Oxytocin: the key to treating lactation-failure and associated diseases

Oxytocin: the key to treating lactation failure and associated diseases Invited video lecture by Translational Biomedicine Yu-Feng Wang, MD, PhD Department of Cellular Biology and Anatomy Louisiana State University Health Sciences Center- Shreveport, LA Shreveport LA, USA 1

Talk 1 I am Yu-Feng Wang. I thank everyone for interest in Y F W th k f i t ti my topic. It is my great pleasure to address the neurochemical mechanisms underlying breastfeeding and the therapeutic potential of oxytocin in solving breastfeeding and associated p g problems. 2

Breastfeeding is the feeding of an infant or young child with breast milk directly from female human breasts via lactation or nursing. Breastfeeding has many benefits for both mother and baby, such as reducing th i id d i the incidence of di b t and obesity. f diabetes d b it To have the full benefit of breastfeeding, the World Health Organization (WHO) recommends exclusive breastfeeding for the first six months of life and then supplemented breastfeeding for at least one year. Breastfeeding is a natural human activity, while nursing difficulties are not uncommon. According to the Centers for Disease Control (CDC), among children born in 2007 in the USA , the rate of breastfeeding at g g early postpartum was 75.0%, at 6 months of age was 43.0%, and at 12 months was 22.2%. Apparently, more than 50% of mothers failed to breastfeed their babies adequately, and thus face a risk of lactation- failure associated diseases such as postpartum depression and premenopausal breast cancer. 3

Talk 2 Recently, enormous efforts have been made to study the failure to start lactation for about 25% of mothers, such as those with preterm babies. However, mechanisms of lactation-failure for about 32% of mothers who have once started breastfeeding are largely unknown. To improve breastfeeding rates and prevent lactation failure and associated diseases, understanding the mechanisms that promote normal breastfeeding is an essential step. Our approach of the last 17 years tries to achieve better understanding of neurochemical mechanisms responsible for the milk letdown reflex, or milk-ejection reflex. In milk-letdown milk ejection addition, we have also started to consider the translation of our results into treatment and prevention of lactation- failure associated diseases diseases. 4

In this lecture, I will first discuss neurochemical mechanisms underlying the milk letdown reflex, particularly suckling-elicited burst firing f fi i of OXT neurons mediated b OXT di t d by OXT. Then, I will use data from a lactation-failure rat model to show what happens to OXT neurons during lactation failure and to confirm the potential to use oxytocin to treat lactation failure. Following this section I will discuss how oxytocin may be useful in section, treating or preventing lactation-failure associated diseases. Finally, I will briefly mention some of my considerations of how to use y, y y OXT appropriately. 5

Talk 3 Successful b S f l breastfeeding i tf di involves milk production, l ilk d ti secretion and ejection controlled by a series of humoral and neural processes. Among them, p g neurochemical events leading to milk letdown or milk ejection are the most fragile processes. Thus, studying the milk-letdown reflex is critical to solving breastfeeding problems. 6

The reflex involves five basic links: first, sensing the baby’s sucking atthe receptors at nipples; second conducting neural impulses along the second,afferent pathway mediated by mammary nerves; third, relay stations inthe spinal cord and integration in the brain; fourth, conduction alongefferent pathways via neural stalk, neurohypophysis and blood p y , yp p ycirculation and; fifth, myoepithelial effectors in the mammary gland. Inhumans, this reflex can be conditioned by auditory, olfactory and visualstimuli, which can indirectly activate the efferent pathway of the letdownreflex at the hypothalamus. In studying this reflex, the most mysterious processes are the afferentneural processes l di t th activation of magnocellular oxytocin l leading to the ti ti f ll l t i(OXT) neurons in the supraoptic and paraventricular nuclei in thehypothalamus. These two nuclei are also called as, SON and PVN. 7

Talk 4 In studying the regulation of OXT neuronal activity, activity a lactating rat model is often used To used. help us understand the specifics of what happens in OXT neurons during breastfeeding breastfeeding, let’s see a short movie revealing the feature of the milk letdown freflex in lactating rats. 8

At the beginning of suckling, a litter of 10 pups is attached to the nipples, and both mother rat and pups appear asleep. After a long latency, all the pups suddenly suck the nipples actively, appearing as a simultaneous stretch reaction, which indicates the occurrence of milk letdown reflex. 9

