Summary: Researchers report that a protein which affects regulation of the HPA axis may trigger postpartum disorder in some new mothers.
Source: Tufts University.
Postpartum depression affects nearly one in five new mothers, causing symptoms such as anxiety, overwhelming fatigue, difficulty bonding with infants and, in some cases, suicidal thoughts. These maternal difficulties have also been linked to developmental problems in children. Although stress is a recognized risk factor, the biological causes of postpartum depression remain incompletely understood. Neuroscientists at Tufts University School of Medicine have developed a new mouse model of postpartum depression and shown that dysregulation of the hypothalamic-pituitary-adrenal (HPA) stress axis — normally suppressed during and after pregnancy — can produce behaviors that resemble human postpartum depression.
This work, published in Psychoneuroendocrinology, provides an experimentally tractable model that can help researchers investigate mechanisms and potential treatments for postpartum depression, addressing a major gap caused by the previous scarcity of reliable animal models.
Under normal conditions, stress activates the HPA axis and triggers physiological responses associated with “fight-or-flight.” During pregnancy and the postpartum period, this activation is typically reduced, which helps shield the developing offspring from stress hormones. Dysregulation of the HPA axis has been hypothesized to contribute to postpartum depression, but clinical studies in humans have produced inconsistent results about the role of stress hormones.
Previous animal studies have shown that stress or administration of stress hormones can alter postpartum behaviors, but direct evidence linking the main stress driver, corticotropin-releasing hormone (CRH), and inappropriate HPA activation to postpartum depression was lacking. CRH is produced primarily by a cluster of neurons in the paraventricular nucleus (PVN) of the hypothalamus and plays a central role in initiating the stress response.
“Some clinical studies show a relationship between CRH, HPA axis function and postpartum depression, but others fail to replicate these findings. Direct investigation has been limited by the lack of useful animal models,” said Jamie Maguire, Ph.D., corresponding author and assistant professor in the Department of Neuroscience at Tufts University School of Medicine.
Using the mouse model they developed, the Tufts team provides direct evidence supporting a role for HPA axis dysfunction in postpartum depression. Their experiments identify a specific brain protein, the potassium-chloride cotransporter KCC2, as a key regulator: when KCC2 function is disrupted in CRH neurons, the resulting imbalance can be sufficient to induce postpartum depression–like behaviors and impair maternal care.
Maguire’s group had earlier established that KCC2 is critical for controlling CRH neurons and the physiological stress response. In the new study, the researchers measured KCC2 expression in the PVN of virgin, pregnant and postpartum mice. They found that stress reduced KCC2 levels in virgin mice, but KCC2 remained stable during pregnancy and the postpartum period. The authors suggest that maintenance of KCC2 during the peripartum period contributes to the normal suppression of HPA activity seen in pregnancy, consistent with lower glucocorticoid levels reported in both mice and humans during this time.
To test KCC2’s role more directly, the team created mice lacking KCC2 specifically in CRH neurons and compared them to normal littermates. These knockout mice showed increased stress reactivity around the time of birth, failed to exhibit the typical reduction in anxiety seen postpartum, and demonstrated impaired maternal behaviors relative to wildtype postpartum mice. Using chemogenetic techniques to selectively activate or silence CRH neurons in the PVN, the researchers linked these behavioral changes to activity of those neurons: activating CRH neurons produced abnormal postpartum behaviors, while silencing them improved maternal behaviors in KCC2-deficient mice.
First author Laverne Camille Melón, Ph.D., a postdoctoral fellow in the Maguire laboratory, emphasized the translational potential of these findings. “Pregnancy involves profound, often invisible changes in brain chemistry and circuitry that help maintain mental health and maternal behavior after delivery. By showing that stability of KCC2 in CRH neurons is important for regulating the postpartum stress axis and maternal care, we’ve identified a potential molecular target that could guide development of new treatments for postpartum depression and anxiety,” she said.
Melón and Maguire stress that HPA axis dysfunction is unlikely to account for all cases of postpartum depression. “Psychiatric disorders are often heterogeneous: different mechanisms may underlie similar symptoms in different individuals,” Melón said. The researchers plan to use their model to explore how KCC2-related pathways interact with other risk factors to produce postpartum mood disorders.
Beyond postpartum depression, Maguire noted that KCC2 deficits have been implicated in several neurological and psychiatric conditions, including epilepsy, chronic pain and autism. Their model may therefore help evaluate therapeutic strategies relevant to a range of disorders linked to altered inhibitory signaling and stress responses.
Additional authors on the paper include Andrew Hooper, Ph.D.; Xuzhong Yang; and Stephen Moss, Ph.D. The work was supported by grants from the National Institutes of Health, including awards from the National Institute of Neurological Disorders and Stroke and the National Institute of Mental Health, as well as institutional training grants that supported postdoctoral research.
Funding: Supported by National Institutes of Health grants: RO1NS073574, NS102937, NS087662, NS047243 (NINDS); MH106954 (NIMH); and K12GM074869 (NIGMS Institutional Research and Academic Career Development Awards postdoctoral training grant).
Original research: “Inability to suppress the stress-induced activation of the HPA axis during the peripartum period engenders deficits in postpartum behaviors in mice” by Laverne Camille Melón, Andrew Hooper, Xuzhong Yang, Stephen J. Moss and Jamie Maguire. Published online December 21, 2017 in Psychoneuroendocrinology. doi:10.1016/j.psyneuen.2017.12.003
Abstract
Inability to suppress the stress-induced activation of the HPA axis during the peripartum period engenders deficits in postpartum behaviors in mice
Normally, stress-induced activation of the hypothalamic-pituitary-adrenal axis is reduced during pregnancy. Dysregulation of this axis has been proposed as a contributor to postpartum depression, but direct experimental evidence has been limited by a lack of appropriate animal models. Building on prior work showing a role for the potassium-chloride cotransporter KCC2 in GABAergic control of CRH neurons in the PVN, this study examined KCC2’s role during pregnancy and the postpartum period. The authors show that maintaining KCC2 in the PVN is necessary for suppressing stress-induced HPA activation in the peripartum period. Mice engineered to lack KCC2 specifically in CRH neurons display HPA axis dysregulation and postpartum behavioral abnormalities, including deficits in maternal care. Chemogenetic activation of PVN CRH neurons reproduces these postpartum behaviors, while chemogenetic silencing ameliorates the deficits in KCC2-deficient mice. These results demonstrate that failure to suppress HPA axis activation during the peripartum period is sufficient to induce abnormal postpartum behaviors in mice, supporting a role for HPA axis dysfunction in the biology of postpartum depression.