How Hormones May Affect Addiction and Depression

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We're often told how the foods we eat, the amount of exercise we do, and even the quality of our sleep, can all impact our mood and mental health. But have you ever considered the role that reproductive hormones might play in shaping that same mental landscape?

A growing body of scientific evidence draws attention to the connections between our brain, hormones, and emotional well-being. To deepen an understanding of the relationship between ovarian hormones and depression, a recently published animal study turned its lens on a small yet highly influential area of the brain, known as the medial preoptic area (mPOA). This study [1] presents a compelling case for the role of this region as a focus of action for reproductive hormones regulating depression.

Evidence gathered from a variety of sources, such as epidemiological studies, has long suggested a strong link between hormonal fluctuations and the incidence of mood disorders. For example, many women experience premenstrual dysphoric disorder, postpartum depression, or perimenopausal depression—all corresponding to periods of significant hormonal change.

However, understanding the precise neural mechanisms that underlie these patterns has been a major challenge.

Using a mouse model the study described here [1] showed that shifting levels of ovarian hormones can lead to changes in mood, particularly leading to depressive-like behaviors in these animals. The study suggests that the mPOA, a region of the brain that is primarily known for its role in reproductive behaviors, acts as a hub, transmitting these hormonal fluctuations into depressive-like symptoms.

The researchers used a combination of cutting-edge techniques, such as optogenetics and chemogenetics, enabling them to manipulate neural activity with high precision, as well as using sophisticated behavioral assays to assess the impact of their manipulations on behavior. They started their work by identifying a key player in this system: A type of brain cell in the mPOA that contains GABA, a very small but important inhibitory chemical in the brain.

These GABAergic neurons were found to be especially responsive to estrogen, one of the primary female-reproductive hormones. It appears that when estrogen levels are altered, for example, due to natural cycles or developmental events such as menopause, the activity of these GABAergic neurons is also affected.

Effectively, this study demonstrated that reducing the activity of mPOA neurons in female mice during the low-hormone phase of their cycle, analogous to the human menstrual phase, resulted in a significant increase in depressive-like behaviors. These behaviors were reduced when mPOA neuron activity was enhanced, further emphasizing the importance of this area in mood regulation.

The study also showed that the connection between the mPOA and depressive behaviors is not a one-size-fits-all kind of relationship. In fact, it appears that there are different types of GABAergic brain cells in the mPOA, each responsible for particular depressive symptoms.

Some of them send their fibers to the ventral tegmental area (VTA), the hub of the brain’s reward system, influencing anhedonia—a symptom characterized by a lack of pleasure or interest in previously enjoyable activities. Other neurons in the mPOA project to the periaqueductal gray, a region involved in mood and anxiety, thereby influencing immobility, another common symptom of depression.

These findings offer a promising insight: Can we target these neurons therapeutically to treat depression related to hormonal fluctuations? Given the non-clinical nature of this study, however, much more research is still needed before we can answer this question. But the data are, nevertheless, both exciting and highly promising.

So that we may fully understand the significance of these findings, let us briefly place the spotlight on major depressive disorders. A debilitating illness that affects over 280 million people worldwide, major depressive disorder is twice as common in women as it is in men.

This disparity has intrigued behavioral neuroscientists for years, and many have questioned if the menstrual cycle, specifically ovarian hormones, might be the missing puzzle piece in understanding the female prevalence of depression. This brings us back to our star player, the mPOA. Rich in receptors for estrogen and progesterone—two key hormones that fluctuate throughout the menstrual cycle—the mPOA is perfectly poised to respond to these hormonal shifts. This is a major reason why researchers might wish to dig deeper into how ovarian hormones and the mPOA are intertwined in the neural dance responsible for depression.

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At this point, it is important to mention one additional aspect of the mPOA, which is made especially important by the greater prevalence of depression in women compared to men: The mPOA is involved in the regulation of sex differences.

This brain region is heavily implicated in parental and mating behaviors, which are known to exhibit sex differences. In multiple animal studies, damage to the mPOA has been shown to disrupt these sex-specific behaviors. Furthermore, sex differences in neural connectivity and hormone receptor expression within the mPOA have been documented, further suggesting its role in sex-specific behaviors.

So, not surprisingly, the mPOA is no stranger to the behavioral neuroscience community, particularly those of us who study the neurological underpinnings of motivated behaviors. In fact, it has been under the microscope in many earlier studies from my own laboratory exploring its involvement in not just sexual behaviors but also substance abuse disorders, and the parallels drawn are striking.

In a parallel line of research, my laboratory at The University of Texas at Austin has mapped out a direct line from the mPOA to the VTA, and the brain's reward centers. Members of my laboratory have been studying the connections between the mPOA and the brain's reward system, particularly in the context of drug addiction.

As described previously, our brain's reward system is largely controlled by the VTA, which sends projections throughout the brain, including to the nucleus accumbens—another key component of the reward system.

Several members of my laboratory have focused on the interaction between estradiol, a form of estrogen, in the mPOA and the VTA. We found that estradiol in the mPOA influences the output of GABA to the VTA, which in turn influences the brain's reward response to addictive drugs, particularly cocaine.

We found, for example, that damage to the mPOA or injections of estradiol directly into the mPOA increased the cocaine-induced release of dopamine, a key neurotransmitter involved in reward, in the nucleus accumbens [2 and 3]. This showed that the mPOA has a direct and significant impact on the brain's reward system, influencing the effect of addictive substances.

Moreover, my former graduate student, Julia Martz, now at Massachusetts College of Pharmacy and Health Sciences, recently showed that the pattern of VTA innervation was comparable between male and female rats, but that sex differences existed in the hormone-receptor profile of projections to the VTA.

Specifically, females had a greater percentage of cells in the mPOA that expressed estrogen receptors and projected to the VTA, whereas males had a greater percentage expressing androgen receptors, particularly in the central region of the mPOA [4]. This sexually dimorphic connection could potentially influence a wide range of sex differences in reward responses, and possibly, in depression as suggested in the study described above [1].

In other words, sex differences in depression and substance abuse disorders may be, at least partly, dependent on activity in the mPOA.

Looking at both lines of research, a fascinating picture begins to emerge. It appears that the mPOA, through its sensitivity to hormones, such as estradiol and progesterone, and its connectivity to the reward system, plays a significant role in both addiction and depression—two major psychiatric disorders with profound implications.

This opens new possibilities for future research and treatment strategies. For example, could interventions that modulate activity in the mPOA, either through pharmacological agents or more direct methods, such as deep brain stimulation, provide a novel approach to treating mood disorders or substance abuse disorders?

As always in science, each new answer brings with it a host of new questions. And with these significant insights into the role of the mPOA in both depression and addiction, researchers now have a rich vein of inquiry to mine in the years to come.