Talk 5 In the whole suckling process, milk-letdown occurs intermittently, echoing patterned firing activity in OXT neurons and its ensuing bolus release of OXT Now OXT. let’s see what happens to hypothalamic OXT neurons. 10

Here is an example of simultaneous recordings of the firing activity of OXT neurons and intramammary pressure. In the first 10 min of suckling, the firing rate of OXT neurons remains stable. Then, shortly before the occurrence of milk ejection as indicated by the increase of intramammary pressure, the firing rate of OXT neurons of the right and left SON suddenly increases to 20-40 times higher than that before the milk ejection. Thi patterned fi i activity i called a milk- b f th ilk j ti This tt d firing ti it is ll d ilk ejection burst, or a burst. The burst and ensuing milk ejection recur intermittently with an interval of several minutes while the basal firing rate increases periodically between two bursts bursts. 11

Interestingly, the burst firing can also be evoked in brain slices by simulating th neurochemical environment around oxytocin i l ti the h i l i t d t i neurons. The figure in the top panel shows the burst-firing of OXT neurons evoked by phenylephrine, an alpha 1 adrenergic agonist, in a low calcium artificial CSF The lower panel shows exemplary CSF. burst firing evoked by OXT. This finding provides a novel approach to study neurochemical modulatory process of the reflex at hypothalamic level. 12

The b t h Th burst phenomenon is a critical f t i iti l feature of th milk l td f the ilk letdown reflex. Synchronous burst of a large pool of OXT neurons triggers a bolus release of OXT and causes milk letdown. Correspondingly, Correspondingly studying neurochemical mechanisms responsible for the burst and the transient milk-letdown, become the most important step in understanding the letdown reflex. 13

From suckling stimulation to the occurrence of burst firing in OXT neurons, many modulatory levels are involved, including the afferent neural pathway of suckling signals synaptic input and glial neuronal signals, glial-neuronal interaction, neurochemical environment, receptors and intracellular signaling processes, and electrogenic organelle activity, etc. 14

First, let s First let’s see the afferent pathway in the schematic drawing Suckling drawing. signals carried by mammary nerves enter the spinal cord, relay in the lateral cervical nucleus, and then cross to the contralateral side of the brainstem at the medulla. Relayed in the lateral tegmentum of the y g midbrain, the afferent signals enter the hypothalamus diffusely, primarily terminating in the dorsal medial and posterior hypothalamus, but apparently not directly in the SON and/or PVN. Thus, suckling information is likely integrated before being sent to OXT neurons via local neural circuits. 15

Our studies focus on the integrative processes of afferent neural pathways in the brain for synchronizing bursting among OXT neurons. We have found that,1. Afferent inputs from the lateral tegmentum partially cross to the contralateral side of th h t l t l id f the hypothalamus (W th l (Wang et al, 1995); t l 1995)2. This crossing pathway is responsible for the summation of suckling signals, which is a basis of burst generation (Wang et al, 1996);3.3 Burst synchrony of OXT neurons in the SON and PVN of bilateral sides depends on signals from the ventral posterior hypothalamus (Wang et al, 1997; Yang et al, 1999);4.4 OXT neurons have mutual structural and functional connections with the nuclei of the mammillary body and a special group of interneurons in the SON and perinuclear zone, which provides a periodic synaptic input to OXT neurons with an inhibitory p p y period before the burst and an active period following the burst (Wang et al, unpublished data);5. Mammillary body and associated structures innervate bilateral OXT neurons simultaneously while receiving feedback modulation from OXT neurons, and function as a “Synchronization center” (Wang et al, 8th WCNH, 2009). 16

Now, Let’s see some structural and functional features of synaptic innervation of OXT neurons during lactation and suckling. fO 1. Direct synaptic innervation of OXT neurons is limited to a few brain areas including the nucleus of the solitary tract (NTS) (NTS), posterior hypothalamus, dorsal medial hypothalamus, perinuclear zone, bed nucleus of the stria terminalis (BNST), and SON and PVN on the contralateral side (Wakerley etal, 1994). 2. Lactation increases the number of direct synapses on OXT neurons (Hatton et al, 2004; Theodosis et al,2008); 3. OXT reduces tonic EPSCs (Kombian et al, 1997, Pittman et al, 2000) and IPSCs (Brussaard, 1995), but increases intermittent clustered EPSCs (Israel et al, 2003; Wang and Hatton, 2004, 2007, 2009) and likely clustered IPSCs as well (Moos 1995); 4. 4 OXT can elicit periodic changes i synaptic i li i i di h in i inputs ffrom the BNST h (Lambert et al, 1994), histaminergic tuberomammillary nuclear neurons and intra-SON interneurons (Wang et al, 8th WCNH, 2009), 2009) as well as a fraction of perinuclear zone neurons (Dyball & Leng, 1986). 17

