1 2008 Vol: 9(1):11-25. DOI: 10.1038/nrn2280

The expectant brain: adapting for motherhood

A successful pregnancy requires multiple adaptations of the mother's 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 mother's brain, predominantly through changes in neuroendocrine systems, and these changes are primarily driven by the hormones of pregnancy. By contrast, adaptations in the mother's 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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Figures
Figure 1: CRH and oxytocin responses to IL1 signalling are suppressed during 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 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 hypothalamus–pituitary–adrenal (HPA)-axis and oxytocin–neurohypophysial responses, respectively. Figure 2: Magnocellular oxytocin neurons in late pregnancy.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. Figure 3: Magnocellular oxytocin neurons at parturition.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 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. 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, 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. Figure 5: Factors that might predispose mothers to post-partum mood disorders.Post-partum (maternity) blues is experienced by >50% of women within a few days of giving birth; puerperal depression follows within 3 months in 10–13% 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 progesterone's 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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References
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    • . . . 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 . . .
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    • . . . 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 hypothalamus–pituitary–adrenal (HPA) axis (Box 1). . . .
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    • . . . During pregnancy, -opioids (dynorphin, Met-enkephalin-Arg6 Phe7 and Met-enkephalin-Arg6 Gly7 Leu8) co-produced by oxytocin neurons pre-terminally inhibit oxytocin release in the posterior pituitary55, 56 . . .
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    • . . . 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 in utero6, 7, 8, 9 . . .
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    • . . . 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 . . .
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    • . . . In rats this hyporesponsiveness is evident from day 15 of gestation and persists through pregnancy17, parturition18 and lactation, until weaning19 . . .
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    • . . . In rats this hyporesponsiveness is evident from day 15 of gestation and persists through pregnancy17, parturition18 and lactation, until weaning19 . . .
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    • . . . In rats this hyporesponsiveness is evident from day 15 of gestation and persists through pregnancy17, parturition18 and lactation, until weaning19 . . .
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    • . . . These CRH neurons express 1-adrenergic receptors21 and are directly excited by noradrenaline22, which induces CRH gene transcription23, 24 . . .
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    • . . . These CRH neurons express 1-adrenergic receptors21 and are directly excited by noradrenaline22, which induces CRH gene transcription23, 24 . . .
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    • . . . These CRH neurons express 1-adrenergic receptors21 and are directly excited by noradrenaline22, which induces CRH gene transcription23, 24 . . .
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    • . . . These CRH neurons express 1-adrenergic receptors21 and are directly excited by noradrenaline22, which induces CRH gene transcription23, 24 . . .
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    • . . . 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 . . .
    • . . . 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 endogenous opioids. . . .
    • . . . 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 . . .
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    • . . . 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 . . .
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    • . . . 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 . . .
    • . . . Furthermore, POMC mRNA levels and -endorphin content in the arcuate nucleus are modestly increased in late pregnancy29. . . .
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    • . . . 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 . . .
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    • . . . 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 . . .
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    • . . . In non-pregnant rats, centrally released oxytocin reduces HPA-axis responses to stress33, 34 . . .
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    • . . . 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 endogenous intracerebral oxytocin does not maintain HPA hyporesponsiveness at this time. . . .
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    • . . . 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 . . .
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    • . . . 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 . . .
    • . . . Circulating and brain levels of allopregnanolone increase during pregnancy, as a consequence of increasing progesterone secretion36 . . .
    • . . . 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 . . .
    • . . . 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 post-partum148 . . .
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    • . . . Both of these converting enzymes are expressed in the brain38 and in the liver39, 40 . . .
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    • . . . Both of these converting enzymes are expressed in the brain38 and in the liver39, 40 . . .
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    • . . . Both of these converting enzymes are expressed in the brain38 and in the liver39, 40 . . .
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    • . . . 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 . . .
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    • . . . Indeed, treatment with allopregnanolone reduces stress-induced HPA activity in both male42 and female43 rats. . . .
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    • . . . Indeed, treatment with allopregnanolone reduces stress-induced HPA activity in both male42 and female43 rats. . . .
    • . . . 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 . . .
  44. Blyth, B. J., Hauger, R. L., Purdy, R. H. & Amico, J. A. The neurosteroid allopregnanolone modulates oxytocin expression in the hypothalamic paraventricular nucleus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 278, R684-R691 , (2000) .
    • . . . 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. . . .
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    • . . . 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. . . .
  46. Russell, J. A. & Brunton, P. J. Oxytocin: peripheral/central actions and their regulation. In The New Encyclopedia of Neuroscience (eds Squire, L. et al.) (in the press) , .
    • . . . Oxytocin is produced by neurons in the PVN and the supraoptic nuclei (SON)46 of the hypothalamus . . .
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    • . . . Oxytocin released centrally during parturition facilitates the rapid onset of maternal behaviour and modulates emotionality47 . . .
  48. Russell, J. A., Leng, G. & Douglas, A. J. The magnocellular oxytocin system, the fount of maternity: adaptations in pregnancy. Front. Neuroendocrinol. 24, 27-61 , (2003) .
    • . . . Burst-firing depends on positive feedback by dendritically released oxytocin in the PVN or SON48. . . .
    • . . . Oxytocin neurons burst-fire during parturition and in response to suckling, in late pregnancy as well as in lactation48, 66 . . .
    • . . . 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 . . .
    • . . . These mechanisms explain how a locally applied oxytocin antagonist disrupts parturition by preventing dendritic oxytocin release and action48, 71. . . .
