The Intermediate and Remote Effects of Acute Juvenile Stress upon Auditory Fear Learning, Recognition Memory, and Anxiety Measures in a Rodent Model of PTSD

Abstract Early-life stress is a risk factor for increased susceptibility to stress- and trauma-related disorders, including Posttraumatic Stress Disorder (PTSD). PTSD is characterized by exposure to trauma that results in exaggerated and extinction-resistant fear responses that persist for over a month. Understanding how the severity of early-life stressors in animal models impacts adult behavior, cognition, and underlying neurobiology could aid in the development of more effective PTSD treatments. Various early-life stress models, especially in infant rats, have been used to induce stress and assess PTSD like-symptoms. Different stressors impact short- and long-term behavior, with some effects influenced by developmental timing of exposure. Most studies focus on the pre-weaning period, leaving post-weanling juveniles largely understudied. The juvenile period is a critical phase of neurodevelopment, during which stress-related plasticity differs from that of infancy or adulthood. Understanding stress effects during this stage could improve PTSD developmental models. However, it's still unclear if different stressors cause similar or distinct short- and long-term impacts on cognition, fear, and anxiety. A framework explaining how different stress protocols affect assessed behaviors could enhance research on stress- and trauma-related disorders. Stress during infancy is well known to alter both immediate and long-term affect and learning processes. Investigating the effects of different juvenile stressors across recent and remote time points on anxiety, recognition memory, and auditory fear learning provides insight into how distinct stressors shape rodent anxiety, cognition, and their biological underpinnings. In Chapter 1, I provide background information on fear learning, memory, stress, and adolescence. Chapter 2 validates a weight-based scaling approach for adapting the novel object recognition (NOR) test, initially designed for adults, to juvenile animals. I then examine how different types and intensities of juvenile stress affect intermediate (Chapter 3) and remote (Chapter 4) anxiety, recognition memory, and cued-fear learning. I hypothesized that juvenile stress exposure would lead to both recent (6 days) and remote (66 days) alterations in anxiety and fear learning, that these changes would increase with stress intensity, and that females would exhibit more severe, sustained, long-term effects. These experiments suggest that footshock stress provides a more robust and controllable stress induction model of PTSD than restraint stress. Furthermore, they offer insight into the ontogeny of PTSD by identifying key phases of the Stress-Enhanced Fear Learning (SEFL) model at different time points: the initial SEFL trial induces dynamic changes in cognition and arousal, which, in turn, enhance fear learning and expression in response to future aversive stimuli. Most importantly, these studies reveal long-term—but not short-term—enhancement of auditory fear learning following juvenile stress exposure using the SEFL model, extending our understanding of how stress impacts fear learning behavior and development. Together, these findings contribute to a more integrative framework for characterizing stressor-specific PTSD-related mechanisms across developmental stages.