During suckling, afferent neural signals directly or indirectly activatethese neural structures having direct synaptic connections with OXTneurons in the SON and PVN. OXT neurons of bilateral sidessimultaneously receive noradrenergic, glutamatergic, oxytocinergic,GABAergic, and histaminergic synaptic innervation. These synapticinfluences reduce continuous f t synaptic ii fl d ti fast ti input while increasing the t hil i i thincidence of intermittent clustered synaptic input on OXT neurons. Inaddition, synaptic input also directly modulates OXT neuronal activityby periodically releasing neurotransmitters time locked with the neurotransmitters, time-lockedburst firing.These activities form a facilitative environment around OXT neuronswhile providing a trigger for burst generation. 18

Talk 6 While receiving presynaptic innervation, magnocellular OXT neurons are also under t i modulation b l d tonic d l ti by surrounding astrocytes. As reported by Hatton’s lab and Theodosis lab, during transition from pregnancy to , g p g y lactation, astrocytes in the SON show dramatic morphological plasticity, which facilitates burst firing and synchrony. synchrony 19

Most astrocytes are located in the ventral region of the SON the SON, ventral glial lamina. As shown by immunostaining for GFAP, the astrocyte cytoskeletal element, these ventrally-located astrocytes send processes dorsally and form a natural barrier between neighboring OXT neurons as indicated by combined immunostaining of OXT-neurophysin. The question is what happens to astrocytes during suckling/OXT actions. 20

By sampling the SON at different stages of suckling and simulating theneurochemical environment around oxytocin neurons in brain slices, wehave observed a GFAP-mediated acute astrocyte plasticity in responsetot suckling or OXT stimulation. Before suckling/OXT stimulation, kli ti l ti B f kli /OXT ti l tiastrocyte processes with scaffolding of GFAP lie between membranesof neighboring OXT neurons. Suckling reduced the abundance of GFAPfilaments,filaments which was partially reversed after the occurrence of milkejection. Simulating the increased release of OXT during suckling byincubation of the slices with OXT, we also observed a GFAP reduction;and a reversal of OXT-elicited GFAP reduction was simulated by OXT elicitedtransient 12 mM K+ exposure, a phenomenon observed in OXT-secreting system accompanying the milk ejection. Thus, astrocytepplasticity mirrors OXT neuronal activity and ensuing neurochemical y y genvironment changes. 21

Further t di i di t that, F th studies indicate th t1. Acute astrocyte plasticity is essential for suckling-evoked burst firing in OXT neurons and ensuing milk letdown (Wang and Hatton, 2009).2. Astrocytes promote glutamate release, and partially mediate effects of OXT on tonic and clustered EPSCs (Wang and Hatton, 2009).3. Suckling and OXT cause acute retraction of astrocyte processes around OXT neurons (Wang and Hatton, 2007) b d d (W d H tt by depolymerizing l i i GFAP filaments (Wang and Hatton, 2009), which reflects the dynamic activity of OXT neurons via neurogenic neurochemical changes. changes4. GFAP plasticity modulates OXT neuronal activity by changing water transportation, morphology, and glutamate metabolism in astrocytes.5.5 In addition astrocyte plasticity is also related to increased addition, prostaglandin synthesis (Wang and Hatton, 2006) and ATP metabolism (Ponzio et al, 2006), which together with bolus g glutamate release pprovide an external driving force for burst g generation. 22

Talk 7 Contributions of synaptic input and astrocyte modulation of oxytocin neuronal activity are mainly achieved via release of neurochemicals such as OXT, norepinephrine, glutamate, prostaglandins, and ATP Cl ifi ti of th l t t t l di d ATP. Clarification f the regulation of local neurochemical environments will provide further insight into the burst generation process. Now, let’s see the relationship between local neurochemical environment and the burst in OXT neurons. 23

