. We find that infusing bicuculline to lation of anxiety-relevant GABA systems is not mediated alleviate tonic GABAergic inhibition in the cPAGv, but by hormones and instead by somatosensory inputs from not dorsal to the cPAGv (i.e., in the dorsal cPAG and supe- infants. At the level of the GABAA receptor, the postpar- rior colliculus), significantly increases anxiety to levels typ- tum rat forebrain has increased affinity for GABA, but ically found in virgins [348, Miller, Peabody, and Lonstein, functional interpretation of this result is complicated by in preparation; Fig. 4]. Neural pathways providing somato- the concurrent reduction in receptor density [280]. The sensory and other inputs to maintain tonically high net result seems to be suppression of neuronal excitability GABAergic tone in the cPAGv, or elsewhere in the brain, compared to virgin females. This occurs in some areas of have not been examined. As discussed in the next section, the brain associated with emotional regulation, including we believe the ventral BST provides at least some of this the cingulate and prefrontal cortices, and depends on inhibitory input to the cPAGv. recent contact with pups [1,238]. This reduction in neural activity is behaviorally significant, because postpartum rats 6.5. Norepinephrine peripherally injected with GABA receptor antagonists show elevated anxiety [188,191,308]. Activity of the noradrenergic system is an important Specific neural sites where GABA antagonists produce determinant of both human and animal anxiety. Anxiety these effects on anxiety in postpartum rats might not disorders, and anxiety symptoms in depressed patients, 126 J.S. Lonstein / Frontiers in Neuroendocrinology 28 (2007) 115–141 are often associated with increased peripheral and central ergic input to the PVN [342,418,419]. However, this Fos measures of noradrenergic activity [172,236,252,254,354, expression is observed after dams are separated from pups 359,373,384,479]. Strongly suggesting a functional relation- for 48 h and then reunited for 90 min [256], and may reflect ship between this system and anxiety is that reuptake inhib- an increase in NE release specifically when dams are sepa- itors affecting norepinephrine (SNRIs) are greatly effective rated from and then reunited with pups, such as that anxiolytics [104,395,429]. How the noradrenergic system observed in the PVN by Bealer and Crowley [33]. Expres- influences anxiety during the peripartum period in humans sion of various noradrenergic receptors in the PVN is also is not well studied. In pregnant women, measures of norad- modified during lactation in dams continually housed with renergic activity in CSF are either decreased [9] or do not their litters [439], further reducing PVN responsiveness to differ [125,126,431] from those of non-pregnant women. noradrenergic stimulation [471]. Basal plasma norepinephrine is lower, and its release in Changes in noradrenergic activity during lactation affect response to psychosocial stress blunted, in breastfeeding the reflexive startle response made to sudden acoustic stim- women, but breastfeeding does not need to be very recent uli, which is modified by emotional state, and dams’ acou- for this to occur [8,200]. This reduced basal and stimulated stic startle can be increased by peripheral administration of peripheral NE release may have more to do with the hyp- a-2 antagonist yohimbine, but reduced by the a-2 agonist oresponsiveness to stress found in breastfeeding women clonidine [438]. Site-specific injections of these agents are [116], rather than central control of anxiety because posi- necessary to determine if they are acting in the PVN or else- tive correlations between plasma and central NE levels where in the brain to affect startle responding. If this occurs are not always found in humans [124,172,262,431]. Fur- within the PVN, many neurochemicals are synthesized here thermore, the one study examining a relationship between that can contribute to this effect. For example, noradrener- plasma NE levels and postpartum anxiety shows no signif- gic terminals contact OT-synthesizing cells in the PVN of icant association between them [278]. both rats and monkeys [174,306], and the number of these Noradrenergic acitivity changes considerably during lac- contacts increases during lactation [306]. Most OTergic tation in rats. Suckling by pups increases plasma NE [82], cells in the PVN are depolarized by NE [49,218], consistent but because artificial stimulation of the mammary nerve with findings that NE or noradrenergic agonists stimulate does not [82], it is unclear if suckling or some other sensory OT release in lactating rats, while noradrenergic inhibitors cue from pups is responsible. Of course, measures of nor- decrease OT release when dams are suckled [33,83; how- adrenergic activity in the central nervous system are more ever, see 211,403]. Similar