adapting for motherhood

The maternal brain is a major force in driving essential physiological changes during pregnancy. These changes include adaptations that cushion the impact on the fetus of the mothers experience of stress during the preg-nancy, that reset the control of metabolism to favour energy flow to the fetus and that store energy as adipose tissue in preparation for lactation. The mothers brain also undergoes changes that prepare the neuroendocrine systems that regulate the pulsatile release of oxytocin secretion at parturition and during lactation, and that regulate the secretion of prolactin to ensure that milk is produced after birth1.

A new mother displays a dramatic change in behav-iour as soon as the babies are born: she immediately cares for the young and defends them. The expression of these essential components of maternal behaviour is the cul-mination of changes, controlled by pregnancy hormones, in the activity of neural circuitry in late pregnancy, but is held in check until the fetuses are delivered (again under the control of the pregnancy hormones). However, the changes in the brain that permit motherhood involve altered emotionality, and are not without cost. The sudden withdrawal of the pregnancy hormones before and at birth not only permits the activation of essential post-partum maternal behaviours and neuroendocrine functions for lactation, but may also predispose the new mother to depression.

Recently, major progress has been made in our under-standing of the organization and molecular mechanisms of the neuroendocrine networks that govern mammalian parturition, lactation, maternal behaviour and maternal stress responsiveness. Understanding these processes

might help improve the management of pregnancy to assist an optimal outcome for the infant, and might lead to an explanation of the mental health disturbances that often occur in women after even a successful pregnancy. Such knowledge might have wider implications for the development of new therapeutic approaches to mental ill-health.

This Review discusses the mechanisms that protect the fetus from maternal glucocorticoids and the adapta-tions in maternal neuroendocrine systems that are nec-essary for normal pregnancy, parturition and lactation. It then describes the adaptations in the brain that are required for maternal behaviour and successful rearing of the offspring. Finally, it considers the implications of these adaptations for post-partum mood disorders.

Protecting the fetusExposure to stress or synthetic glucocorticoids during pregnancy can affect the development of physiological systems in the offspring, resulting in increased suscep-tibility to cardiovascular2 and metabolic disease3 and to affective disorders in adulthood4. This phenomenon has been termed fetal programming. There are in-built mechanisms that protect the fetus from this potentially detrimental programming. As a last line of defence, the placenta expresses 11-hydroxysteroid dehydrogenase 2 (11HSD2)5, an enzyme that acts as a barrier that limits the exposure of the fetus to circulating mater-nal glucocorticoids by converting corticosterone to inert 11-dehydrocorticosterone; a first line of defence is provided by changes in the activity of the maternal hypothalamuspituitaryadrenal (HPA) axis (BOX1).

Laboratory of Neuroendocrinology, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, Scotland, UK.Correspondence to: J.A.R.email: [email protected]:10.1038/nrn2280Publishedonline12December2007

The expectant brain: adapting for motherhoodPaula J. Brunton & John A. Russell

Abstract | A successful pregnancy requires multiple adaptations of the mothers physiology to optimize fetal growth and development, to protect the fetus from adverse programming, to provide impetus for timely parturition and to ensure that adequate maternal care is provided after parturition. Many of these adaptations are organized by the mothers brain, predominantly through changes in neuroendocrine systems, and these changes are primarily driven by the hormones of pregnancy. By contrast, adaptations in the mothers brain during lactation are maintained by external stimuli from the young. The changes in pregnancy are not necessarily innocuous: they may predispose the mother to post-partum mood disorders.

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The maternal nutritional state during pregnancy also has an impact on fetal development and on metabolic regulation in the offspring in later life. Protein restriction or obesity during pregnancy has adverse programming effects on the health of the offspring that are similar to those that result from excess glucocorticoid exposure inutero69. However, it has not been established that maternal nutritional state programmes the fetus through glucocorticoid transfer.

HPA-axis activity in pregnancy. During pregnancy, the basal activity of the HPA axis is reduced. In the rat, corticotropin-releasing hormone (CRH) mRnA levels in the parvocellular region of the paraventricular nucleus (pPvn) are lower on day 21 of pregnancy (the day before parturition) than in non-pregnant females10. median eminence CRH content and anterior pituitary pro-opiomelanocortin (PomC) mRnA and CRH recep-tor levels are also lower at the end of pregnancy. The circadian variation in adrenocorticotropin hormone

(ACTH) secretion that is evident early in pregnancy diminishes after mid-gestation owing to reduced evening peak levels11. Circadian variation in corticosterone secre-tion is maintained throughout pregnancy, but absolute levels decline in early pregnancy, reaching a minimum by day 10 of gestation and then increasing progressively to term (although there is no concomitant rise in ACTH secretion). This altered ACTHcorticosterone relation-ship in pregnancy might be accounted for by oestrogen-induced increases in the sensitivity of the adrenal gland to ACTH12,13 and/or by enhanced negative feedback that reduces ACTH secretion.

The responsiveness of the HPA axis to a wide range of physical and psychological stressors is also markedly reduced, or even abolished, in late pregnancy in rats, mice14 and humans15,16. In rats this hyporesponsiveness is evident from day 15 of gestation and persists through pregnancy17, parturition18 and lactation, until weaning19. It is reflected by reduced ACTH and corticosterone secretion following stress and involves adaptations at the

Box 1 | Changes in HPA-axis activity in the late-pregnant rat

Stressors are generally categorized as either psychological or physical, and different brain circuitries convey information about these different types of stressor to the HPA axis (see figure): psychological stressors primarily involve processing through limbic brain regions, whereas physical stressors rely more on direct brainstem inputs165. Both types of stressor activate neurosecretory corticotropin-releasing-hormone (CRH) neurons and arginine-vasopressin (AVP) neurons in the parvocellular region of the hypothalamic paraventricular nucleus (pPVN). On activation, these neurons release CRH and AVP from nerve terminals at the median eminence into the hypophysial portal blood system. CRH and AVP stimulate adrenocorticotropic hormone (ACTH) release from anterior pituitary corticotrophs, which in turn stimulates the secretion of glucocorticoids (corticosterone in rodents) from the adrenal cortex.

In late pregnancy, CRH mRNA levels in the PVN10, CRH content in the median eminence and pro-opiomelanocortin (the ACTH precursor) mRNA and CRH receptor levels in the pituitary17 are lower than in virgin rats under basal conditions. In late-pregnant rats, CRH neurons and AVP neurons in the pPVN are stimulated less by stressors than in virgin rats166 this is reflected by reduced CRH and AVP biosynthesis and hence reduced ACTH and corticosterone secretion. In addition, pituitary corticotrophs secrete less ACTH in response to administered CRH17 or AVP161 than in virgin rats. Furthermore, in late-pregnant rats the excitatory drive to the PVN neurons from both the limbic forebrain20 and the brainstem nuclei25 is reduced compared to virgin ratsin response to emotional and physical stressors, respectively. Glucocorticoids inhibit their own release by providing feedback inhibition at several levels, including the pituitary and hypothalamus. In late pregnancy there is increased activity of the enzyme 11-hydroxysteroid dehydrogenase 1 (11HSD1, which reactivates inert 11-dehydrocorticosterone to active corticosterone) in the PVN and anterior pituitary10, which might enhance local glucocorticoid negative feedback.

