Postpartum Depression Tied to Disruption of Stress System in Mouse Study

Postpartum depression is not uncommon — nearly one in five new mothers may experience anxiety, severe fatigue, inability to bond with their children, and suicidal thoughts. Moreover, this depression has also been associated with infants’ developmental difficulties.

A new study by neuroscientists at Tufts University School of Medicine in Boston uses a mouse model to explore the role of stress toward development of the condition.

Researchers generated a novel preclinical model of postpartum depression and demonstrated involvement of the neuroendocrine system. This body system mediates how a person responds to stress — in particular the physiological response called the hypothalamic-pituitary-adrenal (HPA) axis — which is normally suppressed during and after pregnancy.

The findings in mice provide the first empirical evidence that disruption of this system may create behaviors that mimic postpartum depression in humans. This study, to be published in the journal Psychoneuroendocrinology and now available online, provides a much-needed research model for further investigation into the causes of and treatment for postpartum depression.

In the past, the scarcity of animal models has led researchers to rely on less robust study designs such as correlational studies. Stress is known to activate the HPA axis, which triggers the fight-or-flight response seen in many species.

During and after pregnancy, such activation is normally blunted which helps to insulate developing offspring from stress. Dysregulation of the HPA axis has been suggested as playing a role in the physiology of postpartum depression.

The effects of stress on postpartum behavior are thought to be influenced by stress hormones because animal experiments show that stress and exogenous stress hormones can induce abnormal postpartum behaviors.

However, clinical data on stress hormones in women with postpartum depression has been inconsistent. To date, research has not directly demonstrated a role for corticotropin-releasing hormone (CRH), the main driver of the stress response.

This hormone is primarily secreted by a cluster of neurons in the hypothalamus called the paraventricular nucleus (PVN). Moreover, prior research has determined that inappropriate activation of the HPA axis occurs in postpartum depression.

“Some clinical studies show a relationship between CRH, HPA axis function and postpartum depression, but others fail to replicate these findings. Direct investigation into this relationship has been hindered due to the lack of useful animal models of such a complex disorder,” said Jamie Maguire, Ph.D.

“Using a mouse model that we developed, our new study provides the first empirical evidence supporting the clinical observations of HPA axis dysfunction in patients with postpartum depression. The animal model also shows for the first time that dysregulation of the HPA axis and a specific protein in the brain, KCC2, can be enough to induce postpartum depression-like behaviors and deficits in maternal care,” she continued.

Identifying molecular targets and biological markers for postpartum depression is a challenge.

“Pregnancy obviously involves great changes to a woman’s body, but we’re only now beginning to understand the significant unseen adaptations occurring at the neurochemical and circuitry level that may be important to maintaining mental health and maternal behavior in the first few weeks to months following delivery,” said Laverne Camille Melón, Ph.D., first author on the paper.

“By uncovering the role for stability of KCC2 in the regulation of CRH neurons, the postpartum stress axis, and maternal behavior, we hope we have identified a potential molecular target for the development of a new class of compounds that are more effective for women suffering from postpartum depression and anxiety.”

Melón and Maguire do not believe that HPA axis dysfunction is the only pathological mechanism at work. “Many psychiatric and neurological disorders are a constellation of symptoms and represent an unfortunate synergy of heterogeneous maladaptations. The mechanisms underlying one woman’s postpartum depression may differ from another’s,” said Melón.

The researchers hope that continued work will enable them to identify a biological marker that characterizes women who may be vulnerable to postpartum depression because of dysregulation of the stress axis, potentially leading to new treatment options.

Source: Tufts University