Date of Award

1-1-2022

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Psychology

Program

Behavioral Neuroscience

Content Description

1 online resource (x, 209 pages) : illustrations (chiefly color)

Dissertation/Thesis Chair

Andrew M Poulos

Committee Members

Damian Zuloaga, Christine K Wagner

Keywords

Fear, Neuroanatomy, Pavlovian Learning, PTSD, Fear in children, Memory, Neuropsychology, Conditioned response, Sex differences (Psychology), Context effects (Psychology), Amygdaloid body, Hippocampus (Brain)

Subject Categories

Biological Psychology | Neuroscience and Neurobiology | Psychology

Abstract

AbstractFear is an evolutionarily conserved mechanism that allows an organism to discern potential harm and act accordingly by engaging in defensive behaviors. While fear is an adaptive response, dysregulation of fear by means of a traumatic event can lead to psychiatric conditions such as post-traumatic stress disorder (PTSD). Animal research using rodents in Pavlovian context fear conditioning experiments allows for the ability to study the underlying neural circuitry of threat-appropriate and aberrant fear learning and memory that may contribute to PTSD. However, despite reports that women are more than two times more likely to develop PTSD compared to men, the vast majority of research dedicated to describing how fear memories are acquired, stored, and retrieved has been conducted in adult male rodents. The dynamic nature of fear memory and its neural correlates across extended retention intervals in female and developing animals has not been characterized. This dissertation uses methods of context fear conditioning, Fos immunoreactivity (Fos-ir), and retrograde neuronal tract tracing to explore these gaps in knowledge across five chapters. Chapter 1 provides a review on all topics presented in this dissertation. Chapter 2 of this dissertation investigates the experimental conditions and patterns of Fos-ir that may lead to the incubation (increase) of fear across recent and remote intervals. The neural circuitry supporting recent and remote memories is described by systems consolidation theory wherein recent memories are dependent on the hippocampus, but remote memories are dependent on the prefrontal cortex and no longer require the functional contributions of the hippocampus. However, some studies assert that the hippocampus plays a permanent role in supporting context fear memories. In this chapter, adult mice were context fear conditioned and tested for context fear memory at 3- and 28-day retention intervals. Fos-ir was then used as a proxy of neuronal activation of fear-related brain regions at the time of memory retrieval that included the basolateral amygdala complex, dorsal hippocampus, and medial prefrontal cortex. Results provide evidence for 1) increasing levels of fear across retrieval intervals, 2) a persistent activation of the dorsal hippocampus in context fear memory, 3) dissociable roles for the anterior and posterior basolateral amygdala, and 4) increasing levels of Fos-ir throughout the medial prefrontal cortex across retrieval intervals. Chapter 3 expands upon my investigation of recent versus remote context fear memories by exploring the importance of sex and developmental age under low levels of conditioning in juvenile (24 day old) and adult (90 day old) male and female rats. Rats were fear conditioned and subsequently tested 1 (recent) or 60 (remote) days later. Experiment 1 showed that overall, adult male rats exhibited greater levels of freezing compared to adult females. At the recent interval, males exhibited differential freezing behavior in an age-dependent manner that was not observed in females. While adults showed consistent levels of freezing across recent and remote retention intervals, juveniles exhibited forgetting in adulthood as evidenced by negligible levels of freezing at the remote retention interval. In experiment 2, we tested the hypothesis that this forgetting in rats conditioned in juvenility and tested in adulthood was the result of a retrieval failure by administering a shock at the end of a 60-day retrieval test. The original context fear memory was able to be recovered as measured by a savings test, and subsequent testing of context specificity in context B revealed that animals shocked at both juvenility and adulthood exhibited greater generalization than those only shocked in adulthood. While female rats conditioned in juvenility exhibited forgetting in adulthood, rats conditioned in adulthood displayed sustained levels of freezing across recent and remote intervals. This differential pattern of freezing led to the hypothesis for chapter 4 that the status of the fear circuit changes from P24 to P90. Thus, in experiment 1 of chapter 4, I utilized the retrograde tract tracer Fluorogold (FG), which was iontophoretically injected into the BLA of juvenile and adult female rats. I then quantified the number of FG-labeled cells in the medial prefrontal cortex, ventral CA1, and contralateral BLA. Results showed greater projections from the prelimbic area and ventral CA1 in P90s compared to P24s. Experiment 2 explored patterns of Fos-ir in these regions and found increases in the prelimbic and infralimbic areas, as well as the ventral CA1 of shocked animals. Chapter 5 discusses the overall findings of the previous chapters and explores their significance in the field of learning and memory as well as the limitations of the current series of experiments. The chapters outlined in this dissertation provide novel findings regarding sex and developmental differences in the persistence of context fear memory retrieval across recent and remote intervals and its underlying neural correlates. Fear is not a stagnant process and results derived from adult male-dominated studies may not be generalizable to females or developing animals. Thus, the results from these studies may provide insight into the fundamental mechanisms underlying stress and fear-related disorders like PTSD. These insights can then be used to develop targeted interventions in clinical applications.

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