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level of both the anterior pituitary and the hypothalamus (BOX1), as well as at higher brain regions20. Several mech-anisms are involved in establishing and maintaining this hyporesponsiveness and are discussed below.

Noradrenergic drive and endogenous opioids. Brainstem noradrenergic neurons located in the nucleus tractus solitarii (nTS) provide a direct excitatory input to the CRH neurons in the pPvn. These CRH neurons express 1-adrenergic receptors21 and are directly excited by noradrenaline22, which induces CRH gene transcrip-tion23,24. Physicalstressors, including systemic adminis-tration of cholecystokinin (CCK) and interleukin-1 (Il1; an immune challenge), exert their effects on the HPA axis by activating noradrenergic (A2) neurons in the nTS, evoking noradrenaline release from the neurons terminals in the Pvn (FIG.1). However, in late-pregnant

rats, both systemic administration of Il125 and forced swimming26 fail to evoke local noradrenaline release in the Pvn and hence do not activate the HPA axis. This is not a result of impaired transduction mechanisms in the medulla, as cell bodies in the nTS are similarly acti-vated in pregnant and non-pregnant rats, at least by Il1 administration25. whereas decreased 1-adrenergic-receptor mRnA levels in the pPvn26 might contribute to reduced basal HPA-axis activity, the suppressed HPA-axis responses to stress in pregnancy are attributable to inhibition by endogenousopioids.

Endogenous opioids have a modulatory role in HPA-axis regulation. In males and non-pregnant females opioids potentiate HPA-axis responses to stress, whereas in pregnancy opioids have a net inhibitory effect on HPA activity. Hence, pre-treatment with the opioid receptor antagonist naloxone enhances the ACTH response in late-pregnant rats to Il125, CCK26 and forced swim-ming27, as well as to parturition-related stimuli18. opioids exert these inhibitory actions centrally (in the Pvn), preventing Il1-evoked noradrenaline release and the stimulation of CRH gene transcription25.

Several central sources of opioids could potentially restrain the responses of CRH neurons in pregnancy. -endorphin cells in the arcuate nucleus project directly to the Pvn28, and PomC mRnA and -endorphin levels in this area are increased in late pregnancy29. However, -endorphin is unlikely to mediate opioid actions on responses to acute stress because -endor-phin neurons respond slowly30. The nTS is a more likely source of endogenous opioids: nTS neurons synthesize enkephalins and dynorphins31,32, and gene expression for pEnK-A and -opioid receptors is increased in the nTS in late pregnancy25. Thus, in late pregnancy, activation of nTS neurons by Il1 is likely to release more enkepha-lin from the neurons terminals in the Pvn; enkephalin would then act on upregulated -opioid receptors and presynaptically inhibit noradrenaline release, providing a mechanism that selectively inhibits the drive from the nTS to CRH neurons in the Pvn (FIG.1).

Glucocorticoid negative feedback. The HPA axis is under negative-feedback control by glucocorticoids, but the hyporesponsiveness of the HPA axis in pregnancy does not seem to be explained by rapid glucocorticoid feedback actions. In fact, corticosterone is less effective in suppress-ing ACTH secretion after pharmacological adrenalec-tomy in pregnant rats10. Furthermore, mineralocorticoid receptor (mR) gene expression in the hippocampus is unaltered during pregnancy, and glucocorticoid receptor (GR) mRnA levels in the dentate gyrus are only mod-erately increased on day 21 of pregnancy10. However, delayed negative-feedback mechanisms might be more effective in pregnancy: 11-hydroxysteroid dehydro-genase 1 (11HSD1; the enzyme that reactivates inert 11-dehydrocorticosterone to active corticosterone) activity is increased in the Pvn and anterior pituitary in late preg-nancy10; the consequent increased availability of intracel-lular corticosterone might contribute to the late-pregnancy reduction in basal CRH and vasopressin (in the Pvn) and PomC gene expression (in the pituitary).

Figure 1 |crHandoxytocinresponsestoiL1signallingaresuppressedduringpregnancy.Progesterone levels in the brain and the circulation are increased during pregnancy. Progesterone is converted into 5-dihydroprogesterone (5DHP) by 5-reductase (5R), and 5DHP is in turn converted into allopregnanolone by 3-hydroxysteroid dehydrogenase (3HSD). In brainstem nucleus tractus solitarii (NTS) neurons, allopregnanolone increases the levels of proenkephalin-A (pENK-A) mRNA, which is translated into enkephalins (opioid peptides), and possibly also increases -opioid receptor (MOR) mRNA levels. Noradrenergic A2 neurons project to the hypothalamus, specifically to parvocellular corticotropin-releasing-hormone (CRH) neurons and magnocellular oxytocin neurons in the paraventricular nucleus (PVN), and to oxytocin neurons in the supraoptic nuclei (SON). Systemic interleukin-1 (IL1) normally activates these brainstem neurons through a prostaglandin-dependent pathway but, in pregnancy, IL1 fails to evoke noradrenaline release from their terminals in the PVN. This is a result of increased opioid (enkephalin) inhibition acting presynaptically on the upregulated -opioid receptor on the noradrenergic nerve terminals. This inhibitory opioid mechanism in the hypothalamus, induced by the increased levels of allopregnanolone in pregnancy, prevents activation of CRH neurons and oxytocin neurons, thereby inhibiting hypothalamuspituitaryadrenal (HPA)-axis and oxytocinneurohypophysial responses, respectively.

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Endogenous opioidsPeptides,includingdynorphins,endomorphins,endorphinsandenkephalins,thatareproducednaturallyinthebodyand,likemorphine,actthroughopioidreceptors.

Neuroactive steroidAsteroidderivativethatrapidlyaltersneuronalexcitabilitythroughinteractionwithneurotransmitter-gatedionchannels.

Allosteric modulatorAmoleculethatbindstoareceptorataregulatorysitethatisdistinctfromtheactiveligand-bindingsitetoinfluencethereceptorsfunction.

Oxytocin, sex steroids and neuroactive steroids. In non-pregnant rats, centrally released oxytocin reduces HPA-axis responses to stress33,34. However, in late pregnancy an oxytocin antagonist fails to reverse the suppressed HPA-axis responses to stress34, indicating that endog-enous intracerebral oxytocin does not maintain HPA hyporesponsiveness at this time.

