1. Maternal Brain Adaptations in Pregnancy
Chapter 44
Maternal Brain Adaptations in Pregnancy
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

2. FIGURE 44. 1 Hormone secretion profiles during pregnancy in the rat
FIGURE 44.1 Hormone secretion profiles during pregnancy in the rat. Circulating concentrations of (A) progesterone and estradiol, (B) allopregnanolone, (C) prolactin and placental lactogen I and II, (D) relaxin, and (E) leptin, across pregnancy in the rat. Hormone concentrations are expressed as a percentage of the maximum levels found in pregnancy. Sources: Data are derived as follows: progesterone and estradiol;854 allopregnanolone;29 prolactin;424,855 placental lactogen;856,857 relaxin;858 and leptin.859 Reproduced from Brunton & Russell (2010)860 with permission from Elsevier.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

3. FIGURE 44.2 Mechanisms of hyponatremia and hypervolemia in late pregnancy. The organum vasculosum of the lamina terminalis (OVLT) and the subfornical organ (SFO) are both strongly interconnected with the nucleus medianus (NM) in the lamina terminalis. Together these structures comprise the AV3V region (the region anterior and ventral to the third ventricle), which plays a key role in regulating fluid and electrolyte balance. Hypernatremia (high [Na+]) stimulates magnocellular oxytocin and vasopressin neurons in the paraventricular (PVN) and supraoptic (SON) nuclei directly, but also indirectly via osmoreceptive neurons in the OVLT, SFO, and NM. AV3V neurons project to the SON and PVN to regulate the activity of the magnocellular neurons. The projections from the AV3V region involve glutamate (excitatory) and GABA (inhibitory) transmission, atrial natriuretic peptide (ANP), and angiotensin II (ATII). In late pregnancy, relaxin from the corpora lutea acts on subfornical organ (SFO) neurons to stimulate drinking. Relaxin also stimulates magnocellular vasopressin neurons via relaxin receptors in the OVLT and SFO. In early, but not late, pregnancy, relaxin similarly stimulates oxytocin neurons. Increased vasopressin secretion (stimulated by relaxin) acts on the kidney via V2 receptors to increase water retention. This together with increased drinking and reduced natriuresis, as oxytocin secretion is not increased and ANP secretion is decreased, leads to the hyponatremia and hypervolemia of pregnancy.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

4. FIGURE 44.3 Hypothalamic neuropeptides and networks regulating appetite and metabolism. The arcuate nucleus (ARC) contains NPY/AgRP neurons that increase food intake and energy storage via inhibition of adjacent POMC neurons (producing anorexigens-α-MSH and CART) and anorexigenic neurons in the PVN (OT, CRH) and via antagonism of α-MSH action on MC4 receptors that mediate inhibition of MCH neurons in the LHA (“hunger center”), with actions in the VMN (“satiety center”). POMC/CART neurons in the arcuate nucleus decrease food intake and increase metabolism by inhibiting NPY/AgRP neurons, stimulating oxytocin neurons, and inhibiting MCH neurons in the LHA. Arcuate NPY/AgRP neurons are inhibited by leptin and stimulated by ghrelin. Leptin stimulates POMC/CART neurons. Leptin can act at all sites in the network (note leptin receptor distribution, LepR). There are reciprocal connections between PVN anorexigenic oxytocin neurons and the nucleus tractus solitarii (NTS). The NTS processes input via the vagus from gut hormones signaling satiety (CCK, GLP-1, PYY). Noradrenaline, α-MSH (from POMC neurons), PrRP, and GLP-1 are transmitters in the NTS to PVN pathway. In mid- to late pregnancy several changes that alter the network balance in favor of increased food intake and energy storage have been identified to date (*): (1) NPY/AgRP neurons are more active, and evidently leptin resistant as leptin levels are high in pregnancy; (2) LepR expression in the hypothalamus (but not arcuate nucleus) is reduced; (3) leptin resistance (with reduced LepR expression and signaling) develops in the PVN and VMN (induced by prolactin/placental lactogen), and vagal nodose ganglion; (4) activity of PVN oxytocin neurons may be suppressed—they develop resistance to CCK action, and central resistance to anorectic OT actions develops; (5) central resistance to α-MSH develops. Symbols: arrows indicate targets; +: represents excitatory action; −: represents inhibitory action. Regions: 3V, 3rd ventricle; ARC, arcuate nucleus; DMH, dorsomedial nucleus; LHA, lateral hypothalamic area; NTS, nucleus tractus solitarii; PVN, paraventricular nucleus; VMN, ventromedial nucleus. Left: R, Receptors: 5HT2cR, serotonin 2c; CB1R, cannabinoid 1; ERβ, estrogen; InsR, insulin; LepR, leptin; MC4R, melanocortin; PRL-R, prolactin; OTR, oxytocin; OXR, OX1R, OX2R, orexin; Y1, Y5, neuropeptide Y. Right, Neuropeptides: α-MSH, melanocyte stimulating hormone; AgRP, agouti-related peptide; CART, cocaine and amphetamine regulated transcript; CRH, corticotropin releasing hormone; GLP-1, glucagon-like peptide; MCH, melanocyte concentrating hormone; NPY, neuropeptide Y; ORX-A, B, orexins; OT, oxytocin; POMC, pro-opiomelanocortin; PrRP, prolactin releasing peptide; TRH, thyrotropin releasing hormone. Monoamine- NA, noradrenaline. Blood-borne: CCK, cholecystokinin; PYY, peptide YY; GLP-1: glucagon-like peptide. Source: Diagram adapted from Parker & Bloom.163
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