effects of NE and its antagonist pertinent for dams’ anxiety. In non-lactating laboratory are found in hypothalamic tissue in vitro [357]. It might be rats, increased central adrenergic activity promotes anxi- possible that infant contact reduces startle and other mea- ety-related behaviors and physiological responses by acting sures of anxiety through hypothalamic NE release stimu- upon the cortex, amygdala, BST, hypothalamus, and lating OTergic cells. Evidence against this, though, is that brainstem [101,102,137,322,424]. It could be expected that NE turnover is increased in the PVN when mothers are central NE activity is lower in lactating rats to maintain suckled, but only in the rostral PVN [95], where OTergic a low-anxiety state, but NE levels in the CSF of lactating cells project primarily to the posterior pituitary, rather rats are apparently unknown. Early studies focused on than intracerebrally [419]. NE turnover is not increased the hypothalamus, to better understand how catechola- by suckling in the caudal PVN, which has greater projec- mines affect suckling-induced prolactin release, but were tions within the central nervous system [377]. Furthermore, inconsistent and reported that suckling did either not affect most parvocellular neurons in the PVN are not excited by noradrenergic activity in the homogenized hypothalamus NE [98], even though some show Fos expression after [301] or reduced it [311]. unconditioned fearful stimuli [486]. It is unclear how NE More recent work reveals that norepinephrine release in release in the PVN during interactions with pups affects the PVN is low when day 8 postpartum mothers are with anxiety, and it may instead be more involved in PVN-med- their pups and increases when pups are removed [439]. iated effects in the periphery, such as reduced physiological However, if day 8–12 postpartum dams are separated from stress responsiveness when dams are not in the presence of their pups for 4 h and reunited, NE release in the PVN their pups [109,258,457]. increases [33]. This discrepancy may be due to separating Areas of the brain where infant contact reduces NE the mothers from pups, followed by a reunion, before sam- release to alleviate anxiety during the postpartum period pling in the latter study. It could also be due to differences are probably widespread. Possible sites of action could in the location of the microdialysis probe within the PVN, include the amygdala, but work from the Davis laboratory with decreased NE release onto parvocellular PVN cells indicates that the amygdala (including its noradrenergic occurring to dampen HPA activity in response to stress, input) is less important for unconditioned anxiety, such but increased NE release onto magnocellular PVN cells as that most often examined in lactating rats, than for con- necessary for suckling-induced OT release. Fos is expressed ditioned fear [459]. The PAG may be another possibility in TH-immunoreactive cells of the A1 and A6 groups in the [322], but we are currently focusing on the ventral BST brainstem after dams have physical contact with pups as a particularly critical site (BSTv; including parts of the [256], and the A1 group does provide substantial noradren- ventral, magnocellular, ventral principal, anterolateral, J.S. Lonstein / Frontiers in Neuroendocrinology 28 (2007) 115–141 127 and dorsolateral nuclei; [417]). The BST is involved in the inhibiting GABA synthesis within the BST, which would ability to ‘‘cope’’ with anxiogenic stimuli. Large BST impair the function of these projection neurons, may lesions exacerbate the effects of stress on restraint-stress- increase anxiety [387]. GABAergic projections to the induced stomach ulcers and cause male rats to be more PVN could be particularly important for disinhibiting OT behaviorally responsive to fear-associated cues [202].Ina and PRL projecting locally and to distant sites affecting conditioned fear inhibition paradigm, presentation of the anxiety-related behaviors [Fig. 5]. Conversely, when dams stimulus that indicates safety and the absence of electric are separated from pups, NE release in the BSTv might shock increases Fos expression in only a few neural increase, reducing its GABAergic output and increasing sites—including the BSTv [74]. It is also activated during anxiety. We have preliminary data suggesting that BSTv anxiogenic situations in primates [221]. The BSTv also infusion of clonidine (1 ng or 100 lg), an a2 receptor has one of the densest noradrenergic innervations of the antagonist that can act on presynaptic autoreceptors to rat brain [137,478], arising primarily from the A1 and A2 reduce norepinephrine release, does reduce anxiety in dams brainstem groups [362,368,376,478]. Innate fearful stimuli that were separated from their pups before testing [Fig. 6; such as TMT, a component of fox odor, increase NE Smith and Lonstein, unpublished