In the rat, oestrogen and progesterone levels peak dur-ing the last week of pregnancy35,36, making them candidate inducers of pregnancy-related adaptations in HPA-axis activity. However, sex steroids do not have a direct role in the hyporesponsiveness of the HPA axis in pregnancy37.

By contrast, the progesterone metabolite and neuroactivesteroid allopregnanolone (3-hydroxy-5-pregnan-20-one) does have a role. The enzyme 5-reductase (5R) converts progesterone into 5-dihydroprogesterone, which is in turn converted into allopregnanolone by 3-hydroxysteroid dehydrogenase (3HSD). Both of these converting enzymes are expressed in the brain38 and in the liver39,40. Circulating and brain levels of allopregnanolone increase during pregnancy, as a consequence of increasing progesterone secretion36. Allopregnanolone enhances the effectiveness of GABA (-aminobutyric acid) inhibition: it acts as an allostericmodulator at postsynaptic GABAA receptors (including those in the hypothalamus), where it potentiates receptor function by prolonging the Cl channel opening time and by preventing suppression of receptor activity during late pregnancy41. Indeed, treatment with allopregnanolone reduces stress-induced HPA activity in both male42 and female43 rats.

These findings implicate a role for allopregnanolone in suppressed HPA-axis responses in pregnancy. our prelim-inary findings43 with finasteride (which blocks allopreg-nanolone production by inhibiting the activity of 5R36) support such a role: in late pregnancy finasteride restores the ACTH response to systemic Il1. Furthermore, stud-ies with naloxone and finasteride indicate that the actions of allopregnanolone and opioids are linked. Because in pregnancy the increase in allopregnanolone precedes the emergence of inhibition by endogenous opioids, the prediction is that allopregnanolone upregulates opioid expression. Indeed, allopregnanolone seems to rely on the actions of endogenous opioids to exert its suppres-sive effects on HPA-axis reactivity (FIG.1)(P.j.B. & j.A.R., unpublished observations). If allopregnanolone induces the increased opioid expression that is observed in nTS neurons in late pregnancy25, this has major implica-tions owing to the widespread rostral projections of A2 noradrenergic neurons, including those to magnocellular oxytocin neurons in the hypothalamus (see below). The mechanism by which allopregnanolone might regulate opioid expression remains to be elucidated, but it might involve an interaction with GABAA receptors in the nTS, as has been reported for the regulation of neuropeptide expression in the hypothalamus44,45.

Adaptations in the maternal oxytocin systemoxytocin is produced by neurons in the Pvn and the supraoptic nuclei (Son)46 of the hypothalamus. The magnocellular Pvn and Son neurons project to

the posterior pituitary gland, and when action potentials arrive from the cell bodies, the neurons thousands of terminals secrete oxytocin into the general circulation. Parvocellular Pvn oxytocin neurons project centrally to the limbic system or caudally to the nTS and the spinal cord. oxytocin secreted from the posterior pituitary is essential in lactation because it stimulates milk ejections. It is also important, but not essential, in promoting par-turition by stimulating uterine contractions. oxytocin released centrally during parturition facilitates the rapid onset of maternal behaviour and modulates emotional-ity47. It is secreted in pulses spaced a few minutes apart during parturition to stimulate delivery and during suckling to promote milk ejection. This most effective and efficient pattern of oxytocin secretion results from the coordinated high-frequency action potential bursting discharge (burst-firing) of magnocellular neurons and is evoked reflexly, but only by distension of the birth canal or by suckling. Burst-firing depends on positive feedback by dendritically released oxytocin in the Pvn or Son48.

In rats oxytocin is also secreted in response to stres-sors49, including systemic administration of Il150 and CCK51, which act through A2 noradrenergic neurons in the nTS52,53. A2 neurons also relay stimuli from the birth canal54, so quiescence of this pathway during pregnancy is important to minimize the risk of preterm labour. Importantly, allopregnanolone and opioid mechanisms inhibit oxytocin neurons in late pregnancy (FIG.2). This inhibition allows stores of oxytocin to accumulate in the posterior pituitary and in the cell bodies and dendrites of the magnocellular neurons.

Opioid restraint of oxytocin neurons. During pregnancy, -opioids (dynorphin, met-enkephalin-Arg6Phe7 and met-enkephalin-Arg6Gly7leu8) co-produced by oxy-tocin neurons pre-terminally inhibit oxytocin release in the posterior pituitary55,56. opioid inhibition at this level diminishes at the end of pregnancy and, consequently, action potentials trigger oxytocin secretion with greater fidelity during parturition. Instead, central -opioid-receptor-mediated inhibition of oxytocin neurons (FIG.2) emerges in mid-to-late pregnancy (from day 16). Thus, in pregnant rats naloxone enhances the firing rate of oxy-tocin neurons and enhances oxytocin secretion (includ-ing dendritic release) after stimulation by systemic CCK or Il1 administration25,50,51,57. Central opioid inhibition governs the excitation of oxytocin neurons throughout parturition, optimizing the intervals between the birth of pups in a litter so that each newborn receives adequate immediate maternal care58. After parturition the central opioid inhibition of oxytocin release disappears.

As both CCK and Il1 stimulate oxytocin neurons through noradrenergic A2 input from the nTS53,59, in much the same way that CRH neurons are stimulated, the nTS is a likely source of central opioids that inhibit oxytocin and CRH neurons in pregnancy.

GABA inhibition of oxytocin neurons. GABA innerva-tion provides the major inhibitory synaptic input to oxytocin neurons. As magnocellular oxytocin neurons do not express progesterone receptors60, progesterone

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acts indirectly through its metabolite allopregnanolone, which enhances GABAA-receptor function on oxytocin neurons61.

Several adaptations enhance the effectiveness of GABA input to oxytocin neurons in late pregnancy (FIG.2). The GABAA-receptor-mediated current density per oxy-tocin neuron is much greater than in early pregnancy, as a consequence of increased GABA synapse number,

allopregnanolone action and modest enlargement of the oxytocin-neuron perikarya62. In addition, neuroplastic actions of oxytocin in the presence of oestradiol increase the number of active GABA synapses on oxytocin neu-rons near the end of pregnancy63. Peripartum changes in the clustering of GABAA-receptor subunits at synapses on oxytocin neurons further increase sensitivity to GABA62. At term, allopregnanolone production is reduced and the sensitivity of the GABAA receptors to allopregnanolone declines, owing to the action of dendritically released oxytocin, which increases intracellular phosphorylation of the GABAA receptors through the action of protein kinase C62,64. This loss of allopregnanolone action exposes the opioid mechanism as the primary inhibitory control-ler, and the oxytocin neurons remain relatively quiescent until close to term.