    • . . . The morphological changes in glia–oxytocin-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 . . .
  49. Lang, R. E. et al. Oxytocin unlike vasopressin is a stress hormone in the rat. Neuroendocrinology 37, 314-316 , (1983) .
    • . . . 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 . . .
  50. Brunton, P. J., Sabatier, N., Leng, G. & Russell, J. A. Suppressed oxytocin neuron responses to immune challenge in late pregnant rats: a role for endogenous opioids. Eur. J. Neurosci. 23, 1241-1247 , (2006) .
  51. Douglas, A. J. et al. Central endogenous opioid inhibition of supraoptic oxytocin neurons in pregnant rats. J. Neurosci. 15, 5049-5057 , (1995) .
    • . . . 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 . . .
    • . . . 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 . . .
    • . . . These might be oxytocin neurons, because they are inhibited by endogenous opioids in late pregnancy51 and because oxytocin stimulates prolactin secretion92. . . .
  52. Onaka, T., Luckman, S. M., Antonijevic, I., Palmer, R. & Leng, G. Involvement of the noradrenergic afferents from the nucleus tractus solitarii to the supraoptic nucleus in oxytocin release after peripheral cholecystokinin octapeptide in the rat. Neuroscience 66, 403-412 , (1995) .
    • . . . 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 . . .
  53. Buller, K. M., Xu, Y., Dayas, C. V. & Day, T. A. Dorsal and ventral medullary catecholamine cell groups contribute differentially to systemic interleukin-1-induced HPA axis responses. Neuroendocrinology 73, 129-138 , (2001) .
    • . . . 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 . . .
    • . . . 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. . . .
  54. Meddle, S. L., Leng, G., Selvarajah, J. R., Bicknell, R. J. & Russell, J. A. Direct pathways to the supraoptic nucleus from the brainstem and the main olfactory bulb are activated at parturition in the rat. Neuroscience 101, 1013-1021 , (2000) .
    • . . . 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 . . .
  55. Douglas, A. J., Dye, S., Leng, G., Russell, J. A. & Bicknell, R. J. Endogenous opioid regulation of oxytocin secretion through pregnancy in the rat. J. Neuroendocrinol. 5, 307-314 , (1993) .
    • . . . During pregnancy, -opioids (dynorphin, Met-enkephalin-Arg6 Phe7 and Met-enkephalin-Arg6 Gly7 Leu8) co-produced by oxytocin neurons pre-terminally inhibit oxytocin release in the posterior pituitary55, 56 . . .
  56. Leng, G., Dye, S. & Bicknell, R. J. -opioid restraint of oxytocin secretion: plasticity through pregnancy. Neuroendocrinology 66, 378-383 , (1997) .
    • . . . During pregnancy, -opioids (dynorphin, Met-enkephalin-Arg6 Phe7 and Met-enkephalin-Arg6 Gly7 Leu8) co-produced by oxytocin neurons pre-terminally inhibit oxytocin release in the posterior pituitary55, 56 . . .
  57. Russell, J. A. & Brunton, P. J. Neuroactive steroids attenuate oxytocin stress responses in late pregnancy. Neuroscience 138, 879-889 , (2006) .
    • . . . 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 . . .
    • . . . 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. . . .
  58. Leng, G. et al. Endogenous opioid actions and effects of environmental disturbance on parturition and oxytocin secretion in rats. J. Reprod. Fertil. 84, 345-356 , (1988) .
    • . . . 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 . . .
  59. Ericsson, A., Kovacs, K. J. & Sawchenko, P. E. A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons. J. Neurosci. 14, 897-913 , (1994) .
    • . . . 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. . . .
  60. Francis, K., Meddle, S. L., Bishop, V. R. & Russell, J. A. Progesterone receptor expression in the pregnant and parturient rat hypothalamus and brainstem. Brain Res. 927, 18-26 , (2002) .
    • . . . As magnocellular oxytocin neurons do not express progesterone receptors60, progesterone acts indirectly through its metabolite allopregnanolone, which enhances GABAA-receptor function on oxytocin neurons61. . . .
  61. Brussaard, A. B. & Herbison, A. E. Long-term plasticity of postsynaptic GABAA-receptor function in the adult brain: insights from the oxytocin neurone. Trends Neurosci. 23, 190-195 , (2000) .
    • . . . As magnocellular oxytocin neurons do not express progesterone receptors60, progesterone acts indirectly through its metabolite allopregnanolone, which enhances GABAA-receptor function on oxytocin neurons61. . . .
  62. Koksma, J. J., Fritschy, J. M., Mack, V., Van Kesteren, R. E. & Brussaard, A. B. Differential GABAA receptor clustering determines GABA synapse plasticity in rat oxytocin neurons around parturition and the onset of lactation. Mol. Cell. Neurosci. 28, 128-140 , (2005) .
    • . . . The GABAA-receptor-mediated current density per oxytocin 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 . . .
    • . . . 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 . . .
  63. Theodosis, D. T. et al. Oxytocin and estrogen promote rapid formation of functional GABA synapses in the adult supraoptic nucleus. Mol. Cell. Neurosci. 31, 785-794 , (2006) .
    • . . . 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 . . .
  64. Koksma, J. J. et al. Oxytocin regulates neurosteroid modulation of GABAA receptors in supraoptic nucleus around parturition. J. Neurosci. 23, 788-797.This intriguing study shows how oxytocin acts on oxytocin neurons to desensitize GABAA receptors to allopregnanolone at the end of pregnancy , (2003) .