Suckling increases intra-SON and PVN release of OXT (Neumann et al, 1993, Bealer and Crowley, 1998).2. OXT release during suckling depends on actions of g g g p glutamate ( (Parker and Crowley, 1993, 1995), norepinephrine (NE, Bealer and Crowley, 1998), and histamine (HA, Bealer and Crowley, 1999, 2001), releases of which are increased during suckling.3.3 In I modulation of OXT release, synergistic i t d l ti f l i ti interactions between ti b t glutamate and NE (Parker and Crowley, 1993) and between HA and NE (Bealer and Crowley, 1999) are essential.4.4 Prostaglandins (Wang and Hatton, 2006) ATP and adenosine (Ponzio Hatton 2006), et al, 2006) from astrocytes contribute to the changes in the burst- related extracellular milieu.5. In addition, OXT neuronal activity-elicited changes in ion levels also modulate the activity of the OXT-secreting system, such as K+ level (Leng and Shibuki, 1987). 24

The firing activity of oxytocin neurons is closely related to their chemicalenvironment. As shown in the figure, during suckling, tonic synaptic inputand retraction of astrocyte p y processes around OXT neurons increaseextracellular levels of OXT, glutamate, PGs, K+, and others while GABAand Ca2+ levels are reduced, which creates a facilitatory chemicalenvironment for synchronous burst firing. When OXT neurons are ready todischarge bursts intrinsically, bolus release of glutamate will trigger burstactivity. Synchronized burst of a large pool of OXT neurons dramaticallychanges the local neurochemical environment again, particularly a largeincrease i extracellular K+ li in t ll l level, which results i re-expansion of astrocyte l hi h lt in i f t tprocesses. Meanwhile, ATP is converted to adenosine, and GABA andtaurine are likely released from astrocytes, contributing to postburstinhibition of OXT neuronal activity. Following these transient changes the activity changes,extracellular neurochemical environment will largely return to that at thebeginning of suckling stimulation, and a new cycle toward bursting begins. 25

Talk 8 Burst discharges are directly determined by membrane electrogenic activities of OXT neurons in certain spatial and temporal orders. However, none of the suckling- associated neurochemicals elicit bursts directly; thus, a modification of cellullar/molecular signaling processes in OXT neurons is needed to prepare OXT neurons to discharge a burst. 26

In studying pote t a s g a g p ocesses dete study g potential signaling processes determining t e inherent g the ee t burst capacity, it has been found that,1. OXT receptor (OTR) is expressed in both neurons and astrocytes in the SON (Wang and Hatton, 2006).2. The major signaling pathway of the OTR involves Gq/11-type G- proteins (Sanborn et al, 1998; Gimpl and Fahrenholz, 2001).3. OTR-associated Gβγ- subunit is a dominant signal in OXT-evoked bursts (Wang and Hatton, 2007a), can activate ERK1/2 (extracellular signal-regulated protein kinase 1/2) and protein kinase A (PKA) (Sanborn et al, 1998; Zhong et al., 2003).4. In OTR signaling, dynamically changing the phosphorylation of ERK1/2 in a unique spatiotemporal order can trigger burst (Wang and Hatton 2007b) Hatton, 2007b).5. Moreover, OXT induces Cox-2 and promotes prostaglandin (PG) synthesis in OXT neurons and astrocytes, promotes actin polymerization (Wang and Hatton, 2006) and facilitates bursts Hatton 2006), (Wang and Hatton, 2007b). 27

As shown in the schematic drawing, suckling-elicited synaptic input andastrocyte plasticity lead to increases in somatodendritic release of OXT inthe hypothalamus. By mobilizing the Gβγ-dominant signaling cascade,OXT increases phosphorylation of ERK 1/2. PhosphoERK 1/2 together i h h l ti f 1/2 Ph h ERK t thGαq subunit signaling, induces Cox-2 and synthesis of prostaglandins.PhosphoERK 1/2 coordinated with prostaglandin-elicited protein kinase A(PKA) signaling causes reorganization of actin filaments and ensuing filaments,changes in the activity of electrogenic organelles. The functions ofposphoERK 1/2 and PKA are antagonistic in general in OTR signaling.However,However by eliciting their activities in a burst-favorable spatiotemporal burst favorableorder, such contradictory signals are highly coordinated to change thestate of membrane electrogenic organelles (e.g., ion channels, pumps,transporters, gap j p , g p junctions, etc.), leading to decreases in K+ conductance , ), gand increases in Na+, Ca2+ and non-selective cation currents. Whenchanges in the local neurochemical environment are phase-locked withthese intracellular signaling processes, a burst will occur. 28