Allopregnanolone and opioid tone. The induction of central opioid inhibition of oxytocin secretion is in part attributable to chronic oestrogen and progesterone actions37 and the action of relaxin, a pregnancy peptide hormone65. However, allopregnanolone is of prime importance57, considering that finasteride restores the oxytocin-secretory response to systemic Il1 adminis-tration in late pregnancy57. This might not depend on GABAA receptors on oxytocin neurons, as finasteride reverses opioid inhibition of these neurons57.

Local network-distant input. oxytocin neurons burst-fire during parturition and in response to suckling, in late pregnancy as well as in lactation48,66. This capacity to burst-fire is intrinsic to oxytocin neurons: noradrenaline induces burst-firing even invitro67. minor changes in the electrophysiological properties of oxytocin neurons in pregnancy increase their excitability68. At parturition, oes-trogen-dependent local oxytocin-feedback mechanisms generate coordinated bursting of oxytocin neurons.

During parturition, the excitatory drive from A2 noradrenergic neurons projecting to oxytocin neurons is important69 and stimulates local glutamate release48. Glutamate release in the Son increases just before birth, but GABA release does not change, indicating that exci-tatory signals that can overcome inhibitory restraints are more important than presynaptic suppression of the tonic GABA inhibitory input48,69,70. Furthermore, parturition stimulates the somato-dendritic release of oxytocin48,71. This has an essential autoregulatory positive-feedback role (FIG.3), acting through receptors on the oxytocin neurons to stimulate further oxytocin release72. It also stimulates endocannabinoid production and release (from oxytocin neurons), which inhibits glutamate afferents. Thus, neighbouring oxytocin neurons indirectly inhibit one another73. This complex action of oxytocin has the effect of weakly coupling adjacent oxytocin neurons, enabling a surge in glutamatergic synaptic activity to drive coordinated bursts through ionotropic recep-tors74,75 (FIG.3). The consequent bursts are then shaped by properties of the oxytocin neurons75. These mecha-nisms explain how a locally applied oxytocin antagonist disrupts parturition by preventing dendritic oxytocin release and action48,71.

Figure 2 |Magnocellularoxytocinneuronsinlatepregnancy.Interacting mechanisms prevent the premature activation of magnocellular oxytocin neurons, inhibiting their basal firing rate and dendritic oxytocin release. Inhibitory -opioid mechanisms that emerge in the last week of pregnancy prevent the excitation of oxytocin neurons by stimuli that act through the noradrenergic input from nucleus tractus solitarii (NTS) A2 neurons (stimuli such as circulating cholecystokinin (CCK) and interleukin-1 (IL1)). Specifically, proenkephalin-A (pENK-A) and -opioid receptor (MOR) gene expression in NTS neurons is upregulated in late pregnancy, providing -opioid-mediated presynaptic inhibition of noradrenaline release onto oxytocin neurons. Magnocellular oxytocin neurons are also subject to increased GABA (-aminobutyric acid) inhibition during pregnancy. Allopregnanolone prolongs the opening time of GABAA-receptor Cl

channels, enhancing the inhibitory GABA input. It also stimulates dephosphorylation of the GABAA-receptor subunits, maintaining GABA action. Furthermore, oestrogen and oxytocin, acting together, increase the number of GABA synapses and increase GABA inhibitory-current density. Together, these inhibitory mechanisms limit the stimulation of oxytocin secretion by extraneous stimuli, thereby preventing preterm labour and causing the accumulation of oxytocin stores for parturition. This accumulation occurs without an increase in oxytocin gene expression.

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The morphological changes in gliaoxytocin-neuron associations that occur around birth and were previously linked to burst-firing76 appear to be unimportant, as oxy-tocin neurons can burst-fire in late pregnancy, before such changes occur48. moreover, preventing these neuro-glial changes has no impact on parturition or burst- firing during suckling77.

Implications for other brain systems. The finding that, at term, oxytocin acts on oxytocin neurons to desensitize GABAA receptors to allopregnanolone suggests a wider importance for this phenomenon64. At parturition, the central release of oxytocin would be expected, through phosphorylation of GABAA receptors, to wipe out any remaining inhibitory actions of allopregnanolone in networks that express oxytocin receptors (and the appro-priate post-receptor signalling pathways). These might include the networks that are involved in the expression of maternal behaviour, although this remains to be tested. The widespread reduction of GABAA-receptor-mediated inhibition by allopregnanolone, which is reinforced by central oxytocin actions and accompanied by the withdrawal of endogenous-opioid inhibitory actions, is likely to have other consequences as a price for the rapid induction of maternal behaviour post-partum. These might include altered emotionality, post-partum blues and, later, puerperal depression, as discussed below.

Adaptations in the maternal prolactin systemProlactin is essential for the stimulation of milk secre-tion, and during pregnancy it prepares the mammary alveoli for milk production. A temporary increase in appetite occurs during pregnancy, to provide nutrients for the fetus(es), extra energy for the mother and a surplus of energy for storage as fat for lactation (BOX2).

In pregnant women, circulating prolactin increases by 15-fold78. Early in rat pregnancy prolactin is secreted in surges in the afternoon and night and has a luteotrophic role; its secretion is suppressed in mid-pregnancy, when placental lactogen secretion predominates. In the night before parturition, prolactin secretion surges; as pro-lactin acts in the brain to elicit maternal behaviour79, this surge contributes to a successful transition from pregnancy to motherhood.

Prolactin also acts in the brain to reduce HPA-axis responses to stress80, stimulate neurogenesis and regulate its own secretion81,82. Prolactin and placental lactogen enter the brain through the ventral hypothalamus, where the bloodbrain barrier is deficient, and through the choroid plexus.

Feedback control of prolactin secretion. Prolactin secre-tion from the anterior pituitary is primarily regulated through tonic inhibition by dopamine that is secreted from tubero-infundibular dopamine (TIDA) neurons in the hypothalamic arcuate nucleus. During pregnancy, high levels of oestrogen increase the production of the short and, especially, the long isoforms of the prolactin receptor in the choroid plexus, facilitating prolactin entry into the brain83,84. The long-form prolactin receptor is also expressed on TIDA neurons85, and the activated receptor stimulates the expression of the gene for tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis85. Thus, prolactin increases dopamine synthesis in dopamine neurons and so indirectly inhibits its own secretion. Prolactin also opposes dopamine inhibition of tyrosine hydroxylase, by inducing phosphorylation of the enzyme by protein kinases85. From mid-pregnancy onwards, placental lactogen also suppresses maternal prolactin secretion86.

