Paula Brunton

The expectant brain: adapting for motherhood

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.

Adaptive Responses of the Maternal Hypothalamic‐Pituitary‐Adrenal Axis during Pregnancy and Lactation

Over the past 40 years, it has been recognised that the maternal hypothalamic‐pituitary‐adrenal (HPA) axis undergoes adaptations through pregnancy and lactation that might contribute to avoidance of adverse effects of stress on the mother and offspring. The extent of the global adaptations in the HPA axis has been revealed and the underlying mechanisms investigated within the last 20 years. Both basal, including the circadian rhythm, and stress‐induced adrenocorticotrophic hormone and glucocorticoid secretory patterns are altered. Throughout most of pregnancy, and in lactation, these changes predominantly reflect reduced drive by the corticotropin‐releasing factor (CRF) neurones in the parvocellular paraventricular nucleus (pPVN). An accompanying profound attenuation of HPA axis responses to a wide variety of psychological and physical stressors emerges after mid‐pregnancy and persists until the end of lactation. Central to this suppression of stress responsiveness is reduced activation of the pPVN CRF neurones. This is consequent on the reduced effectiveness of the stimulation of brainstem afferents to these CRF neurones (for physical stressors) and of altered processing by limbic structures (for emotional stressors). The mechanism of reduced CRF neurone responses to physical stressors in pregnancy is the suppression of noradrenaline release in the PVN by an up‐regulated endogenous opioid mechanism, which is induced by neuroactive steroid produced from progesterone. By contrast, in lactation suckling the young provides a neural stimulus that dampens the HPA axis circadian rhythm and reduces stress responses. Reduced noradrenergic input activity is involved in reduced stress responses in lactation, although central prolactin action also appears important. Such adaptations limit the adverse effects of excess glucocorticoid exposure on the foetus(es) and facilitate appropriate metabolic and immune responses.

Prenatal Social Stress in the Rat Programmes Neuroendocrine and Behavioural Responses to Stress in the Adult Offspring: Sex-Specific Effects

Stress exposure during pregnancy can ‘programme’ adult behaviour and hypothalamic‐pituitary‐adrenal (HPA) axis stress responsiveness. In the present study, we utilised an ethologically relevant social stressor to model the type of stress that pregnant women may experience. We investigated the effects of social defeat by a resident lactating rat over 5 days during the last week of pregnancy on the pregnant intruder rat HPA axis, and on HPA responsivity to stress and anxiety‐related behaviour in the adult offspring of the socially‐defeated intruder rats. HPA axis responses after social defeat were attenuated in the pregnant rats compared to virgin females. In the adult offspring, systemic interleukin (IL)‐1β or restraint increased adrenocorticotrophic hormone and corticosterone secretion in male and female control rats; however, in prenatally stressed (PNS) offspring, HPA responses were greatly enhanced and peak hormone responses to IL‐1β were greater in females versus males. Male PNS rats displayed increased anxiety behaviour on the elevated plus maze; however, despite marked changes in anxiety behaviour across the oestrous cycle, there were no differences between female control and PNS rats. Investigation of possible mechanisms showed mineralocorticoid mRNA levels were reduced in the hippocampus of male and female PNS offspring, whereas glucocorticoid receptor mRNA expression was modestly reduced in the CA2 hippocampal subfield in female PNS rats only. Corticotropin‐releasing hormone mRNA and glucocorticoid receptor mRNA expression in the central amygdala was greater in PNS males and females compared to controls. The data obtained in the present study indicate that prenatal social stress differentially programmes anxiety behaviour and HPA axis responses to stress in male and female offspring. Attenuated glucocorticoid feedback mechanisms in the limbic system may underlie HPA axis hyper‐reactivity to stress in PNS offspring.

The consequences of early life adversity: neurobiological, behavioural and epigenetic adaptations

During the perinatal period, the brain is particularly sensitive to remodelling by environmental factors. Adverse early‐life experiences, such as stress exposure or suboptimal maternal care, can have long‐lasting detrimental consequences for an individual. This phenomenon is often referred to as ‘early‐life programming’ and is associated with an increased risk of disease. Typically, rodents exposed to prenatal stress or postnatal maternal deprivation display enhanced neuroendocrine responses to stress, increased levels of anxiety and depressive‐like behaviours, and cognitive impairments. Some of the phenotypes observed in these models of early‐life adversity are likely to share common neurobiological mechanisms. For example, there is evidence for impaired glucocorticoid negative‐feedback control of the hypothalamic‐pituitary‐adrenal axis, altered glutamate neurotransmission and reduced hippocampal neurogenesis in both prenatally stressed rats and rats that experienced deficient maternal care. The possible mechanisms through which maternal stress during pregnancy may be transmitted to the offspring are reviewed, with special consideration given to altered maternal behaviour postpartum. We also discuss what is known about the neurobiological and epigenetic mechanisms that underpin early‐life programming of the neonatal brain in the first generation and subsequent generations, with a view to abrogating programming effects and potentially identifying new therapeutic targets for the treatment of stress‐related disorders and cognitive impairment.