5. FIGURE 44. 4 Intracellular leptin receptor signaling
FIGURE 44.4 Intracellular leptin receptor signaling. Binding of leptin to the long form of the leptin receptor (LepRb) results in activation of Janus kinase (Jak2) at the Box 1/2 motif on the LepRb. Activated Jak2 auto-phosphorylates and also phosphorylates (P) tyrosine (Tyr) residues on the LepRb at positions 985, 1077, and Phosphorylated Tyr-985 is a docking site for SH2 domain-containing phosphatase (SHP2). Phosphorylated Tyr-1077 is a docking site for signal transduction and activation of transcription 5 (STAT5), and phosphorylated Tyr-1138 is a docking site for signal transduction and activation of transcription 3 (STAT3). Activated SHP2 activates the extracellular-regulated kinase 1/2 (ERK1/2) signaling pathway that results in increased EGR-1 gene transcription. Activated STAT3 translocates to the nucleus and induces the expression of suppressor of cytokine signaling 3 (SOCS3). SOCS3 negatively feeds back to inhibit leptin signaling by binding to phosphorylated Tyr-985 and phosphorylated Jak2. Functional leptin resistance in pregnancy may be associated with reduced pSTAT3 formation in response to leptin in neurons that mediate anorectic actions of leptin; this may not simply involve increased SOCS3 induction.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

6. FIGURE 44. 5 The hypothalamo-pituitary prolactin system
FIGURE 44.5 The hypothalamo-pituitary prolactin system. Innonpregnant, nonlactating animals prolactin secretion is under tonicinhibition by dopamine (DA) produced by tubero-infundibulardopamine (TIDA) neurons in the hypothalamus and secreted intothe hypothalamo-hypophysial portal system to act on dopamineD2 receptors on the lactotrophs. TIDA neurons are inhibited byendogenous opioid peptides, which can thus stimulate prolactinsecretion. There are several candidate prolactin releasing factors(PRFs), including thyrotropin-releasing hormone (TRH) and oxytocin(OT) produced in the parvocellular division of the paraventricularnucleus (PVN) and vasoactive intestinal peptide (VIP) producedby neurons in the suprachiasmatic nucleus (SCN), which stimulateprolactin secretion. PRF neurons are activated by serotoninergic(5-HT) inputs from the raphe nucleus. Estrogen sensitizes the pituitaryto release prolactin and also inhibits dopamine synthesis inTIDA neurons. Prolactin can enter the brain by being transportedacross the blood–brain barrier via a specific transport mechanism.Prolactin feedback is important in maintaining the rhythm in prolactinsecretion once it is established in early pregnancy (see Figure44.1). Prolactin acts via prolactin receptors (PRL-R) in a shortfeedback loop to stimulate dopamine production by TIDA neurons.From mid-pregnancy increasing production of placental lactogen(not controlled by the brain) acts like prolactin to stimulate TIDAneurons, which eventually become resistant to stimulation, so thatprolactin secretion surges near the end of pregnancy (Figure 44.1).Enkephalins (enk) produced by the TIDA neurons near the end ofpregnancy may contribute to this surge by auto-inhibiting the TIDAneurons. In late pregnancy prolactin prepares the mammary glandsfor milk secretion.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

