Adapting For Motherhood

REVIEWS
The expectant brain: adapting

for motherhood
Paula 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.
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: J.A.Russell@ed.ac.uk
doi:10.1038/nrn2280
Published online
12 December 2007
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 pregnancy, 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 behaviour 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 culmination 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 understanding of the organization and molecular mechanisms
of the neuroendocrine networks that govern mammalian
parturition, lactation, maternal behaviour and maternal
stress responsiveness. Understanding these processes
nature reviews | neuroscience
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 adaptations in maternal neuroendocrine systems that are necessary 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 fetus

Exposure to stress or synthetic glucocorticoids during
pregnancy can affect the development of physiological
systems in the offspring, resulting in increased susceptibility 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 maternal 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).
volume 9 | january 2008 | 11
2008 Nature Publishing Group
REVIEWS
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 receptor 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 secretion 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 relationship in pregnancy might be accounted for by oestrogeninduced 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

Psychological stress
Physical stress
+
Limbic
system
Virgin rat
+
Brainstem
CRH/
AVP
mRNA
CRH/
AVP
mRNA
Late-pregnant rat
Hypothalamus (pPVN)
11HSD1
Local corticosterone
CRH/AVP
Median
eminence
CRH/AVP
Anterior
pituitary
ACTH
Circulation
Sensitivity to CRH
CRH receptors
POMC mRNA
11HSD1
ACTH
Adrenal
cortex
Corticosterone
Circulation
Corticosterone
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 proopiomelanocortin (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 rats in
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 11dehydrocorticosterone to active corticosterone) in the
PVN and anterior pituitary10, which might enhance local
glucocorticoid negative feedback.
Nature Reviews | Neuroscience

12 | january 2008 | volume 9
www.nature.com/reviews/neuro
REVIEWS
Brainstem (NTS)
Hypothalamus
(PVN or SON)
A2 noradrenergic
neuron
Adrenergic
receptor
pENK-A
mRNA
Noradrenaline
Oxytocin or
CRH neuron
MOR
mRNA
-opioid
receptor
Enkephalin
IL1
Allopregnanolone
3HSD
5DHP
Circulation
5R
Progesterone
Oxytocin or
CRH release
( in pregnancy)
Pregnancy
Figure 1 | CRH and oxytocin responses to IL1 signalling

areReviews
suppressed
during
Nature
| Neuroscience
pregnancy. 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 proenkephalinA (pENKA) 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 interleukin1 (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.
Physical stressor
A category of stressor
(including infection and injury)
that poses a real threat to
homeostasis or survival and
automatically activates the
HPA axis.
Cholecystokinin
(CCK). A peptide hormone
from the gastrointestinal tract
that stimulates digestion and
signals satiety to the brain.
Interleukin1
(IL1). A pro-inflammatory
cytokine that is produced by
macrophage cells in response
to infection.
level of both the anterior pituitary and the hypothalamus