    • . . . 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 . . .
    • . . . The finding that, at term, oxytocin acts on oxytocin neurons to desensitize GABAA receptors to allopregnanolone suggests a wider importance for this phenomenon64 . . .
  65. Way, S. A. et al. Endogenous opioid regulation of oxytocin release during parturition is reduced in ovariectomized rats. J. Endocrinol. 138, 13-22 , (1993) .
    • . . . 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 . . .
  66. Jiang, Q. B. & Wakerley, J. B. Analysis of bursting responses of oxytocin neurones in the rat in late pregnancy, lactation and after weaning. J. Physiol. 486, 237-248.This paper describes the emergence, in late pregnancy, of the burst-firing responses of oxytocin neurons to suckling. These responses are classically associated with the milk-ejection reflex in lactation , (1995) .
    • . . . Oxytocin neurons burst-fire during parturition and in response to suckling, in late pregnancy as well as in lactation48, 66 . . .
  67. Wang, Y. F. & Hatton, G. I. Burst firing of oxytocin neurons in male rat hypothalamic slices. Brain Res. 1032, 36-43 , (2005) .
    • . . . This capacity to burst-fire is intrinsic to oxytocin neurons: noradrenaline induces burst-firing even in vitro67 . . .
  68. Teruyama, R. & Armstrong, W. E. Changes in the active membrane properties of rat supraoptic neurones during pregnancy and lactation. J. Neuroendocrinol. 14, 933-944 , (2002) .
    • . . . Minor changes in the electrophysiological properties of oxytocin neurons in pregnancy increase their excitability68 . . .
  69. Herbison, A. E., Voisin, D. L., Douglas, A. J. & Chapman, C. Profile of monoamine and excitatory amino acid release in rat supraoptic nucleus over parturition. Endocrinology 138, 33-40 , (1997) .
    • . . . 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 . . .
  70. Fenelon, V. S. & Herbison, A. E. Progesterone regulation of GABAA receptor plasticity in adult rat supraoptic nucleus. Eur. J. Neurosci. 12, 1617-1623 , (2000) .
    • . . . 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 . . .
  71. Neumann, I., Douglas, A. J., Pittman, Q. J., Russell, J. A. & Landgraf, R. Oxytocin released within the supraoptic nucleus of the rat brain by positive feedback action is involved in parturition-related events. J. Neuroendocrinol. 8, 227-233 , (1996) .
    • . . . Furthermore, parturition stimulates the somato-dendritic release of oxytocin48, 71 . . .
  72. Richard, P., Moos, F. & Freund-Mercier, M. J. Central effects of oxytocin. Physiol. Rev. 71, 331-370 , (1991) .
    • . . . This has an essential autoregulatory positive-feedback role (Fig. 3), acting through receptors on the oxytocin neurons to stimulate further oxytocin release72 . . .
  73. Hirasawa, M. et al. Dendritically released transmitters cooperate via autocrine and retrograde actions to inhibit afferent excitation in rat brain. J. Physiol. 559, 611-624 , (2004) .
    • . . . Thus, neighbouring oxytocin neurons indirectly inhibit one another73 . . .
  74. Leng, G. & Brown, D. The origins and significance of pulsatility in hormone secretion from the pituitary. J. Neuroendocrinol. 9, 493-513 , (1997) .
    • . . . 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) . . .
  75. Wang, Y. F. & Hatton, G. I. Dominant role of subunits of G-proteins in oxytocin-evoked burst firing. J. Neurosci. 27, 1902-1912 , (2007) .
    • . . . 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 . . .
  76. Theodosis, D. T. Oxytocin-secreting neurons: a physiological model of morphological neuronal and glial plasticity in the adult hypothalamus. Front. Neuroendocrinol. 23, 101-135 , (2002) .
    • . . . The morphological changes in glia–oxytocin-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 . . .
  77. Catheline, G., Touquet, B., Lombard, M. C., Poulain, D. A. & Theodosis, D. T. A study of the role of neuro-glial remodeling in the oxytocin system at lactation. Neuroscience 137, 309-316 , (2006) .
    • . . . Moreover, preventing these neuro-glial changes has no impact on parturition or burst-firing during suckling77. . . .
  78. Gaynes, B. N. et al. Perinatal depression: prevalence, screening accuracy, and screening outcomes. Evid. Rep. Technol. Assess. (Summ.) 119, 1-8 , (2005) .
    • . . . In pregnant women, circulating prolactin increases by 15-fold78 . . .
    • . . . 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 10–13% of new mothers develop major puerperal depression (also called postnatal depression or post-partum depression)78, 130 . . .
  79. Mann, P. E. & Bridges, R. S. Lactogenic hormone regulation of maternal behavior. Prog. Brain Res. 133, 251-262.This chapter reviews research that has revealed the importance of prolactin and placental lactogens in the priming of medial preoptic neurons for their key role in the display of maternal behaviour after birth , (2001) .
    • . . . In the night before parturition, prolactin secretion surges; as prolactin acts in the brain to elicit maternal behaviour79, this surge contributes to a successful transition from pregnancy to motherhood. . . .
    • . . . 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. . . .
  80. Torner, L., Toschi, N., Nava, G., Clapp, C. & Neumann, I. D. Increased hypothalamic expression of prolactin in lactation: involvement in behavioural and neuroendocrine stress responses. Eur. J. Neurosci. 15, 1381-1389 , (2002) .
