The influence of ovarian hormones and age on prefrontal encoding of episodic fear memories

/Abstract There is a fundamental gap in understanding the contribution of ovarian hormones to the neural processes supporting aversive memory. This is a major impediment to improving health outcomes for a significant proportion of the aging population because the loss of ovarian hormones in menopause is associated with increased risk for affective disorders and Alzheimer’s disease. This project addresses this gap, in accordance with NIA Strategic Goal 1, by determining how ovarian hormones and age affect prefrontal activity in support of fear memory. This focus aligns with the Notice of Special Interest NOT-OD-24-079 seeking research on health conditions that predominantly affect women. The objective of this proposal is to determine how ovarian hormones shape aversive encoding in an area of the brain, the prefrontal cortex, implicated in emotional dysregulation and cognitive decline in age-related pathologies. The central hypothesis is that estradiol and progesterone promote a cortical activity profile in young adulthood associated with adaptive fear learning, which is dysregulated by reproductive aging in middle-age, prior to the emergence of memory deficits. This hypothesis is based on published and preliminary data by the PI. The approach uses in vivo miniscope calcium imaging to track neural activity in behaving rats during the acquisition, retention, and extinction of episodic fear memory. Aim 1 will determine the contribution of estradiol and progesterone to fear memory encoding in young adult rats. Aim 2 will determine how these encoding patterns change in middle-aged and aged males and females and whether hormone treatment in middle age alters encoding and memory decline. The outcome of this work is expected to provide a new understanding of how the prefrontal cortex encodes threat and threat-predictive cues in both sexes across the lifespan and reveal how ovarian hormones regulate memory-related activity. This contribution is significant because it is expected to provide new insight on the neurobiological basis of aversive learning in an understudied population and advance our understanding of how reproductive aging affects brain mechanisms of emotional memory. Project Number: 1R21AG095422-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: MARIEKE GILMARTIN | Institution: MARQUETTE UNIVERSITY, MILWAUKEE, WI | Award Amount: $424,875 | Activity Code: R21 | Study Section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE] View on NIH RePORTER: https://reporter.nih.gov/project-details/11374228