(BOX1), as well as at higher brain regions20. Several mechanisms 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 transcription23,24. Physical stressors, including systemic administration of cholecystokinin (CCK) and interleukin1 (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 activated in pregnant and non-pregnant rats, at least by IL1
administration25. Whereas decreased 1-adrenergicreceptor mRNA levels in the pPVN26 might contribute
to reduced basal HPA-axis activity, the suppressed HPAaxis responses to stress in pregnancy are attributable to
inhibition by endogenous opioids.
Endogenous opioids have a modulatory role in HPAaxis 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 swimming27, 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 pregnancy 29.
However, endorphin is unlikely to mediate opioid
actions on responses to acute stress because -endorphin neurons respond slowly30. The NTS is a more likely
source of endogenous opioids: NTS neurons synthesize
enkephalins and dynorphins31,32, and gene expression for
pENKA 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 enkephalin 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 suppressing ACTH secretion after pharmacological adrenalectomy 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 moderately increased on day 21 of pregnancy10. However,
delayed negative-feedback mechanisms might be more
effective in pregnancy: 11-hydroxysteroid dehydrogenase 1 (11HSD1; the enzyme that reactivates inert
11-dehydrocorticosterone to active corticosterone) activity
is increased in the PVN and anterior pituitary in late pregnancy10; the consequent increased availability of intracellular corticosterone might contribute to the late-pregnancy
reduction in basal CRH and vasopressin (in the PVN) and
POMC gene expression (in the pituitary).
REVIEWS
Endogenous opioids
Peptides, including dynorphins,
endomorphins, endorphins and
enkephalins, that are produced
naturally in the body and, like
morphine, act through opioid
receptors.
Neuroactive steroid
A steroid derivative that
rapidly alters neuronal
excitability through interaction
with neurotransmitter-gated
ion channels.
Allosteric modulator
A molecule that binds to a
receptor at a regulatory site
that is distinct from the active
ligand-binding site to influence
the receptors function.
Oxytocin, sex steroids and neuroactive steroids. In nonpregnant rats, centrally released oxytocin reduces HPAaxis responses to stress33,34. However, in late pregnancy
an oxytocin antagonist fails to reverse the suppressed
HPA-axis responses to stress34, indicating that endogenous intracerebral oxytocin does not maintain HPA
hyporesponsiveness at this time.
In the rat, oestrogen and progesterone levels peak during 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 neuroactive
steroid allopregnanolone (3-hydroxy5-pregnan20one) 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 allosteric
modulator 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 preliminary findings43 with finasteride (which blocks allopregnanolone production by inhibiting the activity of 5R36)
support such a role: in late pregnancy finasteride restores
the ACTH response to systemic IL1. Furthermore, studies 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 suppressive 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 implications 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.
Opioid restraint of oxytocin neurons. During pregnancy,

opioids (dynorphin, Met-enkephalin-Arg6Phe7 and
Met-enkephalin-Arg6Gly7Leu8) co-produced by oxytocin 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 opioidreceptor-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 oxytocin neurons and enhances oxytocin secretion (including 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.
Adaptations in the maternal oxytocin system

Oxytocin is produced by neurons in the PVN and
the supraoptic nuclei (SON)46 of the hypothalamus.
The magnocellular PVN and SON neurons project to
GABA inhibition of oxytocin neurons. GABA innervation provides the major inhibitory synaptic input to
oxytocin neurons. As magnocellular oxytocin neurons
do not express progesterone receptors60, progesterone
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 parturition by stimulating uterine contractions. Oxytocin
released centrally during parturition facilitates the rapid
onset of maternal behaviour and modulates emotionality47. 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 stressors49, 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.
REVIEWS
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 neurons 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 controller, and the oxytocin neurons remain relatively quiescent
until close to term.
NTS
neuron
pENK-A
mRNA
MOR
mRNA
-opioid receptor
Enkephalin
Noradrenaline
Adrenergic
receptor
+
Dephosphorylation
Allopregnanolone
+
GABA
synapse
GABA
receptor
Oestrogen
and oxytocin
Dendritic
oxytocin
release
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 administration in late pregnancy57. This might not depend on
GABAA receptors on oxytocin neurons, as finasteride
reverses opioid inhibition of these neurons57.
Posterior
pituitary
Local network-distant input. Oxytocin neurons burstfire 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, oestrogen-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 excitatory 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 receptors74,75 (FIG.3). The consequent bursts are then shaped
by properties of the oxytocin neurons75. These mechanisms explain how a locally applied oxytocin antagonist
disrupts parturition by preventing dendritic oxytocin
release and action48,71.
Magnocellular
oxytocin neuron
Firing rate
Oxytocin storage
Figure 2 | Magnocellular oxytocin neurons in late pregnancy. Interacting