data]. release in the BSTv [137]. An increase also occurs in All of this remains to be reconciled with the increase in response to conditioned fearful stimuli [340]. Reducing Fos, not decrease or lack of expression, in A1 noradrener- noradrenergic activity in the BSTv in males by infusing clo- gic cells after dams interact with pups following a 48-h sep- nidine (which acts as a presynaptic autoreceptor to reduce aration [256]. This implies that NE is released from the A1 NE release), or by lesioning noradrenergic fibers, reduces group when dams interact with pups, but only 37% of these freezing during exposure to these stimuli [137,340]. The noradrenergic cells express Fos [256], and it is unknown if effects of simply lesioning the BSTv on unconditioned anx- these particular cells project to the BSTv, or are even acti- iety in rats requires further investigation, as lesions are typ- vated during mother–infant interactions not following such ically very large and include both the dorsal and ventral a long separation. Our hypothesis also will need to accom- BST, and produce inconsistent effects [440,453]. modate the dampening of light-enhanced startle found Recent data from our lab implicate the BSTv in how after dorsal or ventral BST infusion of the AMPA receptor infant contact affects anxiety in lactating rats. As discussed antagonist NBQX, which would decrease glutamatergic above, separating a mother rat from her pups increases her neurotransmission in the BSTv [458]. Alternatively, NE anxiety-related behavior to levels found in diestrous virgins release in the vBST might increase while dams interact with [265,325]. We examined Fos expression in the brains of sep- pups, but that BSTv neurons providing excitatory input to arated and non-separated dams who were placed in the ele- areas promoting anxiety are inhibited by local GABAergic vated plus-maze, or simply left in their home cages. We find that, although the plus-maze behavior differed between the GABA groups, only a small number of neural sites showed differ- ences in Fos expression between separated and non-sepa- _ PVN rated dams. The greatest difference between them was in _ the BSTv, with greater Fos expression in less anxious dams GABA + that had their pups before exposure to the plus-maze [398]. BSTv cPAGv Control dams housed with their pups but not placed in the GABA + _ plus-maze had low levels of Fos in the BSTv, indicating Amygdala lower that the display of maternal behavior before testing did NE not generate this increase in Fos protein [332,333], and that Low Anxiety it was instead in response to being exposed to the plus- A1, A2 _ Behaviors maze. It may be somewhat surprising that dams with pups before testing, and therefore lower anxiety, had increased Fos in the BSTv. NE in the BSTv inhibits glutamate release and cellular activity [78,122,155], so removing this inhibi- tion could increase neural activity and Fos expression in the dams’ BSTv. Recent contact with pups may, therefore, Fig. 5. In a relatively small component of the larger network reducing mothers’ anxiety, we propose that physical interaction with pups decrease NE release in the BSTv when dams are exposed to maintains low norepinephrine release from the brainstem A1 and A2 an anxiogenic situation. Increased glutamate release and groups into the BSTv. This disinhibits GABAergic projections from the BSTv activity could readily inhibit anxiety, as most BSTv BSTv to numerous areas of the brain including the PVN, numerous neurons are GABAergic [317,404,415]. Activation of inhib- subregions of the amygdala, and cPAGv. Potentially excitatory projec- itory projections from the BSTv to many areas of the brain, tions from the PVN and amgydala to the cPAGv are also inhibited. Intracerebral release of OT and PRL within and from the PVN may also including the PVN, amygdala, preoptic area, cPAGv, and result from vBST disinhibition, although excitatory inputs are probably supramammillary nucleus [19], could modulate their activ- also involved. Direct noradrenergic inputs from the brainstem to the PVN, ity to suppress anxiety responses in lactating rats. Indeed, amgydala and cPAGv exist, but are not indicated. 128 J.S. Lonstein / Frontiers in Neuroendocrinology 28 (2007) 115–141

