Lactation interruption can increase maternal stress and breast tumorigenesis; disorders in hypothalamic oxytocin(OXT)-
secreting system and lactation failure could account for these effects. The question is whether abnormal activity of
the OXT -secreting system is causally related to precancerous lesions of maternal mammary glands that could underlie
breast tumorigenesis. To answer this question, we observed effects of lactation interruption on maternal behaviors,
milk availability, OXT neuronal excitability and the histological features of mammary glands of lactating rats that were
intermittently separated from the pups. Separation of lactating dams from pups for four days with four hour consecutive
contacts per day caused losses of maternal interests in the offspring and lactation failure. The separation also caused
early involution of the mammary glands. By simulating OXT release during suckling in isolated rat mammary glands, we
determined that the pulsatile pattern of OXT release was the most effective way to suppress hydroxide peroxide-induced
expressions of phosphorylated extracellular signal-regulated protein kinase 1/2 and cyclooxygenase 2, two proliferative
biomarkers. Dam-pup separation also disrupted the electrical activity of OXT neurons in the supraoptic nucleus and their
responses to excitatory stimuli in brain slices. These findings indicate that lactation failure results from lack of pulsatile
OXT release during suckling, which is causally related to a series of maternal mental disorders and precancerous lesions
of the mammary glands.
Breastfeeding has many beneficial effects on mothers and
the babies. Lactation failure is associated with the high
incidence of breast cancer, type 2 diabetes and obesity in the
mothers and autism, sudden death, and deficiency in maternal
behaviors in the babies. Lactation failure is also associated
with increased incidence of postpartum depression and
premenopausal breast cancer. Successful lactation is
based on coordinated actions of milk production, secretion
and ejection controlled by a series of hormonal events.
These hormones synchronize the development of mammary
glands and hypothalamic plasticity to meet requirements of
lactation. Milk ejections are the most sensitive event in the lactation
and are achieved through the milk-ejection reflex (MER).
During suckling, afferent inputs from nipples are integrated in
the brain into intermittent activation of hypothalamic oxytocin
(OXT) neurons in forms of burst firing. Synchronized
bursts among OXT neurons cause release enough OXT to
trigger a milk-ejection from the mammary glands. OXT
neuronal activity is directly modulated by various cellular
components and neurochemical around OXT neurons. During
lactation, the supraoptic nucleus (SON) undergoes significant
plastic changes which form the basis of burst discharges.
Somatodendritic release of OXT is another dramatic feature
in the SON, which plays permissive and auto-regulatory roles
in neurochemical modulation of OXT neuronal activity. OXT receptors (OXTRs) are localized on both neurons and
astrocytes in the supraoptic nucleus (SON). By activation
of OXTRs, OXT can change the morphology and functions
of supraoptic cells by activation of Gαq/11 type of G protein
coupled receptors and by mobilization of a series of cellular
signals, e.g., cyclooxygenase 2 (Cox-2) and phosphorylated
extracellular signal-regulated protein kinase (pERK) 1/2. Moreover, the findings that mother-baby separation
can decrease blood OXT levels and OXT has anxiolytic effects
suggest the involvement of the OXT-secreting system in the
occurrence of lactation failure[18,19]. However, it remains a
question about the critical loci in the MER pathway that are
responsible for lactation failure. Moreover, it is not answered
whether and how lactation failure is causally related to the
breast tumorigenesis.
Lactation failure is associated with many factors, such as
mother-baby separation, lacking social supports, obesity,
babies’ sickness, poor breast conditions, cesarean section,
mental disorders, and early usages of bottle feeding and milk
substitutes, etc. Among them, mother-baby separation is the
common cause of lactation failure. Thus, to establish
causal relationship between lactation failure and postpartum
health issues in women and to clarify neural mechanisms
underlying lactation failure-associated breast cancer, we used
a maternal separation model to observe effects of lactation
interruption (L-I) on maternal behaviors, OXT neuronal
excitability and proliferative activity of mammary glands of
lactating rats. Lastly we examined different patterns of OXT
applications on the expression of pERK 1/2 and Cox-2 of the
mammary glands in response to oxidative stress in vitro. The
preliminary results have been published in an abstract form.
All procedures in these experiments were in accordance with
the guidelines on the use and care of laboratory animals set
by NIH and approved by the Institutional Animal Care and
Use Committees of the University of California, Riverside, and
Harbin Medical University, respectively.Primiparous Sprague-Dawley rats were used during lactation
as described previously with minor modification. Within
24 h of parturition, litters were adjusted to 10 pups. Dams
had 4 h contacts per day with their pups, beginning on
lactation day 8-9; separated pups were nursed by foster
mothers at all other times. On postpartum day 11-12,
observations were made of the following: maternal behaviors
(e.g., pup retrieval, ano-genital licking, and suckling), signs of
anxiety and depression, litter and dam body weight gains,
the latency and duration of MER. This model was also used
in observations of firing activity of OXT neurons in whole
animals and in brain slices, measurement of intramammary
pressure (IMP), and examination of functional proteins as
described in the followings.
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