    • . . . Prolactin also acts in the brain to reduce HPA-axis responses to stress80, stimulate neurogenesis and regulate its own secretion81, 82 . . .
  81. Grattan, D. R. Behavioural significance of prolactin signalling in the central nervous system during pregnancy and lactation. Reproduction 123, 497-506 , (2002) .
    • . . . Prolactin also acts in the brain to reduce HPA-axis responses to stress80, stimulate neurogenesis and regulate its own secretion81, 82 . . .
  82. Andrews, Z. B. Neuroendocrine regulation of prolactin secretion during late pregnancy: easing the transition into lactation. J. Neuroendocrinol. 17, 466-473 , (2005) .
    • . . . Prolactin also acts in the brain to reduce HPA-axis responses to stress80, stimulate neurogenesis and regulate its own secretion81, 82 . . .
    • . . . Increasing oestrogen levels and, particularly, decreasing progesterone levels might regulate this resetting, through oestrogen and progesterone receptors in TIDA neurons82. . . .
  83. Augustine, R. A., Kokay, I. C., Andrews, Z. B., Ladyman, S. R. & Grattan, D. R. Quantitation of prolactin receptor mRNA in the maternal rat brain during pregnancy and lactation. J. Mol. Endocrinol. 31, 221-232 , (2003) .
    • . . . 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 . . .
  84. Pi, X., Zhang, B., Li, J. & Voogt, J. L. Promoter usage and estrogen regulation of prolactin receptor gene in the brain of the female rat. Neuroendocrinology 77, 187-197 , (2003) .
    • . . . 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 . . .
  85. Ma, F. Y. et al. Prolactin specifically activates signal transducer and activator of transcription 5b in neuroendocrine dopaminergic neurons. Endocrinology 146, 5112-5119 , (2005) .
    • . . . 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 . . .
    • . . . Prolactin also opposes dopamine inhibition of tyrosine hydroxylase, by inducing phosphorylation of the enzyme by protein kinases85 . . .
  86. Lee, Y. & Voogt, J. L. Feedback effects of placental lactogens on prolactin levels and Fos-related antigen immunoreactivity of tuberoinfundibular dopaminergic neurons in the arcuate nucleus during pregnancy in the rat. Endocrinology 140, 2159-2166 , (1999) .
    • . . . From mid-pregnancy onwards, placental lactogen also suppresses maternal prolactin secretion86. . . .
  87. Anderson, G. M. et al. Suppression of prolactin-induced signal transducer and activator of transcription 5b signaling and induction of suppressors of cytokine signaling messenger ribonucleic acid in the hypothalamic arcuate nucleus of the rat during late pregnancy and lactation. Endocrinology 147, 4996-5005 , (2006) .
    • . . . 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 . . .
  88. Andrews, Z. B. & Grattan, D. R. Opioid control of prolactin secretion in late pregnant rats is mediated by tuberoinfundibular dopamine neurons. Neurosci. Lett. 328, 60-64 , (2002) .
    • . . . 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 . . .
  89. Andrews, Z. B. & Grattan, D. R. Opioid receptor subtypes involved in the regulation of prolactin secretion during pregnancy and lactation. J. Neuroendocrinol. 15, 227-236 , (2003) .
    • . . . 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 . . .
  90. Merchenthaler, I., Lennard, D. E., Cianchetta, P., Merchenthaler, A. & Bronstein, D. Induction of proenkephalin in tuberoinfundibular dopaminergic neurons by hyperprolactinemia: the role of sex steroids. Endocrinology 136, 2442-2450 , (1995) .
    • . . . 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 . . .
  91. Soaje, M., Valdez, S., Bregonzio, C., Penissi, A. & Deis, R. P. Dopaminergic mechanisms involved in prolactin release after mifepristone and naloxone treatment during late pregnancy in the rat. Neuroendocrinology 84, 58-67 , (2006) .
    • . . . 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 prolactin-releasing-factor neurons91 . . .
  92. Egli, M. et al. Prolactin secretory rhythm of mated rats induced by a single injection of oxytocin. Am. J. Physiol. Endocrinol. Metab. 290, E566-E572 , (2006) .
    • . . . These might be oxytocin neurons, because they are inhibited by endogenous opioids in late pregnancy51 and because oxytocin stimulates prolactin secretion92. . . .
  93. Bridges, R. S. & Hays, L. E. Steroid-induced alterations in mRNA expression of the long form of the prolactin receptor in the medial preoptic area of female rats: effects of exposure to a pregnancy-like regimen of progesterone and estradiol. Brain Res. Mol. Brain Res. 140, 10-16 , (2005) .
    • . . . 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. . . .
  94. Fleming, A. S., Vaccarino, F. & Luebke, C. Amygdaloid inhibition of maternal behavior in the nulliparous female rat. Physiol. Behav. 25, 731-743 , (1980) .
    • . . . 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 . . .
  95. Bridges, R. S., Mann, P. E. & Coppeta, J. S. Hypothalamic involvement in the regulation of maternal behaviour in the rat: inhibitory roles for the ventromedial hypothalamus and the dorsal/anterior hypothalamic areas. J. Neuroendocrinol. 11, 259-266 , (1999) .
    • . . . 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 . . .
  96. Sukikara, M. H., Mota-Ortiz, S. R., Baldo, M. V., Felicio, L. F. & Canteras, N. S. A role for the periaqueductal gray in switching adaptive behavioral responses. J. Neurosci. 26, 2583-2589 , (2006) .
