Abstract
For women, half of the world’s human population, fluctuations in ovarian hormone levels produce a range of behavioral symptoms, ranging from mild discomfort during the menstrual cycle to severe debilitating disorders like postpartum depression. Understanding the neural circuits altered by ovarian hormone fluctuations will be critical for the development of new and more efficacious treatments. Now, in an outstanding study, it has been found in female mice after ovarian hormone withdrawal (HW) that the sexually dimorphic medial preoptic area (MPOA) GABAergic neurons mediate a range of depressive-like behaviors. HW was found to involve down-regulation of activity of estrogen receptor 1 (Esr1)–expressing GABAergic neurons in the MPOA but not glutamatergic neurons. In HW mice, depressive-like behaviors were reduced by increasing activity of these MPOA neurons, and reducing the activity of these neurons increased depressive-like behaviors. It was also found that a subpopulation of these neurons projecting to the ventral tegmental area mediated anhedonia, while a projection to the periaqueductal gray mediated immobility and that this involved dopamine and serotonin, respectively (Tao and others 2023). The importance of these findings for understanding the neurobiology of depression is strengthened by the facts that allopregnanolone acts as a potent positive allosteric modulator of the γ-aminobutyric acid type A receptor, and the synthetic allopregnanolone drugs brexanolone and zuranolone have been shown to be effective treatments for patients with postpartum depression as well as major depressive disorder. In addition, the elucidation of the mechanisms involved in Esr1 expressing GABAergic neurons in the MPOA on downstream areas involving dopamine and serotonin could help explain the variations in the symptoms seen in the different types of depression.