Irina Esterlis, PhD, and Robert Pietrzak, PhD, MPH, professors of psychiatry at Yale School of Medicine, have been awarded a $4.2 million grant from the National Institute of Mental Health (NIMH) to investigate how menopause affects brain function, mood, and cognition.
The study will be the first to examine in living people how menopause-related changes in brain synaptic density may contribute to a higher risk for depression and cognitive problems in midlife females.
Menopause is a major biological change that affects almost all females and can strongly impact mental health and thinking abilities. Many females experience more severe depression symptoms or the onset of major depressive disorder (MDD), as well as changes in memory and attention.
The menopausal transition has also been linked to a higher risk for memory loss and dementia. Despite how common these symptoms are, there are no treatments that target the specific causes of menopause-related mental health and thinking changes. This shows the urgent need to better understand the biological reasons behind these changes.
The new study will use advanced positron emission tomography (PET) scans to measure the number of connections between brain cells by tracking a protein called synaptic vesicle glycoprotein 2A (SV2A), which shows how healthy these connections are. Earlier research from the Yale team found fewer of these connections in people with moderate to severe depression. Early results also suggest that postmenopausal females, especially those with MDD, have even fewer connections in brain areas that control mood and thinking.
“This study is the first of its kind to directly examine how menopause affects synaptic density in the living human brain,” said Esterlis, the study’s principal investigator. “By integrating state-of-the-art PET imaging with clinical and cognitive assessments, we aim to uncover the neurobiological mechanisms linking menopause to increased risk for depression and cognitive decline. This work is essential for developing targeted, biologically informed treatments for females during this critical life stage.”
The study will include a large group of premenopausal and postmenopausal females, both with and without MDD. It will use the National Institute of Mental Health’s Research Domain Criteria (RDoC) framework to see how changes in brain connections relate to mood, thinking, and brain function. Besides PET scans, participants will have electroencephalography (EEG) tests and complete behavioral and clinical assessments to see how changes in brain connections affect daily life.
“Menopause represents a major, yet understudied, window of vulnerability for psychiatric and cognitive disorders,” said Pietrzak, co-principal investigator on the project. “This study builds on converging evidence from human, postmortem, and preclinical research suggesting that menopause and depression affect shared brain systems involved in synaptic function. By directly measuring these changes in living individuals, we aim to determine whether menopause accelerates synaptic alterations and whether these changes underlie differences in mood and cognition.”
“Ultimately, this study seeks to identify a modifiable neurobiological target to inform the development of novel interventions that improve mental health and cognitive outcomes in midlife and older females worldwide,” Esterlis said.