Figure 3 |Magnocellularoxytocinneuronsatparturition.Parturition starts with locally organized uterine contractions. These stimulate nucleus tractus solitarii (NTS) A2 noradrenergic neurons that project to oxytocin neurons. The noradrenergic input primes and activates a burst mechanism in the oxytocin neurons, and this activation is further enabled by weak coupling between the oxytocin neurons. Noradrenaline also stimulates somato-dendritic oxytocin release which, through binding of oxytocin to autoreceptors, is critically important in driving burst-firing. The coordinated burst-firing of oxytocin neurons leads to pulsatile oxytocin secretion from the posterior lobe of the pituitary into the circulation, promoting uterine contractions. Oxytocin-neuron activity is kept in check by a central opioid mechanism, which tonically inhibits the neuronsand can thus slow or suspend oxytocin secretion and births during environmental disturbance. Increased local oxytocin release and decreased allopregnanolone levels at parturition together reduce GABAA-receptor (-aminobutyric acid A receptor) function. This reduced effectiveness of inhibitory GABA synapses on oxytocin neurons enables greater effectiveness of excitatory input.

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A nocturnal increase in prolactin secretion occurs near the end of pregnancy (at day 2122 in rats), as a result of less effective negative feedback. Sustained exposure to prolactin reduces TIDA-neuron sensitivity to prolactin, through increased expression of the genes for suppressor of cytokine signalling protein 1 (SoCS1) and SoCS3 (rEF.87). These proteins bind to phosphotyrosine residues in janus tyrosine kinase 2 (jak2) or the prolactin receptor, thus blocking STAT5b (signal transducer and activator of transcription 5b) activation and tyrosine hydroxylase induction87. This final resetting of the negative-feedback sensitivity of TIDA neurons permits the increase in prolactin secretion that is required for lactation and the induction of maternal behaviour. Increasing oestrogen levels and, particularly, decreasing progesterone levels might regulate this resetting, through oestrogen and progesterone receptors in TIDA neurons82.

The role of endogenous opioids. TIDA neurons are inhib-ited by endogenous opioids in late pregnancy, and this inhibition facilitates the pre-term prolactin surge88. This indicates that a latent dopamine inhibition of prolactin secretion exists at term despite the attenuated stimulation of tyrosine hydroxylase by prolactin, and that inhibition by endogenous opioids keeps the TIDA neurons quiescent at this time to stimulate prolactin secretion88,89. In non-pregnant rats few TIDA neurons co-express enkephalin, but in pregnancy all of them do, possibly as a result of the combined actions of prolactin and progesterone90; whether progesterone acts through allopregnanolone has not been examined. Enkephalin, which is released when the TIDA neurons are stimulated in pregnancy, might be auto-inhibitory, similar to the inhibitory mechanism that has been proposed for noradrenaline release from nTS A2 noradrenergic terminals in the Pvn in late pregnancy25. Furthermore, PomC mRnA levels and -endorphin content in the arcuate nucleus are modestly increased in late pregnancy29.

A few days before term (day 19 in rats), endogenous opioids seem to inhibit prolactin secretion. Thus, naloxone increases prolactin secretion, provided that the stimula-tory action of progesterone on TIDA neurons is blocked to simulate progesterone withdrawal, as at the end of pregnancy91. As naloxone has no effect on TIDA-neuron activity at this time, it might increase prolactin secretion by reversing the opioid inhibition of putative prolactin-releasing-factor neurons91. These might be oxytocin neu-rons, because they are inhibited by endogenous opioids in late pregnancy51 and because oxytocin stimulates prolactin secretion92.

In summary, prolactin secretion in rat pregnancy is reg-ulated differently in early, mid and late pregnancy. In late pregnancy, dopamine synthesis in TIDA neurons desen-sitizes to stimulation by prolactin, and a surge of prolactin secretion follows shortly before birth. The likely trigger for this is progesterone withdrawal. Endogenous-opioid effects on prolactin secretion change from inhibitory to excitatory at this time, possibly reflecting a switch from predominant inhibition of oxytocin neurons to inhibition of TIDA neurons. The pre-partum surge of prolactin secretion ensures lactogenesis and maternal behaviour.

Box 2 | Adaptations in appetite control in pregnancy

Food intake increases in pregnancy as a result of the resetting of central appetite-control mechanisms. These mechanisms include the actions of leptin, an adipocyte hormone that acts on the leptin receptor (Ob-R) in the brain to reduce appetite, reduce energy storage and increase expenditure. In non-pregnant animals, leptin inhibits orexigenic neuropeptide-Y (NPY)/agouti-related peptide-(AgRP) neurons and stimulates anorectic -melanocyte-stimulating-hormone (-MSH)/cocaine-and-amphetamine-regulated-transcript (CART) neurons in the arcuate nucleus (Arc)167. It also activates satiety neurons in the ventromedial hypothalamus (VMH)168.

In pregnancy (see figure), the concentration of circulating leptin increases169. This is a result of the increased amount of adipose tissue (which produces leptin) and secretion by the placenta. In pregnant animals, centrally administered leptin reduces food intake until mid-pregnancy, when central leptin resistance develops170172 (see figure).

Leptin resistance involves decreased expression of the gene that encodes Ob-Rb (the long form of the leptin receptor, which mediates leptin actions) in the VMH168. In addition, Ob-Rb signalling through the phosphorylation of STAT3 (signal transducer and activator of transcription 3) and the nuclear translocation of pSTAT3 is attenuated in VMH neurons during pregnancy168. Prolactin (and presumably placental lactogen) induces similar changes in the VMH, indicating a role for this hormone in leptin resistance173. Moreover, in early pregnancy, reduced Ob-Ra (the leptin transporter) mRNA levels in the choroid plexus and increased leptin binding to circulating Ob-Re (the secretory isoform of the leptin receptor) decreases entry of the peptide into the brain169, further contributing to the reduction in leptin action during pregnancy. Progesterone might have a role in leptin resistance, as it increases food intake and fat storage and decreases thermogenesis174. It can act through progesterone receptors in VMH and Arc neurons60. Ultimately, leptin resistance during pregnancy permits increased appetite and food intake168, despite increased leptin levels, through increased NPY and AgRP mRNA levels in the Arc175,176 and increased NPY innervation in the VMH177.

Allopregnanolone also stimulates food intake and might thus contribute to hyperphagia in pregnancy178. Oxytocin and corticotropin-releasing hormone (CRH) in the brain are anorectic179,180; in late pregnancy their release from the supraoptic nuclei (SON) and the paraventricular nucleus (PVN) in response to central NPY or orexin is reduced166,181. Glucocorticoids are catabolic: in pregnancy energy is conserved by inhibition of hypothalamuspituitaryadrenal (HPA)-axis responses to central NPY and orexin166,182. Together, these mechanisms ensure that there are sufficient nutrients for the fetus(es), sufficient energy for the extra metabolic strain on the mother and a surplus of energy that can be stored as fat in preparation for lactation.