Relative to other levels, electrical features supporting burst firing are not well understood yet. To explain the transition between low-frequency basal firing and high- frequency synchronized burst, a gating mechanism and a synchronization mechanism were proposed in early studies. Later, Hatton and colleagues identified an increased incidence of junctional coupling among OXT neurons in lactating rats, which likely facilitates the burst gating and synchrony. Then, Stern and Armstrong found, there is a rebound depolarization, following transient hyperpolarization of membrane potential in OXT neurons in lactating rats, which supports a short burst firing. In I an in vitro burst firing model, we h i it b t fi i d l have also f l found th t preceding a b t d that di burst, the rising slope of the afterhyperpolarization is decreased while the rising slope of spikes is increased. Further analysis reveals, in burst firing neurons, the decay time course of the afterhyperpolarization is reduced dramatically y yp p y compared to the non-burst firing neurons (Wang and Hatton, 2004). All these features give OXT neurons a specific capacity to fire spikes in bursts, likely via a dramatic decrease in K+ currents, an increase in the Na+ currents and a larger hyperpolarization activated inward current on the basis hyperpolarization-activated of a general excitation of OXT neuronal activity. 29

As a whole, neurochemical mechanisms u de y g suc s o e, eu oc e ca ec a s s underlying suckling-evoked g e o ed burst firing in OXT neurons through OXT can be summarized as follows: During suckling, a tonic afferent suckling message from the nipples increases OXT level in the SON and PVN. By activating OTR and Gq G proteins, OXT increases phosphoERK 1/2 in the somata and PKA in the processes in a burst-associated temporal order. In astrocytes, OXT causes retraction of astrocyte processes from the surrounding of t ti f t t f th di f OXT neurons, creating a facilitatory neurochemical environment. In OXT neurons, reorganization of actin filaments occurs, preparing OXT neurons to discharge bursts intrinsically Meanwhile presynaptic tonic intrinsically. Meanwhile, inhibition of glutamatergic transmission facilitates bolus release of glutamate, forming a trigger for burst firing. Together, recurring retraction and expansion of astrocyte processes changing the local processes, neurochemical environment, activating intrinsic signaling processes in OXT neurons, adding a bolus release of glutamate from presynaptic terminals result in rhythmic, synchronous bursting of OXT neurons, y , y g , bolus release of OXT, and therefore, intermittent milk ejections. 30

Theoretically, disrupting the modulatory process at any level will result ina failure of activation of OXT neurons and the letdown reflex. Lackingsuckling stimulation is the most common reason for lactation failure,particularly at the start of breastfeeding; however, neural mechanismsunderlying lactation failure in those with successful breastfeedingexperience remain unknown. Moreover, experimental evidenceregarding therapeutic roles of OXT in lactation-failure mothers is stillcontroversial. To restore breastfeeding efficiently, it is necessary toexamine what happens to OXT neurons during lactation failure and howoxytocin can be used to restore breastfeeding. In the next section, let’s see the role of oxytocin in lactation failure. 31

Here, I will use the data from a lactation-failure rat model, to show what happens to OXT neurons and to confirm the potential of using OXT to treat lactation failure. O f In this study, we separated a rat dam from her pups for 20 h per day for four days and pups were nursed by another mother during days, the separation. We then observed electrical responses of OXT neurons in the SON in the anesthetized mother rats after the four- day separation. As we can see in the figure suckling caused a separation figure, burst discharge in the normal lactating rat, but failed to trigger burst firing in the lactation-interrupted rat. This result indicates malfunction of OXT neurons, accounting for the lack of OXT and , g the failure of breastfeeding following maternal separation. 32

Next, let’s see the effect of lactation-interruption on interactions , p between OTR and its downstream signals. We first immuno- precipitated OTR, and then detected Gaq/11 subunits and total ERK (tERK) 2 in Western blot. As shown in the figure, lactation interruption significantly reduced molecular association between OTR and tERK 2 in the upper panel, and OTR and Gaq/11 subunits in the lower panel, compared to those in normal lactating rats. This Thi result indicates functional uncoupling of OTRs with Gaq/11 G lt i di t f ti l li f OTR ith G /11 proteins and ERK proteins, resulting in the failure of burst in OXT neurons. 33