    • . . . 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 . . .
  97. Kinsley, C. H. & Bridges, R. S. Morphine treatment and reproductive condition alter olfactory preferences for pup and adult male odors in female rats. Dev. Psychobiol. 23, 331-347 , (1990) .
    • . . . 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 . . .
  98. Numan, M. Hypothalamic neural circuits regulating maternal responsiveness toward infants. Behav. Cogn. Neurosci. Rev. 5, 163-190.This review synthesizes a large body of research on the details of the neural circuitry that is involved in different components of maternal behaviour, including motivation and reward , (2006) .
    • . . . 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 . . .
    • . . . 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 . . .
    • . . . 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 . . .
  99. Numan, M. et al. The effects of D1 or D2 dopamine receptor antagonism in the medial preoptic area, ventral pallidum, or nucleus accumbens on the maternal retrieval response and other aspects of maternal behavior in rats. Behav. Neurosci. 119, 1588-1604 , (2005) .
    • . . . In particular, the VTA dopamine projection to the NAcc inhibits GABA output to the ventral pallidum99 . . .
  100. Byrnes, E. M., Rigero, B. A. & Bridges, R. S. Opioid receptor antagonism during early lactation results in the increased duration of nursing bouts. Physiol. Behav. 70, 211-216 , (2000) .
    • . . . The withdrawal at birth of upregulated central inhibitory-opioid mechanisms, in particular in the mPOA, facilitates maternal behaviour100, 101. . . .
  101. Byrnes, E. M. & Bridges, R. S. Endogenous opioid facilitation of maternal memory in rats. Behav. Neurosci. 114, 797-804 , (2000) .
    • . . . The withdrawal at birth of upregulated central inhibitory-opioid mechanisms, in particular in the mPOA, facilitates maternal behaviour100, 101. . . .
    • . . . 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. . . .
  102. Sheehan, T. & Numan, M. Estrogen, progesterone, and pregnancy termination alter neural activity in brain regions that control maternal behavior in rats. Neuroendocrinology 75, 12-23 , (2002) .
    • . . . 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 . . .
  103. Mattson, B. J. & Morrell, J. I. Preference for cocaine- versus pup-associated cues differentially activates neurons expressing either Fos or cocaine- and amphetamine-regulated transcript in lactating, maternal rodents. Neuroscience 135, 315-328 , (2005) .
    • . . . 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 . . .
  104. Lonstein, J. S. & De Vries, G. J. Maternal behaviour in lactating rats stimulates c-fos in glutamate decarboxylase-synthesizing neurons of the medial preoptic area, ventral bed nucleus of the stria terminalis, and ventrocaudal periaqueductal gray. Neuroscience 100, 557-568 , (2000) .
    • . . . 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. . . .
  105. Francis, D. D., Champagne, F. C. & Meaney, M. J. Variations in maternal behaviour are associated with differences in oxytocin receptor levels in the rat. J. Neuroendocrinol. 12, 1145-1148 , (2000) .
    • . . . At birth, oxytocin acts in the mPOA, NAcc, VTA, olfactory bulbs, lateral septum, BNST, PVN and amygdala to stimulate maternal behaviour105 . . .
  106. Jin, D. et al. CD38 is critical for social behaviour by regulating oxytocin secretion. Nature 446, 41-45 , (2007) .
    • . . . 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 on maternal behaviour106 . . .
  107. Young, L. J., Muns, S., Wang, Z. & Insel, T. R. Changes in oxytocin receptor mRNA in rat brain during pregnancy and the effects of estrogen and interleukin-6. J. Neuroendocrinol. 9, 859-865 , (1997) .
    • . . . 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 identified107 . . .
  108. Meddle, S. L., Bishop, V. R., Gkoumassi, E., van Leeuwen, F. W. & Douglas, A. J. Dynamic changes in oxytocin receptor expression and activation at parturition in the rat brain. Endocrinology 148, 5095-5104 , (2007) .
    • . . . 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. . . .
  109. Insel, T. R. Postpartum increases in brain oxytocin binding. Neuroendocrinology 44, 515-518 , (1986) .
    • . . . 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. . . .
  110. Windle, R. J. et al. Gonadal steroid modulation of stress-induced hypothalamo-pituitary-adrenal activity and anxiety behavior: role of central oxytocin. Endocrinology 147, 2423-2431 , (2006) .
    • . . . Although progesterone withdrawal might underlie the upregulation of oxytocin-receptor expression in the ventrolateral septum110, a general mechanism of regulation has not been identified107 . . .
  111. Champagne, F., Diorio, J., Sharma, S. & Meaney, M. J. Naturally occurring variations in maternal behavior in the rat are associated with differences in estrogen-inducible central oxytocin receptors. Proc. Natl Acad. Sci. USA 98, 12736-12741 , (2001) .
    • . . . 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. . . .
  112. Lucas, B. K., Ormandy, C. J., Binart, N., Bridges, R. S. & Kelly, P. A. Null mutation of the prolactin receptor gene produces a defect in maternal behavior. Endocrinology 139, 4102-4107 , (1998) .
    • . . . Heterozygous prolactin-receptor-knockout mice have severe maternal-behaviour deficits, demonstrating the essential role of prolactin and/or placental lactogen in initiating maternal behaviour112 . . .
  113. Grattan, D. R. et al. Prolactin receptors in the brain during pregnancy and lactation: implications for behavior. Horm. Behav. 40, 115-124 , (2001) .
    • . . . 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. . . .