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+

+

+ +

+

+

+

+

+

+

Oxytocinreceptor

OestrogenProgesteroneProlactinOpioids

Oxytocin release

Early-to-mid pregnancy

Late pregnancy and parturition Lactation

Pup odour

Olfactory bulb

MeA/CoA

AH PAG

Aversionto pups

PVN

mPOA vBNST

VTA Maternalbehaviour:rewarding andmotivationNAcc

LS Respond to pups,pup retrieval

DA

Glutamate

NA

GABA

Brain adaptations for maternal behaviourjust as the magnocellular oxytocin and prolactin con-trol systems are set to be activated at term once the inhibitory safety catches are released, so the mecha-nisms that lead to the expression of the multiple ele-ments of maternal behaviour are set to operate with the birth of the offspring (FIG.4). Repeated exposure to young over several days induces maternal behaviour in virgin rats, but the rapid expression of this behav-iour at birth requires prolonged exposure (priming) to pregnancy levels of oestrogen, prolactin/placental lactogen and progesterone, followed by progesterone withdrawal79,93.

Maternal neural networks. A core hierarchical neural circuitry organizes the multiple elements of maternal behaviour and appropriate specific motivation (FIG.4). Before parturition, rats display aversive behaviour towards pups and pup odour. This behaviour is medi-ated by olfactory bulb projections to the cortical and medial amygdaloid nuclei94 and thence to the anterior hypothalamus and periaqueductal grey (PAG)95,96. At parturition, activation of the medial preoptic area (mPoA) and the adjacent ventral bed nucleus of stria terminalis (vBnST) overrides the aversive neophobic responses to newborn odour. This activation induces responsiveness to tactile stimuli from the pups and, through a glutamatergic projection from the mPoA and vBnST to mesolimbic dopamine neurons in the

ventral tegmental area (vTA), to activation of the reward circuitry (involving D1 dopamine receptors in the nucleus accumbens (nAcc)), thus leading to maternal behaviour97,98. In particular, the vTA dopamine projection to the nAcc inhibits GABA output to the ventral pallidum99. The mPoA, through its control of reward circuitry, is hence especially important for initiating gathering of the young, which is an essential preliminary for nursing and milk trans-fer. The withdrawal at birth of upregulated central inhibitory-opioid mechanisms, in particular in the mPoA, facilitates maternal behaviour100,101.

Hormone priming of maternal behaviour. At the end of pregnancy, progesterone withdrawal combined with increasing oestradiol levels activates mPoA neurons102, as does pup-seeking behaviour or post-partum expo-sure to pups98,103. Some activated mPoA neurons are GABAergic104; whether allopregnanolone action in the projection sites of these neurons, such as the anterior hypothalamus, is involved in switching responses to pups at term is unknown.

At birth, oxytocin acts in the mPoA, nAcc, vTA, olfactory bulbs, lateral septum, BnST, Pvn and amyg-dala to stimulate maternal behaviour105. In genetically engineered mice with impaired central oxytocin release, maternal behaviour is deficient but is rescued by cen-tral oxytocin injections, providing further support for an important rapid action of central oxytocin release

Figure 4 |neuralnetworksinvolvedinmaternalbehaviour.Maternal behaviour has several elements: nest-building, gathering the young, nursing, cleaning, protecting and non-aggression towards the young. Different, but interconnected, neural networks are responsible for each element. The medial preoptic area (mPOA) has a central role in the regulation of these maternal behaviours. Hormone priming of the mPOA is mediated by oestrogen, progesterone, prolactin and oxytocin, and receptors for these hormones are upregulated. Oxytocin is released in the brain during parturition and acts on oxytocin receptors in the mPOA, nucleus accumbens (NAcc), ventral tegmental area (VTA), ventral bed nucleus of stria terminalis (vBNST), paraventricular nucleus (PVN), olfactory bulbs, lateral septum (LS) and amygdala, leading to the rapid initiation of maternal behaviour. The aversion to pup odour that is evident in non-pregnant and early-to-mid-pregnant rats is mediated by olfactory bulb projections to the cortical (CoA) and medial (MeA) amygdala and thence to the anterior hypothalamus (AH) and periaqueductal grey (PAG). Activation of the hormonally primed mPOA and the adjacent vBNST on the one hand overrides aversive neophobic responses to newborn odour and on the other hand activates the meso-limbic dopaminergic reward circuitry (VTA and NAcc). The withdrawal at birth of inhibitory central opioid mechanisms, in particular in the mPOA, also facilitates maternal behaviour. DA, dopamine; GABA, -aminobutyric acid; NA, noradrenaline.

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Mitral cellAtypeofneuronthatislocatedintheolfactorysystemandthatprocessesandtransmitsinformationfromprimaryolfactorysensoryneuronstootherbrainregions.

TranscriptomeThesetofallmrNAsproducedinacellorapopulationofcells.

on maternal behaviour106. oxytocin-receptor mRnA is upregulated in mid-pregnancy in the lateral septum, amygdala and mPoA107 and during parturition in the olfactory bulb, mPoA, BnST, amygdala and vmH107,108, resulting in more receptors to mediate oxytocin action and explaining the greater oxytocin-receptor binding that has been observed at parturition109.

Although progesterone withdrawal might under-lie the upregulation of oxytocin-receptor expression in the ventrolateral septum110, a general mechanism of regulation has not been identified107. In several brain areas the density of oxytocin receptors and their upregulation by oestrogen shows epigenetic vari-ability. Increased oxytocin-receptor density (resulting from greater sensitivity to upregulation by oestrogen) correlates with the oxytocin-dependent intensity of maternal behaviour that the dams display and that they experienced themselves as pups111 and might explain the epigenetic intergenerational transfer of the quality of maternal behaviour.

Heterozygous prolactin-receptor-knockout mice have severe maternal-behaviour deficits, demonstrat-ing the essential role of prolactin and/or placental lac-togen in initiating maternal behaviour112. Upregulation of mRnA expression for the long-form prolactin receptor in the mPoA in late pregnancy might be important in enhancing the action of prolactin at this site113 and might result from progesterone withdrawal at term101.

The changes in the brain of pregnant rats that allow the establishment of maternal behaviour are temporary and disappear quickly unless they are reinforced by maternal experience post-partum98. In sheep, maternal olfactory memory of the newborn lamb is essential for bonding and depends on noradrenaline actions in the olfactory bulbs. Here, central oxytocin promotes noradrenaline release, which inhibits GABA input to mitralcells as they respond to lamb odour. mitral cells release glutamate which, through the effects of nitric oxide, strengthens mitral-cellgranule-cell synapses, establishing olfactory memory114.

