Descripció del projecte
Fear learning is essential for adapting to threats and anticipating environmental changes. This process relies on evolutionarily conserved mechanisms of synaptic plasticity and is critically shaped by the consolidation of fear memory, which regulates gene expression and protein synthesis in the central nervous system (Maren et al., 2003; Lonsdorf et al., 2010). In humans, fear learning is commonly studied through classical fear conditioning (FC), with the fear onset potential (FEP) and skin conductance response (SCR) serving as key outcome measures. Dysregulations in fear conditioning are implicated in anxiety disorders and have been observed more frequently in women than in men (Lissek et al., 2005). The mechanisms underlying these sex differences remain unclear, but fluctuations in ovarian hormones, particularly estrogen, are strong candidates (Maeng et al., 2017).
Estrogen levels vary across the phases of the menstrual cycle, producing a wide range of physiological and behavioral effects (Goldstein et al., 2010). High levels of estradiol have been associated with extinction recovery in both humans and rodents (Graham & Milad, 2013; Hwang et al., 2015), as well as with altered functional connectivity in fear-related brain networks (Engman et al., 2016). Within the brain, the prefrontal cortex (PFC) plays a central role in the expression and extinction of conditioned fear (Gottfried & Dolan, 2004; Phelps et al., 2004; Milad et al., 2007). Cortical activity during fear learning can be measured using functional near-infrared spectroscopy (fNIRS), which tracks hemodynamic changes, and electroencephalography (EEG), which records electrical activity. The combination of these modalities provides a more complete understanding of neural activity, while allowing participants to move freely in laboratory environments.
This project investigates how menstrual cycle phase and exogenous estrogen use affect fear memory consolidation, and how these patterns compare to men. Approximately 150 healthy participants will be recruited for a two-day differential fear conditioning paradigm (validated in Lonsdorf et al., 2010; Torrents-Rodas et al., 2012). On day 1, participants experience acquisition and extinction phases; on day 2, delayed expression of fear memory is assessed. Psychophysiological responses (FPS, SCR) will be recorded along with EEG and fNIRS activity. Salivary estradiol, genotype, and vaginal cytology will provide biological markers of menstrual phase.
The project has six main objectives: (1) to characterize differences in fear memory consolidation between early follicular (low estrogen) and late follicular (high estrogen) phases; (2) to determine the effects of oral contraceptive use; (3) to compare women and men; (4) to examine cortical activity in relation to estrogen levels; (5) to measure salivary estradiol and genotype participants; and (6) to validate menstrual phase classification with vaginal maturation indices. We hypothesize stronger fear memory consolidation in low estrogen states (early follicular phase and contraceptive users) relative to high estrogen states, with men showing similar patterns to women in the late follicular phase.
The collaboration with David del Rosario and INAB: Experiments and analyses will be carried out in collaboration with the Institute of Neurosciences of the Autonomous University of Barcelona (INAB), facilitating access to state-of-the-art equipment and knowledge. This collaboration will support methodological, technical and analytical aspects of neuroimaging and psychophysiology, as well as potentially facilitating the recruitment of specialized participant populations. This partnership will improve the quality, reliability and impact of research on menstrual cycle-dependent fear memory consolidation.
Collaboration with Roser Nadal i Alemany and the Institute of Neurosciences, Psychology Unit, CIBERSAM: While the core of the PhD focuses on the menstrual cycle modulation of fear learning in adults, the final year of the project aims to extend to the study of fear as a personality trait in children. Fear conditioning deficits are often related to anxiety and stress disorders, where acquisition or retrieval is increased and extinction is reduced. However, the insufficient acquisition of fear responses – or “disgrace” – is less understood. Fear is a characteristic feature of psychopathic traits, particularly cruel-unemotional temperaments in children. With this collaboration, the neurobiological correlates of fear will be examined, focusing on prefrontal cortical dysfunction. By comparing patterns of reduced acquisition in children with high psychopathic traits to adult hormonal modulation of fear, this work will expand our understanding of both adaptive and maladaptive fear processing.
By integrating psychophysiology, neuroimaging, hormonal markers, and genetic data, this project will provide a multidimensional account of how sex and hormones shape fear memory consolidation. The results will shed light on the mechanisms underlying sex differences in anxiety disorders and may inform tailored approaches for prevention and intervention.