7. FIGURE 44.6 Allopregnanolone-opioid mechanisms involvedin suppressed hypothalamo-pituitary-adrenal (HPA) axisresponses to stress in pregnancy. Brain and circulating levels ofallopregnanolone (AP) are increased (↑) in pregnancy (see Figure44.1). In brain stem nucleus tractus solitarii (NTS) neurons, mRNAexpression for proenkephalin-A (Penka) and μ-opioid receptor(MOR; Oprm1) is increased in pregnancy, as a result of increasedAP production. Noradrenergic A2 neurons in the NTS project toparvocellular corticotropin-releasing hormone (CRH) neurons inthe paraventricular nucleus (PVN). Noradrenaline (NA) releasedin the PVN excites the CRH neurons via α1 adrenoceptors, CRH isreleased at the median eminence (ME) and is carried in the hypothalamo-hypophysial portal system to stimulate anterior pituitarycorticotrophs to secrete adrenocorticotropic hormone (ACTH),which stimulates glucocorticoid secretion (corticosterone in rodents;cortisol in humans) by the adrenal glands. In pregnancy, systemicinterleukin-1β treatment (a stressor) fails to evoke noradrenalinerelease from the terminals in the PVN, hence ACTH and corticosteronesecretion are not stimulated, unlike before pregnancy. Thisis a result of increased opioid inhibition (by enkephalin) acting presynapticallyon the upregulated MOR, presumptively on the noradrenergicnerve terminals. In addition, AP may inhibit CRH neuronsby positively modulating GABA inputs to the PVN via actions onGABAA receptors; AP prolongs the opening time of chloride (Cl-)ion channels, enhancing inhibitory GABA neurotransmission.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

8. FIGURE 44. 7 Oxytocin neuron projections and afferents
FIGURE 44.7 Oxytocin neuron projections and afferents. Magnocellular oxytocin (OT) neurons located in the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) send axons to the posterior lobe of the pituitary gland. Oxytocin is secreted into the systemic circulation to act at distant organs, e.g., uterus, mammary glands. Oxytocin is also released from dendrites in the SON and PVN, where it can act locally on the oxytocin neurons themselves, but may also diffuse to influence other hypothalamic neurons, and extrahypothalamic brain regions. Parvocellular oxytocin neurons in the PVN project caudally to the nucleus tractus solitarii (NTS) and spinal cord. They also project rostrally to limbic brain regions and release oxytocin from their axon terminals. Magnocellular oxytocin neurons receive afferent inputs from hypothalamic, extrahypothalamic, and brain stem regions. Sources of input to the parvocellular oxytocin neurons include other hypothalamic nuclei (e.g., the arcuate nucleus) and the NTS.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

9. FIGURE 44. 8 Oxytocin neuron activation at parturition
FIGURE 44.8 Oxytocin neuron activation at parturition. Coordinated burst-firing of magnocellular oxytocin neurons triggers pulsatile oxytocin (OT) secretion into the blood from the nerve terminals in the posterior pituitary. OT acting on upregulated OT receptors (OTR) in the uterus stimulates uterine contractions and increases intrauterine pressure, resulting in pup expulsion. The stretching of the birth canal activates neural pathways to noradrenergic neurons in the A2 region of the nucleus tractus solitarii (NTS). Activation of these noradrenaline (NA)-producing neurons in the NTS can be mimicked experimentally with intravenous infusion of OT pulses in day 22 pregnant rats, which causes Fos (protein product of c-fos, an immediate early gene and indicative of recent activation) induction in the NTS cell bodies. The noradrenergic neurons project to oxytocin neurons in the supraoptic (SON) and paraventricular (PVN) nuclei, where they release noradrenaline, which excites the OT neurons. Experimentally, in late pregnant rats intravenous OT pulses stimulate NA release in the SON. This pathway is a classic positive feedback loop, designated as the “Ferguson reflex.”
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