particularly relevant for low-income mothers of some minority groups, who are at higher risk for postpartum emotional dysregulation [24,213], but the least likely to breastfeed their infants [242,257,375]. It is also a concern for mothers who give birth prematurely or have perinatal complications, because they are also more prone to ele- vated anxiety [61,135,231,249,350,469,485], but less likely to breastfeed [72]. Even independent of such factors, women with the highest trait anxiety, who might benefit the most from the anxiolytic effects of continual infant con- tact, are the least likely to initiate and persist in breastfeed- ing [84,156,344]. The relatively few studies in humans have not revealed much empirical data about the neurochemistry of how Fig. 6. In dams separated from pups four hours before testing, infusion of infant contact regulates maternal anxiety. Research on lab- clonidine (CLON; 1 ng/side), but not saline (SAL), into the BSTv oratory animals reveals that numerous hormones, neuro- increases the percentage of time spent in the open arms of the elevated peptides, and neurotransmitters acting upon multiple * plus-maze. p < 0.05. [Smith and Lonstein, preliminary data]. brain sites are responsible. Neurochemicals not yet investi- gated in detail in the context of postpartum anxiety or dis- neurons within the vBST [see 119,171]. In any case, the cussed here—including serotonin, thyroid hormones, BSTv has connections with both the mesolimbic and emo- vasopressin, galanin, endorphins, substance P, CCK, and tional systems in the brain [154,171,459], and may be a site neurotrophic factors—also have unique patterns of activity of interface between networks controlling the rewarding during the peripartum period, and may eventually be properties of infants and other emotion-laden stimuli in revealed to affect mothers’ anxiety. It is striking that some the environment. Pereira and colleagues [351] have found of the systems discussed here seem to act redundantly. that mothers’ anxiety can be overridden by the presence Pharmacological manipulation of OT, PRL, GABA, or of highly rewarding pups, an effect associated with high NE can each affect anxiety in mother rats to a similar maternal dopamine neurotransmission, and possibly mod- degree. This may be expected, as some neural sites regulat- ulated by the vBST. If this is universal, aberrant vBST ing anxiety—including the BST, amygdala, and PAG— activity could reduce mesolimbic dopamine function in have receptors for all of these neurochemicals human women, diminishing their perception of infants as [26,51,481,484]. The relevant neurochemical factors proba- rewarding, hence leading to reduced infant contact and bly do not only function in parallel and with redundancies, higher anxiety. but also sequentially and interactively. For example, the anxiolytic effects of OT may partly be mediated through its ability to modulate release of excitatory amino acids 7. Conclusions [121] and GABA [64]. Similarly, neurosteroids affect GABAA receptor subunit expression and activity of hypo- Every year, millions of postpartum women and their thalamic OT cells [203]. Another example is that intracere- infants around the world are affected by the onset or wors- bral OT release in response to stressful or anxiogenic ening of maternal anxiety disorders, and yet, there is virtu- stimuli depends on the inherent responsiveness of the ally no information in either humans or animals about the mothers’ HPA axis [46]. Considering how detrimental endocrine, neuroendocrine, and neurotransmitter factors maternal anxiety and other mood disorders are to infant leading to high anxiety during this particular reproductive development, the maternal brain would be best served by state. At least it is known that postpartum anxiety can be a wide array of redundant and interactive systems, to better naturally reduced by infant contact. Studies in humans ensure a positive maternal emotional state. have been somewhat unclear, but physical contact with The sheer number of neurochemical changes occurring infants—even without breastfeeding—seems to be an across pregnancy, parturition, and lactation may explain important contributor to positive mood and reduced anxi- why this topic is understudied and why it is difficult to gen- ety in mothers. This is a somewhat troubling conclusion, as erate an overarching biological model for either the onset infant care in the United States and similar societies or infant-mediated alleviation of postpartum anxiety. Even involves a system of infant ‘‘caching’’, which diminishes small advances in understanding individual components of physical contact between mothers and infants, and differs this enormous sensory, endocrine, neuroendocrine, neuro- dramatically from the pattern of very frequent mother– peptide, and neurotransmitter network could still lead to infant contact that existed over the course of human evolu- valuable interventions. Educating millions of at risk moth- tion [273]. The reduced contact that bottlefeeding mothers ers about the association between infant contact and make with their infants, even in non-feeding contexts reduced anxiety could help optimize maternal mood, and [79,243,248], further compounds the problem. This seems subsequently, mother–infant interaction. Enhancing J.S. Lonstein / Frontiers in Neuroendocrinology 28 (2007) 115–141 129 mother–infant contact, and concomitant release of endog- [6] O.F. Almeida, A. Yassouridis, I. 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