Talk 9 From the results presented above, we can see, lactation failure is due to malfunctions of OXT neurons. Since activation of OXT neurons by suckling is mediated by local release of OXT, nasal delivery of OXT can access brain without the blockade of blood brain barrier, thus, nasal OXT delivery should maintain OXT neuronal activity during lactation interruption. To test this hypothesis, we further examined effects of nasal OXT on intramammary pressure changes during suckling stimulation in lactation interrupted rats lactation-interrupted rats. 34

In the figure, the top row shows, suckling caused intermittentincreases i i ti in intramammary pressure i normal l t ti rat; th in l lactating t themiddle row shows, lactation-interruption suppressed the recurrence ofmilk ejections; and the bottom row shows, when OXT was suppliednasally during lactation interruption regularity of the milk ejections interruption,was largely restored. Noteworthy is, the magnitudes of OXT-elicited intramammarypressure changes are the same among the three groups supporting groups, supporting,the failure of the milk-letdown reflex was due to the lack of OXT.Thus, nasal application of OXT during lactation interruption canmaintain the responsive capacity of the OXT-secreting system to later p p y g ysuckling stimulation. 35

The lTh roles of oxytocin i l t ti f il f t i in lactation-failure can b summarized as f ll be i d follows: 1. Lactation interruption-caused lactation failure is due to a malfunction of OXT neurons and their failure to respond to suckling stimulation. 2. The malfunction of OXT neurons is related to an uncoupling between OXT receptors and the downstream signals, such as Gq G protein and ERK 1/2. t i d 1/2 3. As a consequence, the malfunction of the OXT-secreting system leads to the failure of OXT secretion into the blood during suckling, suckling and the failure of milk letdown letdown. 4. Finally, nasal application of OXT during lactation interruption can rescue the milk letdown reflex. 36

Talk 10 This result is directly meaningful for those service women or working mothers who have to be separated from their babies for weeks or longer while having the desire to breastfeed their babies later. This result also sets a strong experimental basis for using OXT to treat lactation failure- associated diseases. 37

In the next section, I want to look at potential use of OXT to treat or prevent lactation-failure associated diseases, such as postpartum depression and premenopausal b t t d i d l breast cancer. t 38

First, let sFirst let’s consider postpartum depression depression.Lactation failure is associated with a high incidence of anxiety andother mood disorders, including postpartum depression (PPD) .Studies have revealed that postpartum depression affects up to 15%of mothers (Pearlstein et al, 2009). At one hand, women withdepressive symptoms in the early postpartum period may be atincreased risk for negative infant-feeding outcomes (Dennis andMcQueen, 2009). On the other hand, early cessation of breastfeedingor not breastfeeding was associated with an increased risk ofmaternal depression (Ip, et al, 2009).However, almost all the data have been gathered from observationalstudies,studies and the causal relationship between postpartum depressionand breastfeeding failure remains to be verified. 39

In our study, it was found that maternal separation causes signs in the dams y, p gsimilar to those seen in postpartum depression in humans (Wang and Hatton,2009). As shown in the figure, lactation interruption significantly reduced theinterest of mother rats in their offspring, as indicated by the longer latencyand reduced f d d d frequency t li k th pups. In addition, maternal b d weight to lick the I dditi t l body i htgains are also reduced significantly compared to normal lactation rats. It isclear, dam-pup separation caused maternal depression.As observed in the lactation restoration, nasal OXT also increased theinterest of the dams in their pups in the rescue of lactation. Thus, curinglactation failure should also relieve maternal depression. 40

Next, let’s see how OXT may be used in prevention of breast cancer. e t, et s o O ay p e e t o o b east ca ce1. According to the American Cancer Society, over a womans lifetime, the chance of developing invasive breast cancer is about 12%.2. Interestingly, investigations based on special populations reveal a strong cancer preventive effect of breastfeeding. For instance, among women with a first-degree family history of breast cancer, breastfeeding cut the risk of breast cancer by 59 percent (Stuebe et al., 2009). And among younger African-American women, up to 68% of basal-like breast cancer could be prevented by promoting breastfeeding and reducing abdominal adiposity (Millikan et al, 2008).3. However, a systematic review of the literature of all types of studies failed to reveal a consistent effect of insufficient milk supply on breast cancer risk (Cohen et al, 2009).4. Thus, a causal relationship between lactation failure and general breast cancer probability remains to be established established. 41

Talk11 Most breast cancer risk factors work through changes in hormone levels that influence the development of breast p epithelium. OXT induces a significant differentiation of epithelial cells during lactation, and reduces breast cancer susceptibility. If breastfeeding really has anti susceptibility anti- cancer roles, pulsatile OXT actions like that during nursing should be more effective than tonic actions under other phsiological conditions in suppressing the proliferative activity in mammary tissues. To test this hypothesis, we observed effects of pusatile versus tonic yp , p application of OXT on hydrogen peroxide-induced Cox-2 expression in mammary glands in weaning rats. 42

As shown in the figure, treatment of the mammary tissues with 50 μM hydrogen peroxide for 40 min significantly increased Cox-2 levels. Simultaneous application of 0.1 nM OXT with hydrogen peroxide produced different results depending on the patterns of OXT application. It was only the pulsatile application of OXT that significantly reduced hydrogen peroxide-induced Cox- 2 expression. Thi result clearly indicates that pulsatile OXT actions i This lt l l i di t th t l til ti rather than tonic OXT actions have strong anti-proliferative effects following oxidative stress in mammary glands, and demonstrates a causal relationship between lactational OXT and reduced mammary tumorigenesis. 43

From our preliminary studies presented above, we consider the potential of OXT in treating or preventing lactation-failure associated diseases as follows:1. Lactation failure is also accompanied by signs of depression, which are related to the lack of brain OXT from the SON and/or PVN.2.2 OXT can increase serotonin release (Yoshida et al, 2009), and l k of serotonin i i t i l (Y hid t l 2009) d lack f t i is related to the occurrence of postpartum depression. Thus, timely application of OXT may prevent maternal depression during lactation interruption and prevent lactation failure in mothers with pos pa u dep ess o ac a o a u e o es postpartum depression.3. Lactational pattern of OXT actions is also important for prevention of breast cancer. The intermittent pattern of OXT actions during suckling can effectively suppress the proliferative reaction of mammary tissue to oxidative stress, accounting for the reduction in susceptibility of mammary glands to carcinogens following sufficient breastfeeding.4. Finally, lactation failure increases the incidence of premenopausal breast cancer, and nasal application of OXT can restore the regulation of milk letdown. Thus, pp g appropriately applying OXT has the potential to reduce the risk of breast cancer in non-breastfeeding mothers or mothers with insufficient lactation. From our present result, we can also predict that OXT can specifically reduce breast cancer incidence in years following the weaning one of the surges of breast cancer occurrence weaning, occurrence. 44

In the final section, I would like to address several issues regarding public use of OXT OXT. 45

Talk 12OXT is likely beneficial for a large population beyondbreastfeeding mothers. Rb tf di th Recently, OXT has b tl h been a h t t i hot topicfor its effects on social cognition, pair-bonding, enhancing sexquality, reducing fear, anti-autism, and so on. y gCorrespondingly, OXT nasal spray has become availablecommercially. The availability of oxytocin puts forward aserious question regarding its potential risk to public health Itis urgent to define the appropriate targets for OXT use, sinceunwanted side effects of OXT may occur while pursuing itsbeneficial effects. Mb fi i l ff t Moreover, d fi i th appropriate ti defining the i t timesand doses as well as patterns of application is also important,since the action of OXT is strongly time-, dose- and pattern-dependent. Inappropriately applying OXT may cause effectsopposite to those expected. Thus, further studies arerequired to clarify the mechanisms and approaches for OXTactions before OXT is really publicly applicable as a “Cuddle 46chemical.”

At the end of this lecture, I would like to thank my previous supervisors, who contributed to my studies at different stages of my career. Dr. Negoro, the fi t th first mentor guiding me t study th l td t idi to t d the letdown reflex f fl from i vivo in i approaches, Dr. Yamashita and his associates, teaching me the in vitro approaches to study OXT neurons, and Dr. Hatton who was my strongest supporter of translational studies. My studies have also g pp y greatly benefited y from many senior scientists; and here I could only name a few of them. Specific thanks to Dr. Hamilton, who has strongly encouraged me to study interactions between olfaction and hypothalamic neuroendocrine process. I would also like to thank Dr Knight for kindly revising this lecture and Drs Dr. lecture, Drs. Liu and yang for video editing. And I appreciate all members of this and previous labs for ongoing discussions and advice. I also thank the sponsors of my research. y Any questions and comments are welcome 47

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Oxytocin: the key to treating lactation-failure and associated diseases

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Oxytocin: the key to treating lactation-failure and associated diseases Presentation Transcript