Alyssa Hohorst
PhD Dissertation Defense
Advisor: Dr. Ben Greenwood
Department of Integrative Biology
When: Friday, November 7th 2025 10:00am
Where: Science Building, Room 4127
Clarifying the Mechanisms Underlying Estrous Cycle Modulated Fear Extinction and Relapse
Extinction that occurs during high ovarian hormone phases, proestrus or estrus (Pro/Est), or following E2 administration in ovariectomized females, enhances extinction memory retrieval compared to extinction during low ovarian hormone phases, metestrus and diestrus (Met/Di). These effects extend to fear renewal, with females extinguished during Pro/Est showing an absence of renewal, whereas females in Met/Di remain susceptible to renewal. However, it remains unclear whether these effects extend to other relapse phenomena or whether renewal is mediated by E2 levels during extinction. In males, renewal is similarly prevented by enhancing dopamine (DA) signaling within the substantia nigra (SN) and its projection target, the dorsolateral striatum (DLS) during extinction. Stimulated striatal DA release is potentiated in Est females or following E2 administration, suggesting that elevated ovarian hormones may naturally engage the SN-DLS pathway during extinction to confer resistance to renewal. However, the mechanisms underlying estrous phase modulated extinction and renewal remain unknown. To address these gaps, the present experiments examined how sex, estrous phase, and E2 during extinction influence multiple forms of fear relapse and investigated the role of the SN-DLS pathway and DLS network connectivity in relapse-resistant extinction. Undergoing extinction during Pro/Est or following E2 administration prevented renewal and reduced spontaneous recovery compared to other groups. In females extinguished during Pro/Est, this effect depended on SN-DLS pathway activity during extinction, and activation of this pathway during extinction in males was sufficient to prevent renewal. Stimulated DA release in the DLS was greater in Pro/Est females than in Met/Di females and was greater than that in the dorsomedial striatum. During extinction, Pro/Est females demonstrated decreased prefrontal activity, increased medial amygdala activity, and elevated activity within SN and VTA DA neurons compared to other groups. Network analyses in Pro/Est females during extinction revealed strong and dense functional connectivity that uniquely integrated the DLS, including as a hub. These findings identify an estrous phase-dependent shift towards SN-DLS engagement during extinction as a mechanism that may support relapse-resistant extinction in females.