Researchers at the Keck School of Medicine found a strong link between estrogen withdrawal and depression, offering hope for new treatments for postpartum and perimenopausal depression. 

Huizhong Tao and Dr. Can Tao have been studying glutamatergic neurons for almost four years. This specific study stems from a paper they published two years ago, which found that glutamatergic neurons mediate stress and anxiety states within the brain. Tao, a professor of physiology and neuroscience, said questions raised by Nature Neuroscience reviews encouraged them to further research the area.

“One of the reviewer’s comments was that, ‘Oh, this MPOA structure has previously been implicated in parental behavior … and now you’re saying that it’s evoked in anxiety and regulation of anxiety states? What’s the connection between these two phenomena?’” Tao said. “So we realized we do need to look into their relationship.”

  This prompted the researchers to further test if the medial preoptic area where those 

neurons are found played a larger role in mood regulation, specifically around fluctuations in ovarian hormones. 

Researchers removed the ovaries of female mice and then injected them with progesterone and estrogen every day for 21 days, before abruptly stopping. This caused an abrupt drop in the estrogen levels of the mice, mirroring the estrogen drop in postpartum humans. 

As a result of this hormonal drop, the mice exhibited an array of depressive behaviors ranging from not struggling when placed in uncomfortable situations, to not preferring sugar water over normal water, to neglecting to groom and care for their pups.

The researchers were then able to examine how the mice’s brains responded to this lack of estrogen and subsequent depression through the use of cell-type specific electrophysiological recordings, Tao said.

“We found that a group of GABAergic neurons [which produce GABA, the main inhibitory neurotransmitter in the brain] in the MPOA — in particular, estrogen receptors expressing GABAergic neurons — reduce their firing activity,” she said. “We found that by increasing the activity of these GABAergic neurons, we can alleviate the depressive states [in the mice].” 

Can Tao (no relation), a postdoctoral scholar and the initiator of the research project, said these findings were particularly surprising because the MPOA structure had yet to be recognized as playing a role in depression before. 

“It’s very [surprising] to know that almost all the animals that experienced the hormone withdrawal showed very strong, depressive-like behavior, and just with a single dose of the [regulatory neurons], it can quickly rescue [the animals from] all those symptoms at the same time,” Can said. 

The study marks an important step towards improving healthcare for people assigned female at birth. Jay Wenner, a sophomore majoring in neuroscience and psychology, said this research begins to fill in the gaps in current scientific knowledge surrounding estrogen.

“Being able to look at stereotypically female hormones and having that estrogen in low amounts, especially when you have it with relevance to conditions of menopause or postpartum depression … [is] really relevant to endocrinology treatment,” he said. “We understand what happens in high amounts, but … low amounts is a severely under-researched area.”

The results from these findings have strong implications for developing treatments for postpartum depression and perimenopausal depression, which currently are treated by manipulating patients’ serotonin levels with selective serotonin reuptake inhibitors, Dr. Tao said. 

“We now know that these impure neurons are upstream of the dopamine and serotonin releasing loss,” Huizhong Tao said. “Maybe targeting these hypothalamic neurons can have a more potent effect then the current therapeutic approaches.”

Can Tao said this research may also be applicable beyond the treatment of postpartum and perimenopausal depression. Specifically, it may be used to create medications for people diagnosed with major depressive disorder.

Current plans for further research include examining which membrane proteins in the MPOA are impacted, as well as more closely examining the glutamatergic neurons in the area, in order to examine every possible avenue that this depression could stem from, according to an article from Medical Research.