Role of corticolimbic synaptic density in menopause-related psychiatric and cognitive changes

Menopause is a pivotal life stage that brings about lasting changes in mental and cognitive functioning, potentially leading to profound negative effects on multiple life domains in females. During this period, many females may experience the worsening of depressive symptoms or onset of major depressive disorder (MDD), the most prevalent and disabling psychiatric disorder worldwide. Despite the fact that females comprise about half of the global population, evidence that neurochemical alterations observed during menopause may be associated with dementia onset, and higher rates of depression and dementia in females, there are currently no effective treatments targeting the mood and cognitive alterations experienced during menopause. Converging evidence from human clinical studies, postmortem analyses, and preclinical research suggests that both depression and menopause may alter the same brain mechanisms that are crucial for maintaining brain health, particularly through synaptic alterations as possible neurochemical mechanisms. Recent advancements in in vivo quantification of synaptic density in humans have made it possible to measure the density of synaptic vesicle glycoprotein 2A (SV2A), a widely expressed marker of synaptic density, using positron emission tomography (PET) imaging. Our prior studies have revealed that synaptic density is lower in individuals with MDD across young to middle adulthood. In the current study, we aim to conduct the first known in vivo human PET imaging study of how menopause affects synaptic density, whether MDD may exacerbate menopause-related alterations in synaptic density, and how these synaptic changes relate to objective and subjective measures of mood and cognition. Our preliminary data reveal significantly lower synaptic density in corticolimbic regions in post-menopausal females compared to their pre-menopausal counterparts. They further indicate substantially more pronounced deficits in synaptic density in post-menopausal females with MDD compared to pre-menopausal females with MDD, suggesting an acceleration of synaptic degradation. In the proposed study, we seek to confirm these findings in a large, well-characterized sample of females, incorporating a Research Domain Criteria (RDoC) approach to evaluate the role of menopause in moderating the relation between synaptic density and the full spectrum of mood and cognition. To assess the clinical significance of these changes, we will examine how menopause- and MDD-related changes in synaptic density are associated with functional neural (i.e., electroencephalography) and behavioral (i.e., clinical interview) measures of negative and positive valence and cognitive systems. Results of the proposed study will provide the first human in vivo data on the effects of menopause and MDD on brain synaptic density, and whether these changes may underlie the mood and cognitive alterations experienced in menopause. In doing so, they will help inform a modifiable, precision medicine-based target for treatments aimed at improving mood and cognitive alterations associated with this significant life change among females. Project Number: 1R01MH142925-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Irina Esterlis (+1 co-PI) | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $839,329 | Activity Code: R01 | Study Section: Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section[NPAS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11273416