10. FIGURE 44.9 Microenvironment of a magnocellular oxytocin neuron: changes near the end of pregnancy. The dendrites and cell bodies of magnocellular oxytocin (OT) neurons in the supraoptic (SON) and paraventricular (PVN) nucleus receive excitatory (glutamate and noradrenaline) and inhibitory (GABA and opioids) inputs. The noradrenergic input is restrained by endogenous opioids during late pregnancy. Oxytocin is also released from the dendrites, which stimulates endocannabinoid (eCB) production by the oxytocin neurons. In turn, eCBs inhibit glutamatergic and GABA inputs to the oxytocin neurons, while oxytocin directly stimulates glutamate terminals. Allopregnanolone (AP; present in increased concentrations in pregnancy and produced by glial cells) potentiates the inhibitory actions of GABA via actions on GABAA receptors. Allopregnanolone levels decline at the end of pregnancy, and its potentiating effect on GABA inhibition of oxytocin neurons is lost. Oxytocin neurons also produce nitric oxide (NO) when activated, and NO can inhibit the oxytocin neurons both directly and by acting presynaptically on GABAergic inputs. At the end of pregnancy, the NO system in the oxytocin neurons is downregulated, thus oxytocin neurons are more responsive to excitatory inputs, and oxytocin released by the dendrites exerts a predominant control of oxytocin neuron activity. At the posterior pituitary, a κ-opioid mechanism restrains oxytocin secretion in pregnancy. This mechanism is downregulated in late pregnancy, enabling greater stimulation of oxytocin secretion by arriving actions potentials. Synchronized or burst-firing of oxytocin neurons at parturition and in lactation causes secretion of pulses of oxytocin.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

11. FIGURE 44. 10 Dendritic spines in the hippocampus in pregnancy
FIGURE Dendritic spines in the hippocampus in pregnancy. (A) Diagram illustrating hippocampal pyramidal neurons and their dendritic trees. Photomicrographs of dendritic spines in the CA1 region of the dorsal hippocampus from a (B) diestrus female and (C) late pregnant (gestational day 21) rat. Scale bar = 10 μm. Note the increase in the density of spines on the dendrites (indicated by arrow) in late pregnancy compared with diestrus. As dendritic spines represent potential sites for postsynaptic input, an increase in their number is often interpreted as an increased potential for neurotransmission and information processing. Source: Adapted from Kinsley et al.28 with permission from Elsevier.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

12. FIGURE 44. 11 Neural networks organizing maternal behavior
FIGURE Neural networks organizing maternal behavior. Before pregnancy, aversion to young or disinterest is predominant, involving olfactory input to the medial amygdala (MeA) and thence to the periaqueductal gray (PAG) via the anterior hypothalamus (AH). Stimulation of neurogenesis in the olfactory bulbs by prolactin in early pregnancy is important for maternal behavior postpartum. At the end of pregnancy the medial preoptic area (mPOA) GABA output, interacting with oxytocin actions in the olfactory bulbs and amygdala, suppresses aversion to young. The mPOA is primed by actions of estrogen, progesterone, and prolactin in late pregnancy. Progesterone withdrawal and downregulation of μ-opioid action, with upregulation of oxytocin action, lead to display of maternal behavior at parturition. Central release of oxytocin stimulated by parturition, involving noradrenergic input from the nucleus tractus solitarii (NTS), promotes maternal behavior through actions at multiple sites, where oxytocin receptor expression is upregulated. mPOA projections to the meso-limbic dopaminergic (reward) circuitry stimulates motivation to perform maternally, and to provide reward via dopamine release in the NAcc. In the VTA dopamine neurons are stimulated (indirectly) by μ-opioid action, which here promotes maternal behavior, with actions on the mPOA. Activation of μ-opioid input to the PAG switches off maternal behavior. AH, anterior hypothalamus; DA, dopamine; D1, dopamine receptor; GABA, γ-aminobutyric acid; MeA, medial amygdala; mPOA, medial preoptic area; NAcc, nucleus accumbens; NTS, nucleus tractus solitarii; PAG, periaqueductal gray; OT, oxytocin; OT-R, oxytocin receptor; PVN, paraventricular nucleus; vBNST, ventral bed nucleus of stria terminalis; VTA, ventral tegmental area.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition