Oxytocin: the key to treating
lactation failure and associatedlactation-failure and associated
diseases
Invited video lect...
Breastfeeding/lactationBreastfeeding/lactation
1. Breastfeeding is the feeding of an infant or young child with breast
mil...
Outline of this lecture
1. Neurochemical mechanisms underlying the milk
letdown reflex: Suckling-elicited burst firing in
...
The milk letdown reflexThe milk-letdown reflex
Oxytocin (OXT)-
Brain
Tactile,
Oxytocin (OXT)-
Secreting System
NS
SON/PVN
...
S kli i b fi i f OXTSuckling triggers burst firing of OXT
neurons in the supraoptic nucleus (SON)
Paired extracellular rec...
Burst firing of OXT neurons evoked inBurst firing of OXT neurons evoked in
brain slices
Burst
Wang and Hatton, 2004
Wang a...
I Neurochemical mechanismsI. Neurochemical mechanisms
underlying the milk letdown reflex:
S ckling elicited b rst firing i...
Levels of neurochemical modulation of
oxytocin neuronal activityy y
1. Afferent suckling pathway
2. Synaptic innervation
3...
I I Afferent suckling pathway in the CNS
Gating of bursts in
OXT neurons in
I-I. Afferent suckling pathway in the CNS
Sync...
Integrative processes of the afferentIntegrative processes of the afferent
pathway in the hypothalamus
1 Afferent inputs f...
I II Synaptic innervationI-II. Synaptic innervation
1. Direct synaptic innervation of OXT neurons is limited to a few brai...
B t i t d ti tBurst-associated synaptic events
BNST, PNZ, TMTakano et al.,
Boudaba and Tasker, 2006
Israel et al 2003
Pitt...
I III I t ti b t t t dI-III. Interactions between astrocytes and
OXT neurons in the SON
OXT neurons
(OXT-neurophysin stain...
GFAP plasticity during suckling in lactating
rats or OXT stimulation in brain slices
Nuclei GFAP NPs Merge Nuclei GFAP NPs...
Contribution of astrocyte plasticity to theContribution of astrocyte plasticity to the
activation of OXT neurons
1 Acute a...
I IV N h i l i t d b tI-IV. Neurochemical environment and bursts
1. Suckling increases intra-SON and PVN release of OXT (N...
Burst-associated neurochemicalBurst associated neurochemical
environment around OXT neurons
Suckling/OXT Suckling/OXT
Befo...
I V Receptor mediated intracellularI-V. Receptor-mediated intracellular
signaling processes
1. OXT receptor (OTR) has been...
OXT receptor signaling and bursts
I VI El t i ll ti itI-VI. Electrogenic organelle activity
and burst of OXT neurons
1. Burst firing in OXT neurons has stro...
Neurochemical process of OXT elicited burstsNeurochemical process of OXT-elicited bursts
II. Roles of oxytocin in lactation-y
failure
Lactation interruption leads to the failureLactation-interruption leads to the failure
of burst firing during suckling
Nor...
L t ti i t ti l d t liLactation-interruption leads to uncoupling
of OTR with its downstream effectors
tERK 2-WB42 KDa
OTR-...
Nasal OXT restores milk ejection patternNasal OXT restores milk ejection pattern-
intramammary pressure assay
1 mU OXT (i....
Roles of OXT in lactation-failure
1. Lactation interruption-caused lactation failure is due to a
malfunction of OXT neuron...
III. Oxytocin and lactation-failure
associated diseasesassociated diseases
III I P t t d iIII-I. Postpartum depression
1. Postpartum depression (PPD) affects up to 15% of mothers
(P l t i t l 2009)...
Depressive signs in lactation interruptedDepressive signs in lactation-interrupted
rat dams
Wang and Hatton, Frontiers in ...
III II OXT and breast cancerIII-II. OXT and breast cancer
1. According to the American Cancer Society, over a woman's life...
Effects of OXT on H O evokedEffects of OXT on H2O2-evoked
expression of Cox-2 in mammary glands
from weaning ratsfrom wean...
Th ti t ti l f OXTTherapeutic potential of OXT
1. Lactation failure is also accompanied by depressive signs, which are rel...
IV. Issues about publicly using OXT
AcknowledgmentsAcknowledgments
• Previous mentors of this work
• Hideo Negoro, PhD
Academic advices and helps
• Williams R...
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Oxytocin: the key to treating lactation-failure and associated diseasescture video

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This invited video lecture in Translational Biomedicine presents the current understanding of neurochemical mechanisms underlying milk-letdown reflex, and experimental evidence supporting a therapeutic role of oxytocin in some lactation failure-associated diseases.

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Oxytocin: the key to treating lactation-failure and associated diseasescture video

  1. 1. Oxytocin: the key to treating lactation failure and associatedlactation-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 USAShreveport, LA, USA
  2. 2. Breastfeeding/lactationBreastfeeding/lactation 1. Breastfeeding is the feeding of an infant or young child with breast milk directly from female human breasts via lactation or nursing. 2. Breastfeeding has many benefits for both mother and baby. 3. The World Health Organization (WHO) recommends exclusive breastfeeding for the first six months of life and then supplemented breastfeeding for at least one yearsupplemented breastfeeding for at least one year. 4. Breastfeeding is a natural human activity, while nursing difficulties are not uncommon. 5. Lactation failure is associated with postpartum depression (Ip et al, 2009), and premenopausal breast cancer (Stuebe, et al, 2009).
  3. 3. Outline of this lecture 1. Neurochemical mechanisms underlying the milk letdown reflex: Suckling-elicited burst firing in oxytocin (OXT) neurons 2 Therapeutic roles of OXT in lactation-failure2. Therapeutic roles of OXT in lactation failure 3. OXT and lactation failure-associated diseases 4. Issues about publicly using OXT
  4. 4. The milk letdown reflexThe milk-letdown reflex Oxytocin (OXT)- Brain Tactile, Oxytocin (OXT)- Secreting System NS SON/PVN auditory, olfactory, or visual, stimuli OXT NH PRL stimuli Spinal cordMyoepithelia Milk Mammary nerve Circulation Breast Milk
  5. 5. S kli i b fi i f OXTSuckling triggers burst firing of OXT neurons in the supraoptic nucleus (SON) Paired extracellular recordings kes/s Left SON 40spik Right SON Intramammary pressure OXT g 2 min 1mU Wang and Hatton, 2004
  6. 6. Burst firing of OXT neurons evoked inBurst firing of OXT neurons evoked in brain slices Burst Wang and Hatton, 2004 Wang and Hatton, 2007g ,
  7. 7. I Neurochemical mechanismsI. Neurochemical mechanisms underlying the milk letdown reflex: S ckling elicited b rst firing in OXTSuckling-elicited burst firing in OXT neurons
  8. 8. Levels of neurochemical modulation of oxytocin neuronal activityy y 1. Afferent suckling pathway 2. Synaptic innervation 3. Glial-neuronal interaction 4 Neurochemical environment4. Neurochemical environment 5. Receptor-mediated intracellular signaling processes 6 Electrogenic organelle activity6. Electrogenic organelle activity
  9. 9. I I Afferent suckling pathway in the CNS Gating of bursts in OXT neurons in I-I. Afferent suckling pathway in the CNS Synchronization of bursts in OXT neurons OXT neurons in the SON & PVN Lincoln and Wakerley, 1975 bursts in OXT neurons Belin and Moos, 1986 Mesencephalic DMH and PH Dubois-Dauphin et al., 1985b 1975 Lateral cervical nucleus Mesencephalic Lateral tegmentum Juss and Wakerley, 1981 Lateral funiculus of the spinal cord nucleus Dubois-Dauphin et al., 1985a Fukuoka et al, 1984,
  10. 10. Integrative processes of the afferentIntegrative processes of the afferent pathway in the hypothalamus 1 Afferent inputs from the lateral tegmentum cross to the contralateral1. Afferent inputs from the lateral tegmentum cross to the contralateral hypothalamus (Wang et al, 1995); 2. This pathway is responsible for the summation of suckling signals, the basis for burst generation (Wang et al 1996);basis for burst generation (Wang et al, 1996); 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);( g , ; g , ); 4. OXT neurons have mutual structural and functional connections with nuclei of the mammillary body and a special group of interneurons in the SON and perinuclear zone, which mediates periodic synaptic input to OXT neurons (Wang et al, unpublished data); 5. Mammillary body neurons innervate bilateral OXT neurons and function as a “Synchronization center” (Wang et al, 8th WCNH, 2009).
  11. 11. I II Synaptic innervationI-II. Synaptic innervation 1. Direct synaptic innervation of OXT neurons is limited to a few brain areas including the nucleus of the solitary tract (NTS), posterior hypothalamus, dorsal medial hypothalamus, perinuclear zone (PNZ), bed nucleus of the stria terminalis (BNST), and SON and PVN on the contralateral side (Wakerley et al, 1994). 2 L t ti i th b f di t ti i ti f OXT2. Lactation increases the number of direct synaptic innervation of OXT neurons (Hatton et al, 2004; Theodosis et al,2008); 3. Reduced tonic EPSCs (Kombian et al, 1997, Pittman et al, 2000) and IPSCs (Brussaard 1995) in response to OXT stimulation;and IPSCs (Brussaard, 1995) in response to OXT stimulation; 4. Increases in intermittent clustered EPSCs (Israel et al, 2003; Wang and Hatton, 2004, 2007, 2009) and likely IPSCs (Moos 1995); 5 OXT-elicited periodic changes in synaptic inputs from the BNST5. OXT elicited periodic changes in synaptic inputs from the BNST (Lambert et al, 1994), histaminergic tuberomammillary neurons and intra-SON interneurons (Wang et al, 8th WCNH, 2009), and a fraction of PNZ neurons (Dyball & Leng, 1986).( y g, )
  12. 12. B t i t d ti tBurst-associated synaptic events BNST, PNZ, TMTakano et al., Boudaba and Tasker, 2006 Israel et al 2003 Pittman et al, 2000 SON PVN Takano et al., 1990 B d Israel et al, 2003 Dorsal medial hypothalamus PVN Wakerley and Lincoln 1973 Brussaard, 1995 Ventral posterior hypothalamus hypothalamus and Lincoln, 1973 Takano et al., 1992 Honda & Higuchi, 2007 NTS hypothalamus Weiss et al., 1989 Tribollet et al., 1985 Moos et al., 2004 Cumbers et al, 2007,
  13. 13. I III I t ti b t t t dI-III. Interactions between astrocytes and OXT neurons in the SON OXT neurons (OXT-neurophysin staining) Histology of the SON OXT neurons Ventral glial l i AVP neurons lamina Astrocytes (GFAP staining) Hatton and Wang , 2008 neurons
  14. 14. GFAP plasticity during suckling in lactating rats or OXT stimulation in brain slices Nuclei GFAP NPs Merge Nuclei GFAP NPs Merge In Vivo In Vitro Non- Suckling Suckling Control OXTSuckling Milk l td OXT 12 mM K+ i OXT Modified from Wang and Hatton, 2009 letdown in OXT 20 μM
  15. 15. Contribution of astrocyte plasticity to theContribution of astrocyte plasticity to the activation of OXT neurons 1 Acute astrocyte plasticity is essential for suckling evoked burst firing1. 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)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, 2009), which reflects OXT neuronal activities via neurogenic neurochemical changes.g g 4. GFAP plasticity modulates OXT neuronal activity by changing water transportation, morphology, and glutamate metabolism in astrocytes. 5. Astrocyte plasticity is also related to increased prostaglandin synthesis (Wang and Hatton, 2006) and ATP metabolism (Ponzio et al, 2006), which together with bolus glutamate release provide an external driving force for burst generation.
  16. 16. I IV N h i l i t d b tI-IV. Neurochemical environment and bursts 1. Suckling increases intra-SON and PVN release of OXT (Neumann et al 1993 Bealer and Crowley 1998)al, 1993, Bealer and Crowley, 1998). 2. OXT release during suckling depends on actions of 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. In modulation of OXT release, synergistic interactions between glutamate and NE (Parker and Crowley, 1993) and between HA and NE (Bealer and Crowley 1999) are essentialNE (Bealer and Crowley, 1999) are essential. 4. Prostaglandins (Wang and Hatton, 2006), ATP and adenosine (Ponzio et al, 2006) from astrocytes contribute to the changes in the burst- related extracellular milieu.related extracellular milieu. 5. 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).
  17. 17. Burst-associated neurochemicalBurst associated neurochemical environment around OXT neurons Suckling/OXT Suckling/OXT Before burst After burst Ca2+ OXT Glu Oxytocin neuron Glu K+K+ K+ HAGl Oxytocin neuron Oxytocin neuron PGsATP Ca2+ Glu Glu GABAGABA NE K Glu Glu GABAAdenosine K K+K+Ca2+Ca2+ K+ HAGlu Astrocyte Hatton and Wang , 2008; Wang and Hamilton, 2009 AstrocyteAstrocyte
  18. 18. I V Receptor mediated intracellularI-V. Receptor-mediated intracellular signaling processes 1. OXT receptor (OTR) has been identified in both SON neurons and1. OXT receptor (OTR) has been identified in both SON neurons and astrocytes (Wang and Hatton, 2006). 2. The major signaling pathway of 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. Phosphorylation of ERK1/2 in a unique spatiotemporal order can trigger burst (Wang and Hatton, 2007b). 5 OXT induces Cox 2 and prostaglandin (PG) synthesis in OXT5. OXT induces Cox-2 and prostaglandin (PG) synthesis in OXT neurons and astrocytes, promotes actin polymerization (Wang and Hatton, 2006), and facilitates bursts (Wang and Hatton, 2007b).
  19. 19. OXT receptor signaling and bursts
  20. 20. I VI El t i ll ti itI-VI. Electrogenic organelle activity and burst of OXT neurons 1. Burst firing in OXT neurons has strong features of gating (Lincoln and Wakerley, 1975) and synchronization (Belin and Moos, 1986). 2. Lactation increases junctional communication between OXT ti b t h (H tt d Y 1994)neurons, promoting burst synchrony (Hatton and Yang, 1994). 3. There is a rebound depolarization following a transient hyperpolarization of membrane potential, which underlies the burst gating (Stern and Armstrong 1997)gating (Stern and Armstrong, 1997). 4. During seconds preceding a burst, the rising slope of the afterhyperpolarizations (AHPs) is decreased while the rising slope of spikes is increased; in burst firing neurons the decay timeof spikes is increased; in burst firing neurons, the decay time course of the AHPs is shortened dramatically, which favors burst onset (Wang and Hatton, 2004).
  21. 21. Neurochemical process of OXT elicited burstsNeurochemical process of OXT-elicited bursts
  22. 22. II. Roles of oxytocin in lactation-y failure
  23. 23. Lactation interruption leads to the failureLactation-interruption leads to the failure of burst firing during suckling Normal lactating rats Burst Lactation-interrupted ratsLactation interrupted rats Wang and Hatton, Frontiers in Neuroscience, 2009
  24. 24. L t ti i t ti l d t liLactation-interruption leads to uncoupling of OTR with its downstream effectors tERK 2-WB42 KDa OTR-IP Gαq/11 subunits WB40 KDa 66 KDa OTR-IP Gαq/11 subunits-WB 66 KDa 40 KDa
  25. 25. Nasal OXT restores milk ejection patternNasal OXT restores milk ejection pattern- intramammary pressure assay 1 mU OXT (i.v.) Normal lactation 1 mU OXT (i.v.) Lactation interruption Interruption plus OXT 5 min5 min
  26. 26. Roles of OXT in lactation-failure 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. 3. The malfunction of the OXT-secreting system leads to the failure of OXT secretion into the blood during suckling, and the failure of milk letdown. 4 Nasal application of OXT during lactation interruption can rescue4. Nasal application of OXT during lactation interruption can rescue the milk letdown reflex.
  27. 27. III. Oxytocin and lactation-failure associated diseasesassociated diseases
  28. 28. III I P t t d iIII-I. Postpartum depression 1. Postpartum depression (PPD) affects up to 15% of mothers (P l t i t l 2009)(Pearlstein et al, 2009). 2. Women with depressive symptoms in the early postpartum period may be at increased risk for negative infant feedingperiod may be at increased risk for negative infant-feeding outcomes (Dennis and McQueen, 2009). 3 Early cessation of breastfeeding or failure to breastfeed was3. Early cessation of breastfeeding or failure to breastfeed was associated with an increased risk of maternal postpartum depression (Ip, et al, 2009). 4. However, almost all the data were gathered from observational studies so the causality of postpartum depression and breastfeeding failure remains to be verified.
  29. 29. Depressive signs in lactation interruptedDepressive signs in lactation-interrupted rat dams Wang and Hatton, Frontiers in Neuroscience, 2009
  30. 30. III II OXT and breast cancerIII-II. OXT and breast cancer 1. According to the American Cancer Society, over a woman's lifetime, the chance of developing invasive breast cancer is about 12%. 2. 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 i k f b t b 59 t (St b t l 2009) A drisk 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)reducing abdominal adiposity (Millikan et al, 2008). 3. 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)risk (Cohen et al, 2009). 4. Thus, a causal relationship between lactation failure and general breast cancer probability remains to be established.
  31. 31. Effects of OXT on H O evokedEffects of OXT on H2O2-evoked expression of Cox-2 in mammary glands from weaning ratsfrom weaning rats
  32. 32. Th ti t ti l f OXTTherapeutic potential of OXT 1. Lactation failure is also accompanied by depressive signs, which are related to the lack of brain OXT from the SON and/or PVN. 2. OXT can increase serotonin release (Yoshida et al, 2009), and lack of serotonin 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 depressive mothersinterruption and prevent lactation failure in depressive mothers. 3. 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 to carcinogens following sufficient breastfeeding. 4. Lactation failure increases the incidence of premenopausal breast cancer, whereas nasal application of OXT can restore the regulation of milk letdown. Thus appropriately applying OXT has the potential to reduce the risk ofThus, appropriately applying OXT has the potential to reduce the risk of premenopausal breast cancer in non-breastfeeding mothers or mothers with insufficient lactation. From present result, we predict that OXT can also reduce breast cancer incidence in years following the weaning.
  33. 33. IV. Issues about publicly using OXT
  34. 34. AcknowledgmentsAcknowledgments • Previous mentors of this work • Hideo Negoro, PhD Academic advices and helps • Williams R. Crowley, PhDg , • Hiroshi Yamashita, PhD • Glenn I. Hatton, PhD y • Harold Gainer, PhD • Joan Y. Summy-Long, PhD • Jeffrey G. Tasker, PhD • Critical Reading of David S. Knight, PhD. • Video editing of Xiaoli Liu, PhD. y , • Jonathan B. Wakerley, PhD • John A. Russell, PhD • Takashi Higuchi, PhDVideo editing of Xiaoli Liu, PhD. and Hai-Peng Yang, MD. • All members of the laboratory g , • Kazumasa Honda, PhD • Diansheng Yang, MD for ongoing discussions • Kathryn A. Hamilton, PhD Research has been supported by NIH, Japanese Monbusho, Jiamusi University, UC-Riverside, and LSUHSC-Shreveporty, , p

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