Nature
Reviews
| Neuroscience
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
interleukin1 (IL1)). Specifically, proenkephalinA (pENKA) 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.
Endocannabinoid
A signalling molecule that is
structurally related to tetra
hydrocannabinol (the main
active substance found in
cannabis). Endocannabinoids
released by neurons act
through cannabinoid receptors
to modulate synaptic input.
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 oxytocin neuron is much greater than in early pregnancy,
as a consequence of increased GABA synapse number,

REVIEWS
Lactogen
A peptide hormone that
stimulates milk production (for
example, prolactin and
placental lactogen).
The morphological changes in gliaoxytocin-neuron

associations that occur around birth and were previously
linked to burst-firing76 appear to be unimportant, as oxytocin neurons can burst-fire in late pregnancy, before
such changes occur48. Moreover, preventing these neuroglial changes has no impact on parturition or burstfiring during suckling77.
NTS A2
neurons
Noradrenaline
Adrenergic
receptor
+
+
Dendritic
oxytocin
release
Coupling
Oxytocin
receptor
Central
opioid
mechanisms
Burst firing
GABA
function
Allopregnanolone
Posterior
pituitary
Oxytocin release
Circulation
Oxytocin
Uterus
Figure 3 | Magnocellular oxytocin neurons at parturition. Parturition starts with

locally organized uterine contractions. These stimulate nucleus tractus solitarii (NTS) A2
Nature
Reviews | Neuroscience
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 neurons and 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.
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 appropriate 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 system

Prolactin is essential for the stimulation of milk secretion, 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 secretion 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 ratelimiting 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.
REVIEWS
Box 2 | Adaptations in appetite control in pregnancy
Food intake increases in pregnancy as a result of the resetting of central appetitecontrol mechanisms. These mechanisms include the actions of leptin, an adipocyte
hormone that acts on the leptin receptor (ObR) 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-andamphetamine-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.
Leptin signalling
Choroid
plexus:
Ob-Ra
Circulation:
Ob-Re binding
Arc:
NPY mRNA
AgRP mRNA
VMH:
Ob-Rb mRNA
STAT3
pSTAT3
NPY innervation
Leptin resistance
+
Lactogen
Appetite,
food intake
Leptin
+
Placenta
Adipose
tissue
+
SON/PVN:
OT release
CRH mRNA
Energy
expenditure
HPA axis:
Glucocorticoid
Progesterone
Nature Reviews | Neuroscience

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 inhibited 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 nonpregnant 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 stimulatory 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 prolactinreleasing-factor neurons91. These might be oxytocin neurons, because they are inhibited by endogenous opioids in
late pregnancy51 and because oxytocin stimulates prolactin
secretion92.
In summary, prolactin secretion in rat pregnancy is regulated differently in early, mid and late pregnancy. In late
pregnancy, dopamine synthesis in TIDA neurons desensitizes 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.
REVIEWS
Late pregnancy and parturition
Early-to-mid
pregnancy
Lactation
NA
+
Pup odour
Olfactory bulb
+
mPOA
vBNST
VTA
DA
+
PAG
Glutamate
+
GABA
MeA/CoA
+
AH
PVN
Oxytocin
receptor +
Oxytocin
release
+
Oestrogen
Progesterone
Prolactin
Opioids
NAcc
Maternal
behaviour:
rewarding
and
motivation
+
LS
Respond to pups,
pup retrieval
Aversion
to pups
Figure 4 | Neural networks involved in maternal behaviour. Maternal behaviour has several elements: nest-building,
gathering the young, nursing, cleaning, protecting and non-aggression towards the young. Different,
interconnected,
Naturebut
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| Neuroscience
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.
Brain adaptations for maternal behaviour