  114. Kendrick, K. M. Oxytocin, motherhood and bonding. Exp. Physiol. 85, 111S-124S , (2000) .
    • . . . Mitral cells release glutamate which, through the effects of nitric oxide, strengthens mitral-cell–granule-cell synapses, establishing olfactory memory114. . . .
  115. Rosenblatt, J. S. Psychobiology of maternal behavior: contribution to the clinical understanding of maternal behavior among humans. Acta Paediatr. Suppl. 397, 3-8 , (1994) .
    • . . . 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 PAG116 . . .
  116. Lonstein, J. S. & Gammie, S. C. Sensory, hormonal, and neural control of maternal aggression in laboratory rodents. Neurosci. Biobehav. Rev. 26, 869-888.This paper reviews the remarkable emergence of aggressive behaviour in female rodents after birth and its mechanisms; it touches upon the relationship between aggressive behaviour and anxiety , (2002) .
    • . . . 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 PAG116 . . .
    • . . . Several neurotransmitters and neuropeptides are implicated in the regulation of maternal aggression, including GABA, nitric oxide, oxytocin, vasopressin, opioids, serotonin, dopamine and CRH116. . . .
    • . . . Low serotoninergic activity is associated with high levels of aggression116 . . .
  117. Gammie, S. C. et al. Altered gene expression in mice selected for high maternal aggression. Genes Brain Behav. 6, 432-443 , (2007) .
    • . . . Studies of the molecular and genetic basis of maternal aggression in mice have shown roles for pheromones and neuronal nitric oxide synthase117 . . .
  118. Gammie, S. C., Bethea, E. D. & Stevenson, S. A. Altered maternal profiles in corticotropin-releasing factor receptor 1 deficient mice. BMC Neurosci. 8, 17 , (2007) .
    • . . . 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. . . .
  119. Ferreira, A., Picazo, O., Uriarte, N., Pereira, M. & Fernandez-Guasti, A. Inhibitory effect of buspirone and diazepam, but not of 8-OH-DPAT, on maternal behavior and aggression. Pharmacol. Biochem. Behav. 66, 389-396 , (2000) .
    • . . . 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 allopregnanolone, allosterically modify GABAA receptors) alters maternal aggression: higher doses inhibit and lower doses enhance aggression levels119, 120. . . .
  120. Lee, G. & Gammie, S. C. GABA enhancement of maternal defense in mice: possible neural correlates. Pharmacol. Biochem. Behav. 86, 176-187 , (2007) .
    • . . . 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 allopregnanolone, allosterically modify GABAA receptors) alters maternal aggression: higher doses inhibit and lower doses enhance aggression levels119, 120. . . .
  121. Klink, R., Robichaud, M. & Debonnel, G. Gender and gonadal status modulation of dorsal raphe nucleus serotonergic neurons. Part I: effects of gender and pregnancy. Neuropharmacology 43, 1119-1128 , (2002) .
    • . . . Oestrogen and progesterone 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 progesterone receptors, suggesting an indirect action of progesterone or modulation by allopregnanolone121 . . .
    • . . . 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 . . .
  122. Klink, R., Robichaud, M. & Debonnel, G. Gender and gonadal status modulation of dorsal raphe nucleus serotonergic neurons. Part II. Regulatory mechanisms. Neuropharmacology 43, 1129-1138 , (2002) .
    • . . . Oestrogen and progesterone might influence the firing rate of dorsal raphe serotonin neurons and modulate forebrain serotonin receptors and serotonin transport and metabolism121, 122 . . .
    • . . . The increased activity of dorsal raphe serotonin neurons 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 . . .
  123. Robichaud, M. & Debonnel, G. Modulation of the firing activity of female dorsal raphe nucleus serotonergic neurons by neuroactive steroids. J. Endocrinol. 182, 11-21 , (2004) .
    • . . . The increased activity of dorsal raphe serotonin neurons 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 . . .
  124. Kaura, V., Ingram, C. D., Gartside, S. E., Young, A. H. & Judge, S. J. The progesterone metabolite allopregnanolone potentiates GABAA receptor-mediated inhibition of 5-HT neuronal activity. Eur. Neuropsychopharmacol. 17, 108-115 , (2007) .
    • . . . By contrast, acute exposure to allopregnanolone potentiates GABAA-receptor-mediated inhibition of dorsal raphe serotonergic neurons in non-pregnant females124 . . .
  125. Bosch, O. J., Meddle, S. L., Beiderbeck, D. I., Douglas, A. J. & Neumann, I. D. Brain oxytocin correlates with maternal aggression: link to anxiety. J. Neurosci. 25, 6807-6815 , (2005) .
    • . . . Maternal aggression is positively correlated with oxytocin release and action in the PVN and in the central nucleus of the amygdala125, 126 . . .
  126. Bosch, O. J., Musch, W., Bredewold, R., Slattery, D. A. & Neumann, I. D. Prenatal stress increases HPA axis activity and impairs maternal care in lactating female offspring: implications for postpartum mood disorder. Psychoneuroendocrinology 32, 267-278 , (2007) .
    • . . . Maternal aggression is positively correlated with oxytocin release and action in the PVN and in the central nucleus of the amygdala125, 126 . . .
  127. Neumann, I. D. Alterations in behavioral and neuroendocrine stress coping strategies in pregnant, parturient and lactating rats. Prog. Brain Res. 133, 143-152 , (2001) .