Maternal aggression. Aggressive behaviour towards intruders begins to emerge in late pregnancy. It remains strongly expressed post-partum and is sustained by ongoing contact with pups. maternal aggression has been linked to reduced fearfulness and anxiety115,116 and involves several brain areas, including the olfac-tory bulbs and olfactory processing circuitry, mPoA, BnST, lateral septum, Pvn, amygdala, ventromedial hypothalamus, lateral hypothalamus and PAG116. Several neurotransmitters and neuropeptides are implicated in the regulation of maternal aggression, including GABA, nitric oxide, oxytocin, vasopressin, opioids, serotonin, dopamine and CRH116.

Studies of the molecular and genetic basis of maternal aggression in mice have shown roles for pheromones and neuronal nitric oxide synthase117. A comparison of the preoptic area/hypothalamus transcriptome of mice bred for extremes of maternal aggressiveness with that of normal mice implicates

reduced nPy receptor 2 (an auto-inhibitory receptor) and increased CRH-binding-protein mRnA levels in extreme aggressiveness: the aggressive phenotype might therefore involve increased actions of nPy and reduced effects of CRH (which are anxiolytic and anxiogenic, respectively)118.

A role for changes in allopregnanolone levels at term in maternal aggression has not been tested, however, GABAA receptors are involved because administration of benzodiazepines (which, like allo-pregnanolone, allosterically modify GABAA receptors) alters maternal aggression: higher doses inhibit and lower doses enhance aggression levels119,120.

Serotonin, progesterone, allopregnanolone and oxytocin. low serotoninergic activity is associated with high levels of aggression116. oestrogen and pro-gesterone might influence the firing rate of dorsal raphe serotonin neurons and modulate forebrain serotonin receptors and serotonin transport and metabolism121,122. The firing activity of serotonin neurons doubles in pregnancy but decreases sharply at term and then increases slightly post-partum121. These changes closely follow plasma progesterone levels, however, serotonergic neurons lack proges-terone receptors, suggesting an indirect action of progesterone or modulation by allopregnanolone121. The increased activity of dorsal raphe serotonin neu-rons during pregnancy reflects reduced inhibition through GABA or 5-hydroxytryptamine 1A (5-HT1A) receptors, and can be induced in non-pregnant rats by chronic central infusion of allopregnanolone122,123. By contrast, acute exposure to allopregnanolone potentiates GABAA-receptor-mediated inhibition of dorsal raphe serotonergic neurons in non-pregnant females124. It is possible that chronic allopregnanolone exposure in pregnancy alters GABA-receptor subunit expression on serotonin neurons or acts on their inhibitory input.

maternal aggression is positively correlated with oxytocin release and action in the Pvn and in the central nucleus of the amygdala125,126. Central oxytocin administration is anxiolytic127,128, and treatment with an oxytocin antagonist reveals a tonic anxiolytic action of oxytocin in late pregnancy127. Hence, the activation of central oxytocin mechanisms at birth both reduces anxiety and fear and stimulates maternal aggressive-ness. Allopregnanolone withdrawal at term might ini-tiate maternal aggression by removing inhibition on centrally projecting oxytocin neurons or decreasing the activity of serotonin neurons.

Implications for post-partum mood disordersPost-partum blues and puerperal depression. Depressed mood in the first few days after birth, also known as the maternity blues, occurs in at least 50% of women129; within 3 months 1013% of new mothers develop major puerperal depression (also called post-natal depression or post-partum depression)78,130. Both conditions compromise motherinfant interactions131 and have been related to dysregulated brain responses

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Mentalstate

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Otherfactors

Depression during pregnancy

Low serotonin Low thyroid hormone

Genetic predisposition

Oestrogen Progesterone Allopregnanolone Cortisol

High CRH Low oxytocin Low lactogen Low opioids

Steroidwithdrawal

Centralpeptidechanges

Post-partummood disorders

Vulnerability

Partu

rition

-indu

ced c

hang

es

Interaction

History ofdepression

in susceptible women to the dramatic changes in hormone levels that occur after birth (FIG.5).

most women who develop puerperal depression are also depressed during the pregnancy132, which might reflect a U-shaped relationship between mood and oestrogen and progesterone levels or between mood and basal ACTH and cortisol secretion, which is high in women in late pregnancy and lower post-partum133. As women who are depressed in pregnancy are more likely to develop puerperal depression132, post-partum depressed mood might have pre-partum origins. The neurochemical changes that underlie motherinfant interactions, such as those that occur in the oxy-tocin and prolactin systems130,134, might contribute to post-partum mood changes.

withdrawal of the pregnancy hormones is an obvi-ous putative cause of altered mood states after birth, but sex-steroid levels in post-partum women do not

correlate reliably with mood. Rather, women who have experienced puerperal depression show greater sensitivity to experimental oestrogen and proges-terone withdrawal135. This could reflect differences in progesterone metabolism or in responsiveness to allopregnanolone.

low thyroid activity in pregnant women has also been linked to post-partum depression136. oestrogen receptors and thyroid hormone receptors compete at the promoter regions of several genes, including the oxytocin and pEnK-A genes, so that low levels of thy-roid hormone enhance the stimulation by oestrogen of transcription of these genes137.

Possible rodent models of post-partum depression that test for depression-like behaviour (increased immobility) in the forced-swim (Porsolt) test have been proposed. Rat mothers show such behaviour after prenatal stress138, postnatal corticosterone treatment139 or repeated separation from pups140. However, these findings were not validated by testing reversal with anti-depressant treatment, and the mechanisms that underlie the behavioural changes are unknown.

Allopregnanolone and mood. Allopregnanolone has anxiolytic and antidepressant actions in animal mod-els141, probably through its actions on GABAA receptors. GABA-receptor binding in the forebrain is increased in late-pregnant rats, and this reverses post-partum, sug-gesting that changes in allopregnanolone levels might be involved in post-partum mood changes142. The reduced depression-like behaviour in late-pregnant rats depends on allopregnanolone synthesis and reverses a few days post-partum, when hippocampal allopreg-nanolone content decreases143. Plasma levels of the allopregnanolone precursor 5-dihydroprogesterone, but not of allopregnanolone itself, are greater in late pregnancy in depressed women, suggesting that synthesis of allopregnanolone might be reduced in these women144. The greatly elevated circulat-ing levels of progesterone and allopregnanolone in late pregnancy decrease dramatically post-partum, although allopregnanolone levels remain increased for more than a week145; serum allopregnanolone levels are lower in women with post-partum blues144 and are also decreased in non-pregnant women with major depression141. By approximately 3 months post- partum, plasma allopregnanolone levels are lower than in women who were not recently pregnant and cere-bral cortical GABA concentrations are also reduced; however, neither allopregnanolone nor GABA levels correlate with puerperal depression146. The concen-tration of GABA in cerebrospinal fluid is already reduced in late pregnancy147. Post-partum mood dis-orders might result, in vulnerable individuals, from a combination of lower allopregnanolone levels (com-pared with non-pregnant women) with a failure to adapt to low GABA release146,147. In addition, GABAA receptors might function less effectively as a result of changes in subunit expression that are induced by exposure to high levels of allopregnanolone in preg-nancy36 followed by decreased allopregnanolone levels