Release of oxytocin in the hypothalamic paraventricular nucleus, but not central amygdala or lateral septum in lactating residents and virgin intruders during maternal defence

In lactating rats, the neuroendocrine responses of the oxytocinergic system and the hypothalamo-pituitary-adrenal axis to various kinds of stressors are attenuated. In this study, using intracerebral microdialysis in combination with a highly sensitive radioimmunoassay, we characterised oxytocin (OXT) release within the paraventricular nucleus (PVN), the central amygdala (CeA), and the medio-lateral septum (mS) before, during and after a psycho-social stressor (the maternal defence test) in both the virgin intruder and the lactating resident rat (day 3 of lactation). Within the PVN, local OXT release was found to increase significantly in virgin intruders during exposure to the resident (2.1-fold, P < 0.05), as well as in lactating residents when exposed to the virgin intruder, though to a lesser extent when compared with basal levels (1.7-fold, P < 0.05). In contrast, OXT release remained unchanged within the CeA and the mS of both virgin intruders and lactating residents. Release of OXT under basal conditions was clearly above the detection limit of the radioimmunoassay, and did not differ between lactating and virgin rats in any of the brain regions studied. Our study also demonstrates that recent surgery or ongoing intracerebral microdialysis does not affect the behavioural performance of the intruders or residents when comparing dialysed and non-dialysed rats. The results indicate that exposure to the maternal defence test is a relevant stressor for the brain OXT system which becomes activated in both intruder and resident rats, although to varying degrees depending upon their reproductive status and in a region-dependent manner. The behavioural and/or neuroendocrine functions of intra-PVN released OXT during this psycho-social challenge remain to be clarified.

Endogenous opioids and attenuated hypothalamic-pituitary-adrenal axis responses to immune challenge in pregnant rats

In late pregnant rats, the hypothalamic-pituitary-adrenal (HPA) axis is hyporesponsive to psychogenic stressors. Here, we investigated attenuated HPA responses to an immune challenge and a role for endogenous opioids. ACTH and corticosterone were assayed in blood samples from virgin and 21 d pregnant rats before and after endotoxin [lipopolysaccharide (LPS); 1 μg/kg, i.v.], interleukin-1β (IL-1β; 500 ng/kg, i.v.), or vehicle. In virgins, plasma ACTH concentrations increased 1 h after LPS and 15 min after IL-1β, as did corticosterone, with no responses in pregnant rats. In situ hybridization revealed increased corticotrophin releasing hormone (CRH) mRNA expression in the dorsomedial parvocellular paraventricular nucleus (pPVN) and increased anterior pituitary pro-opiomelanocortin mRNA expression 4 h after IL-1β in virgins; these responses were absent in pregnant rats. In contrast, immunocytochemistry showed that Fos expression was similarly increased in the nucleus tractus solitarius (NTS) A2 region in virgin and pregnant rats 90 min and 4 h after IL-1β. Naloxone pretreatment (5 mg/kg, i.v.) restored ACTH and pPVN CRH mRNA responses after IL-1β in pregnant rats but reduced the CRH mRNA response in virgins without affecting ACTH. Proenkephalin-A and μ-opioid receptor mRNA expression in the NTS was significantly increased in the pregnant rats, indicating upregulated brainstem opioid mechanisms. IL-1β increased noradrenaline release in the PVN of virgin, but not pregnant, rats. However, naloxone infused directly into the PVN increased noradrenaline release after IL-1β in pregnant rats. Thus, the HPA axis responses to immune signals are suppressed in pregnancy at the level of pPVN CRH neurons through an opioid mechanism, possibly acting by preterminal autoinhibition of NTS projections to the pPVN.

Central Opioid Inhibition of Neuroendocrine Stress Responses in Pregnancy in the Rat Is Induced by the Neurosteroid Allopregnanolone