    • . . . Central oxytocin administration is anxiolytic127, 128, and treatment with an oxytocin antagonist reveals a tonic anxiolytic action of oxytocin in late pregnancy127 . . .
  128. Mantella, R. C., Vollmer, R. R., Li, X. & Amico, J. A. Female oxytocin-deficient mice display enhanced anxiety-related behavior. Endocrinology 144, 2291-2296 , (2003) .
    • . . . Central oxytocin administration is anxiolytic127, 128, and treatment with an oxytocin antagonist reveals a tonic anxiolytic action of oxytocin in late pregnancy127 . . .
  129. Harris, B. et al. Maternity blues and major endocrine changes: cardiff puerperal mood and hormone study II. BMJ 308, 949-953 , (1994) .
    • . . . 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 10–13% of new mothers develop major puerperal depression (also called postnatal depression or post-partum depression)78, 130 . . .
  130. Zonana, J. & Gorman, J. M. The neurobiology of postpartum depression. CNS Spectr. 10, 792-799 , (2005) .
    • . . . 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 10–13% of new mothers develop major puerperal depression (also called postnatal depression or post-partum depression)78, 130 . . .
    • . . . The neurochemical changes that underlie mother–infant interactions, such as those that occur in the oxytocin and prolactin systems130, 134, might contribute to post-partum mood changes. . . .
  131. Forman, D. R. et al. Effective treatment for postpartum depression is not sufficient to improve the developing mother-child relationship. Dev. Psychopathol. 19, 585-602 , (2007) .
    • . . . Both conditions compromise mother–infant interactions131 and have been related to dysregulated brain responses in susceptible women to the dramatic changes in hormone levels that occur after birth (Fig. 5). . . .
  132. Kammerer, M., Taylor, A. & Glover, V. The HPA axis and perinatal depression: a hypothesis. Arch. Womens Ment. Health 9, 187-196 , (2006) .
    • . . . 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 . . .
    • . . . Whether this reflects a trait associated with abnormal adaptation to the post-partum fall in cortisol level and consequent depressed mood needs investigation132. . . .
  133. Magiakou, M. A. et al. The maternal hypothalamic-pituitary-adrenal axis in the third trimester of human pregnancy. Clin. Endocrinol. 44, 419-428 , (1996) .
    • . . . 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 . . .
  134. Torner, L. et al. In vivo release and gene upregulation of brain prolactin in response to physiological stimuli. Eur. J. Neurosci. 19, 1601-1608 , (2004) .
    • . . . The neurochemical changes that underlie mother–infant interactions, such as those that occur in the oxytocin and prolactin systems130, 134, might contribute to post-partum mood changes. . . .
  135. Bloch, M. et al. Effects of gonadal steroids in women with a history of postpartum depression. Am. J. Psychiatry 157, 924-930.This is an elegant hypothesis-driven study in which the authors show that women who experienced postpartum depression were more vulnerable to developing low mood after experimental progesterone and estrogen withdrawal , (2000) .
    • . . . Rather, women who have experienced puerperal depression show greater sensitivity to experimental oestrogen and progesterone withdrawal135 . . .
  136. Pedersen, C. A. et al. Antenatal thyroid correlates of postpartum depression. Psychoneuroendocrinology 32, 235-245 , (2007) .
    • . . . Low thyroid activity in pregnant women has also been linked to post-partum depression136 . . .
  137. Vasudevan, N., Ogawa, S. & Pfaff, D. Estrogen and thyroid hormone receptor interactions: physiological flexibility by molecular specificity. Physiol. Rev. 82, 923-944 , (2002) .
    • . . . 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 thyroid hormone enhance the stimulation by oestrogen of transcription of these genes137. . . .
  138. Smith, J. W., Seckl, J. R., Evans, A. T., Costall, B. & Smythe, J. W. Gestational stress induces post-partum depression-like behaviour and alters maternal care in rats. Psychoneuroendocrinology 29, 227-244 , (2004) .
    • . . . Rat mothers show such behaviour after prenatal stress138, postnatal corticosterone treatment139 or repeated separation from pups140 . . .
  139. Brummelte, S., Pawluski, J. L. & Galea, L. A. High post-partum levels of corticosterone given to dams influence postnatal hippocampal cell proliferation and behavior of offspring: a model of post-partum stress and possible depression. Horm. Behav. 50, 370-382 , (2006) .
    • . . . Rat mothers show such behaviour after prenatal stress138, postnatal corticosterone treatment139 or repeated separation from pups140 . . .
  140. Boccia, M. L. et al. Repeated long separations from pups produce depression-like behavior in rat mothers. Psychoneuroendocrinology 32, 65-71 , (2007) .
    • . . . Rat mothers show such behaviour after prenatal stress138, postnatal corticosterone treatment139 or repeated separation from pups140 . . .
  141. Eser, D. et al. Neuroactive steroids and affective disorders. Pharmacol. Biochem. Behav. 84, 656-666 , (2006) .
    • . . . Allopregnanolone has anxiolytic and antidepressant actions in animal models141, probably through its actions on GABAA receptors . . .
    • . . . 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 week145; serum allopregnanolone levels are lower in women with post-partum blues144 and are also decreased in non-pregnant women with major depression141 . . .
    • . . . The actions of SSRIs include the stimulation of central neuroactive steroid synthesis141, 153, which is decreased in depression and is normalized by SSRI treatment154 . . .
  142. Majewska, M. D., Ford-Rice, F. & Falkay, G. Pregnancy-induced alterations of GABAA receptor sensitivity in maternal brain: an antecedent of post-partum 'blues'? Brain Res. 482, 397-401 , (1989) .