Just as the magnocellular oxytocin and prolactin control systems are set to be activated at term once the
inhibitory safety catches are released, so the mechanisms that lead to the expression of the multiple elements 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 behaviour 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 mediated 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 behaviour 97,98. 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 transfer. 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 exposure 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 central oxytocin injections, providing further support for
an important rapid action of central oxytocin release
REVIEWS
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 underlie the upregulation of oxytocin-receptor expression
in the ventrolateral septum110, a general mechanism
of regulation has not been identified 107. In several
brain areas the density of oxytocin receptors and their
upregulation by oestrogen shows epigenetic variability. 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, demonstrating the essential role of prolactin and/or placental lactogen 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
mitral cells 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.
Mitral cell
A type of neuron that is
located in the olfactory system
and that processes and
transmits information from
primary olfactory sensory
neurons to other brain regions.
Transcriptome
The set of all mRNAs produced
in a cell or a population of cells.
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 olfactory bulbs and olfactory processing circuitry, mPOA,
BNST, lateral septum, PVN, amygdala, ventromedial
hypothalamus, lateral hypothalamus and PAG 116.
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 synthase 117.
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, GABA A receptors are involved because
administration of benzodiazepines (which, like allopregnanolone, 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 progesterone might influence the firing rate of dorsal
raphe serotonin neurons and modulate forebrain
serotonin receptors and serotonin transport and
metabolism 121,122. 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 progesterone receptors, suggesting an indirect action of
progesterone or modulation by allopregnanolone121.
The increased activity of dorsal raphe serotonin neurons during pregnancy reflects reduced inhibition
through GABA or 5-hydroxytryptamine 1A (5HT1A)
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 aggressiveness. Allopregnanolone withdrawal at term might initiate maternal aggression by removing inhibition on
centrally projecting oxytocin neurons or decreasing
the activity of serotonin neurons.
Implications for post-partum mood disorders

Post-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 postnatal depression or post-partum depression)78,130. Both
conditions compromise motherinfant interactions131
and have been related to dysregulated brain responses
REVIEWS
es
ng
e
ln
Vu
Genetic
factors
Other
factors
y
lit
bi
ra
Mental
state
History of
depression
Depression
during pregnancy
ch
-in
ur
rt
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n
tio
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uc
Oestrogen
Progesterone
Allopregnanolone
Cortisol
Steroid
withdrawal
High CRH
Low oxytocin
Low lactogen
Low opioids
Central
peptide
changes
Genetic predisposition
Low serotonin
Low thyroid
hormone
Interaction
Post-partum
mood disorders
Figure 5 | Factors that might predispose mothers to post-partum mood

disorders. Post-partum (maternity) blues is experienced by
>50%
of women
within a
Nature
Reviews
| Neuroscience
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-releasinghormone (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.
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 Ushaped 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 oxytocin and prolactin systems130,134, might contribute to
post-partum mood changes.
Withdrawal of the pregnancy hormones is an obvious 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 progesterone 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 pENKA genes, so that low levels of thyroid 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 models141, probably through its actions on GABAA receptors.
GABA-receptor binding in the forebrain is increased in
late-pregnant rats, and this reverses post-partum, suggesting that changes in allopregnanolone levels might
be involved in post-partum mood changes 142. The
reduced depression-like behaviour in late-pregnant
rats depends on allopregnanolone synthesis and reverses
a few days post-partum, when hippocampal allopregnanolone content decreases 143. 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 women 144. The greatly elevated circulating levels of progesterone and allopregnanolone in
late pregnancy decrease dramatically post-partum,
although allopregnanolone levels remain increased
for more than a week 145; 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 postpartum, 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 concentration of GABA in cerebrospinal fluid is already
reduced in late pregnancy147. Post-partum mood disorders might result, in vulnerable individuals, from a
combination of lower allopregnanolone levels (compared 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 pregnancy36 followed by decreased allopregnanolone levels
REVIEWS
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 activity 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 tryptophan 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 tryptophan 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 secretion157. However, the salivary cortisol response to a
standard social-stress test is undiminished in the second 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 exogenous 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 production 160.
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 (possibly vasopressin) production by pPVN neurons163,164.
Similar studies in post-partum women have not yet
been reported.
Conclusions and future perspectives