The hypothalamus–pituitary–adrenal (HPA) axis is the major neuroendocrine stress response system. Corticotropin-releasing hormone (CRH) neurons in the parvocellular paraventricular nucleus (pPVN) play a key role in coordinating responses of this system to stressors. The cytokine interleukin-1β (IL-1β), mimicking infection, robustly activates these CRH neurons via a noradrenergic input arising from the nucleus tractus solitarii (NTS). In late pregnancy, HPA axis responses to stressors, including IL-1β, are attenuated by a central opioid mechanism that auto-inhibits noradrenaline release in the PVN. Here we show that the neuroactive progesterone metabolite allopregnanolone induces these changes in HPA responsiveness to IL-1β in pregnancy. In late pregnancy, inhibition of 5α-reductase (an allopregnanolone-synthesizing enzyme) with finasteride restored HPA axis responses (rapidly increased pPVN CRH mRNA expression, ACTH, and corticosterone secretion) to IL-1β. Conversely, allopregnanolone reduced HPA responses in virgin rats. In late pregnancy, activity of the allopregnanolone-synthesizing enzymes (5α-reductase and 3α-hydroxysteroid dehydrogenase) was increased in the hypothalamus as was mRNA expression in the NTS and PVN. Naloxone, an opioid antagonist, restores HPA axis responses to IL-1β in pregnancy but had no additional effect after finasteride, indicating a causal connection between allopregnanolone and the endogenous opioid mechanism. Indeed, allopregnanolone induced opioid inhibition over HPA responses to IL-1β in virgin rats. Furthermore, in virgin rats, allopregnanolone treatment increased, whereas in pregnant rats finasteride decreased proenkephalin-A mRNA expression in the NTS. Thus, in pregnancy, allopregnanolone induces opioid inhibition over HPA axis responses to immune challenge. This novel opioid-mediated mechanism of allopregnanolone action may alter regulation of other brain systems in pregnancy.

Hypothalamic-pituitary-adrenal responses to centrally administered orexin: A are suppressed in pregnant rats

Orexins are hypothalamic neuropeptides that stimulate arousal and food intake but also activate the hypothalamic‐pituitary‐adrenal (HPA) axis. During late pregnancy in the rat, the responsiveness of the HPA axis to stressors is attenuated, and thus we investigated HPA axis responses to centrally administered orexin‐A during pregnancy. Intracerebroventricular injection of orexin‐A (0.5 µg, 140 pmol) significantly increased plasma adrenocorticotropic hormone and corticosterone concentration within 10 min in virgin female Sprague‐Dawley rats, but had no effect in day 21 pregnant rats. Orexin‐A significantly increased corticotropin‐releasing hormone (CRH) mRNA expression, measured by in situ hybridization, in the paraventricular nucleus (PVN) of the virgin group but not in the pregnant group. Thus, the responsiveness of PVN CRH neurones to orexin‐A, and hence the pituitary‐adrenal axis, is markedly reduced in pregnancy. This may favour anabolic adaptations in pregnancy.

Endocrine induced changes in brain function during pregnancy

The female sex steroid hormones, estrogens and progesterone, are produced in large amounts in pregnancy, increasing as pregnancy progresses. These hormones have essential peripheral actions to maintain pregnancy, and to secure safe delivery at term. They also have important actions on the brain in pregnancy, generally through interactions with neuropeptide systems in the brain, or through modulating the actions of circulating peptide hormones on the brain. Together, these steroid-peptide links form short chains that evoke changes in central physiological systems that favour the pregnancy, including altered control of water and electrolyte balance, appetite and energy partitioning and stress responses. In parallel such links prepare the brain, through inhibition of oxytocin secretion until it is needed to support parturition and for immediate expression of maternal behaviour postpartum. We focus here on recent advances in understanding some of these steroid-peptide links, especially on non-classical progesterone actions through allopregnanolone, its neuroactive steroid metabolite, and opioid peptide mechanisms.

Reduced Hypothalamo‐pituitary‐adrenal Axis Stress Responses in Late Pregnancy

In late pregnancy, the hypothalamo‐pituitary‐adrenal (HPA) axis is less responsive to a range of psychological and physical stressors as a result of reduced central drive to the corticotropin‐releasing hormone (CRH) neurons in the paraventricular nucleus (PVN). Most stressors activate the brain stem noradrenergic system, which innervates the majority of networks involved in regulating stress responses, including the PVN. Forced swimming, systemic interleukin‐1β (IL‐1β), and cholecystokinin (CCK) all activate brain stem noradrenergic cell groups, stimulate noradrenaline release in the PVN, and activate the HPA axis in nonpregnant rats. However, in late pregnancy we have shown that forced swimming and IL‐1β fail to evoke noradrenaline release in the PVN and hence HPA axis responses are suppressed. HPA axis responses to IL‐1β and CCK can be reinstated in pregnant rats by systemic administration of the opioid receptor antagonist naloxone, and when infused directly into the PVN, naloxone restores noradrenaline release in the PVN following IL‐1β treatment. Adrenaline release into the blood following stress is also attenuated in late pregnancy, despite increased adrenomedullary expression of tyrosine hydroxylase mRNA at this time. This review describes the mechanisms underlying attenuated HPA axis stress responses in pregnancy, focusing on the role of endogenous opioids and the central noradrenergic system.