Figure 5 |Factorsthatmightpredisposemotherstopost-partummooddisorders.Post-partum (maternity) blues is experienced by >50% of women within a few days of giving birth; puerperal depression follows within 3 months in 1013% of new mothers. The blues might result from the dramatic withdrawal after birth of the high levels of steroid hormones, including cortisol, oestrogen, progesterone and progesterones neuroactive metabolite, allopregnanolone. Allopregnanolone has anxiolytic and antidepressant actions, and in pregnancy it modulates the activity of several types of neuron that have been implicated in the regulation of mood, including serotonin, endogenous-opioid, oxytocin and corticotropin-releasing-hormone (CRH) neurons. Reversal of these actions post-partum might swing the balance of activity from neurons that favour feeling good (serotonin and opioid neurons, which are stimulated by allopregnanolone in pregnancy) to those that induce feeling low (CRH neurons, which are inhibited by allopregnanolone in pregnancy). In principle, subnormal central actions of oxytocin (and prolactin) are expected to have negative effects on mood post-partum. Puerperal depression might be a late consequence of the changes that might underlie the blues combined with antenatal factors. Factors that might increase susceptibility to puerperal depression include depression during the pregnancy, low thyroid-hormone levels, increased cortisol response to stress, lowering of mood by rapid withdrawal of oestrogen and progesterone (and, presumably, allopregnanolone) and hypoactive serotonin neurons. Selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of puerperal depression.

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post-partum148. Rodent studies indicate that the effects of allopregnanolone withdrawal on mood might relate to decreased central opioid production.

Serotonin and mood. Considering the role of central serotonin in mood regulation, an increase in the activ-ity of dorsal raphe serotonin neurons in late pregnancy might explain the feelings of elation and well-being in women at this time121. Conversely, an abrupt decrease in the electrical activity of serotonin neurons at the end of pregnancy, compounded by reduced tryp-tophan availability, might contribute to the emergence of maternal aggression in rats and low mood after delivery in humans149. Peripartum immune activation and the consequent drive by cytokines of tryptophan metabolism to kynurenine might explain the reduced tryptophan availability: reduced plasma levels of tryp-tophan are found in major depression, but reduced tryptophan availability seems not to explain depressed mood post-partum150. nonetheless, altered serotonergic activity has a role, as a serotonin-transporter gene polymorphism predisposes to puerperal depression151 and selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of this condition152. The actions of SSRIs include the stimulation of central neuroactive steroid synthesis141,153, which is decreased in depression and is normalized by SSRI treatment154. Also, 5HT1A-receptor binding is reduced in women with puerperal depression, especially in the anterior cingulate and mesiotemporal cortices, which are brain regions where 5HT1A-receptor binding is reduced in non-pregnant people with major depression155. It seems likely that the interacting combination of reduced serotonin action and allopregnanolone withdrawal post-partum underlies puerperal depression.

HPA axis and mood. Cortisol or central CRH might also have a role in puerperal depression. In general, cortisol responses to various stressors are reduced in pregnant women156, and women in late pregnancy show a suppressed salivary cortisol response to a physical stressor, presumably reflecting reduced ACTH secre-tion157. However, the salivary cortisol response to a standard social-stress test is undiminished in the sec-ond and third trimesters158. moreover, pregnant women who show greater cortisol and emotional responses to a social-stress test are more likely to experience depressed mood post-partum159. This suggests a causal relationship between greater stress responsiveness in pregnancy and risk of post-partum mood disorder159. whether this reflects a trait associated with abnormal adaptation to the post-partum fall in cortisol level and consequent depressed mood needs investigation132.

To date, investigations in humans of HPA-axis function post-partum have been limited. In the first few weeks post-partum, ACTH responses to exog-enous CRH are reduced whereas cortisol responses are increased. women with post-partum blues have lower than normal ACTH responses to CRH, which might indicate low endogenous CRH production160. This interpretation is opposite to the situation in rats,

in which reduced CRH and vasopressin production by pPvn neurons in late pregnancy10,161 is followed by increased CRH mRnA levels in lactation162.

In most patients with non-pregnancy-related major depression, changes in the central control of the HPA axis are revealed by reduced suppression of ACTH secretion with dexamethasone and increased ACTH and cortisol responses to CRH administration, which is interpreted as increased secretagogue (pos-sibly vasopressin) production by pPvn neurons163,164. Similar studies in post-partum women have not yet been reported.

Conclusions and future perspectivesIn pregnancy, adaptations in several brain systems ensure that the fetus(es) are protected, safely delivered and then cared for. we aimed to identify the signals that might drive these adaptations, and the common mechanisms in the brain that might coordinate these changes.

Progesterone-receptor and oestrogen-receptor-mediated actions in preparing the expectant brain for motherhood are well established. Beyond these are the actions of allopregnanolone, which can act through GABAA receptors on neurons that lack progesterone receptors, for example, oxytocin neurons, to restrain their activity. Peptide hormones that are unique to pregnancy (placental lactogen and relaxin) or are secreted in greater amounts during pregnancy (leptin and prolactin), alter the setpoint of neuroendocrine circuitry and elicit the behaviours that are conducive to an optimal pregnancy outcome. Hence, prolactin and placental lactogen prime maternal behaviour circuitry, override the inhibitory control of prolactin and contribute to leptin resistance, which permits increased appetite.

In the brain, these pregnancy signals upregulate oxytocin receptors, which are important for mater-nal behaviour; alter intracellular signalling in appe-tite-regulating neurons; suppress the activity of the TIDA neurons that regulate prolactin; and inhibit the responses of oxytocin and CRH neurons to stimulation. Induction of central inhibitory-opioid mechanisms, perhaps by allopregnanolone, provides enhanced restraint of noradrenergic, oxytocin, CRH and TIDA neurons and the maternal behaviour cir-cuitry. The withdrawal of the actions of pregnancy hormones on the brain just before birth enables partu-rition, maternal behaviour and lactation; concomitants are maternal aggression in rodents and, commonly, low mood in women. The post-partum normaliza-tion of the multiple pregnancy-related neurochemical changes in the brain is presumed to lead to depres-sion in women who are vulnerable because of genetic factors or predisposing circumstances in the preg-nancy. Thus, normal pregnancy provides remarkable opportunities to characterize the neurobiological basis of changes in appetite, aggressiveness, mood and stress responses, with a view to translating the findings into the novel management of relevant disorders in pregnant and non-pregnant individuals.

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