In 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-receptormediated 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 maternal behaviour; alter intracellular signalling in appetite-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 circuitry. The withdrawal of the actions of pregnancy
hormones on the brain just before birth enables parturition, maternal behaviour and lactation; concomitants
are maternal aggression in rodents and, commonly,
low mood in women. The post-partum normalization of the multiple pregnancy-related neurochemical
changes in the brain is presumed to lead to depression in women who are vulnerable because of genetic
factors or predisposing circumstances in the pregnancy. 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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Acknowledgements
This work was supported by grants from the Biotechnology
and Biological Sciences Research Council (BBSRC) UK.
DATABASES
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
3HSD | 5R | 11HSD1 | 11HSD2 | CCK | CRH | Il1 | leptin |
ObR | POMC | prolactin
FURTHER INFORMATION
Paula J. Bruntons homepage:
http://www.cip.ed.ac.uk/members/HRB/brunton/index.htm
John A. Russells homepage:
http://www.cip.ed.ac.uk/members/HRB/russell/index.htm
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REVIEWS

The expectant brain: adapting

Abstract | A successful pregnancy requires multiple adaptations of the mothers

The maternal brain is a major force in driving essential

nature reviews | neuroscience

might help improve the management of pregnancy to

Protecting the fetus

2008 Nature Publishing Group

(ACTH) secretion that is evident early in pregnancy

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

Stressors are generally categorized as either psychological

Nature Reviews | Neuroscience

Figure 1 | CRH and oxytocin responses to IL1 signalling

level of both the anterior pituitary and the hypothalamus

nature reviews | neuroscience

rats, both systemic administration of IL125 and forced

2008 Nature Publishing Group

Opioid restraint of oxytocin neurons. During pregnancy,

Adaptations in the maternal oxytocin system

14 | january 2008 | volume 9

the posterior pituitary gland, and when action potentials

Allopregnanolone and opioid tone. The induction of

Figure 2 | Magnocellular oxytocin neurons in late pregnancy. Interacting

acts indirectly through its metabolite allopregnanolone,

nature reviews | neuroscience

volume 9 | january 2008 | 15

The morphological changes in gliaoxytocin-neuron

Figure 3 | Magnocellular oxytocin neurons at parturition. Parturition starts with

16 | january 2008 | volume 9

Implications for other brain systems. The finding that, at

Adaptations in the maternal prolactin system

2008 Nature Publishing Group

nature reviews | neuroscience

Nature Reviews | Neuroscience

A nocturnal increase in prolactin secretion occurs near

Brain adaptations for maternal behaviour

ventral tegmental area (VTA), to activation of the

2008 Nature Publishing Group

Maternal aggression. Aggressive behaviour towards

nature reviews | neuroscience

reduced NPY receptor 2 (an auto-inhibitory receptor)

Implications for post-partum mood disorders

2008 Nature Publishing Group

Figure 5 | Factors that might predispose mothers to post-partum mood

in susceptible women to the dramatic changes in

correlate reliably with mood. Rather, women who

2008 Nature Publishing Group

in which reduced CRH and vasopressin production

Conclusions and future perspectives

2008 Nature Publishing Group

Russell, J.A., Douglas, A.J. & Ingram, C.D.

19. Windle, R.J. et al. Endocrine and behavioural

22 | january 2008 | volume 9

37. Douglas, A.J., Johnstone, H., Brunton, P. & Russell,

78. Gaynes, B.N. et al. Perinatal depression:

nature reviews | neuroscience

96. Sukikara, M.H., Mota-Ortiz, S.R., Baldo, M.V.,

volume 9 | january 2008 | 23

137. Vasudevan, N., Ogawa, S. & Pfaff, D. Estrogen and

24 | january 2008 | volume 9

157. Kammerer, M., Adams, D., Castelberg, B. v. & Glover, V.

179. Sahu, A. Leptin signaling in the hypothalamus:

nature reviews | neuroscience