    • . . . 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 changes142 . . .
  143. Frye, C. A. & Walf, A. A. Hippocampal 3,5-THP may alter depressive behavior of pregnant and lactating rats. Pharmacol. Biochem. Behav. 78, 531-540 , (2004) .
    • . . . The reduced depression-like behaviour in late-pregnant rats depends on allopregnanolone synthesis and reverses a few days post-partum, when hippocampal allopregnanolone content decreases143 . . .
  144. Nappi, R. E. Serum allopregnanolone in women with postpartum "blues". Obstet. Gynecol. 97, 77-80 , (2001) .
    • . . . 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 circulating 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 . . .
  145. Pearson Murphy, B. E., Steinberg, S. I., Hu, F. Y. & Allison, C. M. Neuroactive ring A-reduced metabolites of progesterone in human plasma during pregnancy: elevated levels of 5-dihydroprogesterone in depressed patients during the latter half of pregnancy. J. Clin. Endocrinol. Metab. 86, 5981-5987 , (2001) .
    • . . . 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 week145; serum allopregnanolone levels are lower in women with post-partum blues144 and are also decreased in non-pregnant women with major depression141 . . .
  146. Epperson, C. N. et al. Preliminary evidence of reduced occipital GABA concentrations in puerperal women: a 1H-MRS study. Psychopharmacology (Berl.) 186, 425-433 , (2006) .
    • . . . By approximately 3 months post-partum, plasma allopregnanolone levels are lower than in women who were not recently pregnant and cerebral cortical GABA concentrations are also reduced; however, neither allopregnanolone nor GABA levels correlate with puerperal depression146 . . .
    • . . . 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 . . .
  147. Altemus, M. et al. Changes in cerebrospinal fluid neurochemistry during pregnancy. Biol. Psychiatry 56, 386-392 , (2004) .
    • . . . 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 . . .
  148. Smith, S. S. et al. Withdrawal from 3-OH-5-pregnan-20-one using a pseudopregnancy model alters the kinetics of hippocampal GABAA-gated current and increases the GABAA receptor 4 subunit in association with increased anxiety. J. Neurosci. 18, 5275-5284 , (1998) .
    • . . . 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 post-partum148 . . .
  149. M'Baïlara, K. et al. Decreased brain tryptophan availability as a partial determinant of post-partum blues. Psychoneuroendocrinology 31, 407-413 , (2006) .
    • . . . 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 . . .
  150. Maes, M., Ombelet, W., Verkerk, R., Bosmans, E. & Scharpe, S. Effects of pregnancy and delivery on the availability of plasma tryptophan to the brain: relationships to delivery-induced immune activation and early post-partum anxiety and depression. Psychol. Med. 31, 847-858 , (2001) .
    • . . . 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 . . .
  151. Coyle, N., Jones, I., Robertson, E., Lendon, C. & Craddock, N. Variation at the serotonin transporter gene influences susceptibility to bipolar affective puerperal psychosis. Lancet 356, 1490-1491 , (2000) .
    • . . . 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 . . .
  152. Whitby, D. H. & Smith, K. M. The use of tricyclic antidepressants and selective serotonin reuptake inhibitors in women who are breastfeeding. Pharmacotherapy 25, 411-425 , (2005) .
    • . . . 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 . . .
  153. Matsumoto, K., Puia, G., Dong, E. & Pinna, G. GABAA receptor neurotransmission dysfunction in a mouse model of social isolation-induced stress: possible insights into a non-serotonergic mechanism of action of SSRIs in mood and anxiety disorders. Stress 10, 3-12 , (2007) .
    • . . . The actions of SSRIs include the stimulation of central neuroactive steroid synthesis141, 153, which is decreased in depression and is normalized by SSRI treatment154 . . .
  154. van Broekhoven, F. & Verkes, R. J. Neurosteroids in depression: a review. Psychopharmacology (Berl.) 165, 97-110 , (2003) .
    • . . . The actions of SSRIs include the stimulation of central neuroactive steroid synthesis141, 153, which is decreased in depression and is normalized by SSRI treatment154 . . .
  155. Moses-Kolko, E. L. et al. Serotonin 1A receptor reductions in postpartum depression: a positron emission tomography study. Fertil. Steril. 80, 554-549 , (2007) .
    • . . . 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 . . .
  156. de Weerth, C. & Buitelaar, J. K. Physiological stress reactivity in human pregnancy: a review. Neurosci. Biobehav. Rev. 29, 295-312 , (2005) .
    • . . . 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 . . .
  157. Kammerer, M., Adams, D., Castelberg, B. v. & Glover, V. Pregnant women become insensitive to cold stress. BMC Pregnancy Childbirth 2, 8 , (2002) .
    • . . . 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 . . .
  158. Nierop, A. et al. Prolonged salivary cortisol recovery in second-trimester pregnant women and attenuated salivary -amylase responses to psychosocial stress in human pregnancy. J. Clin. Endocrinol. Metab. 91, 1329-1335 , (2006) .
    • . . . However, the salivary cortisol response to a standard social-stress test is undiminished in the second and third trimesters158 . . .
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    • . . . 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 . . .
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    • . . . Women with post-partum blues have lower than normal ACTH responses to CRH, which might indicate low endogenous CRH production160 . . .
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    • . . . 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. . . .
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    • . . . 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. . . .
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    • . . . 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 . . .
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    • . . . 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 . . .
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