Date of Award

12-1-2021

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, 214 pages) : illustrations (chiefly color)

Dissertation/Thesis Chair

Andrew M Poulos

Committee Members

Christine K Wagner, Damian G Zuloaga

Keywords

Development, Fear Conditioning, Sex Differences, Fear, Anxiety, Conditioned response, Neuropsychology, Psychobiology

Subject Categories

Neuroscience and Neurobiology

Abstract

Over the span of five decades, staggering progress has been made in elucidating the neural circuits involved in fear learning. Research focused on rodents and healthy individuals has been instrumental in elucidating how abnormalities in this circuitry may lend to increased prevalence of various fear and anxiety disorders. However, many of the key findings concerning the acquisition, storage, and retrieval of fear memories have been established in the adult male rodent, leaving a gap in knowledge as to whether females and developing animals process fear and stress inducing information in a similar fashion. Compared to men, women are twice as likely to develop anxiety-and stress-related disorders (Breslau et al., 1997; Kessler et al., 1994, Kessler et al., 1995; Kessler et al., 2005; Tolin & Foa, 2008; Breslau, 2009; McLean et al., 2011; Maeng & Milad, 2015). This sex-specific elevated risk for developing fear and anxiety disorders may be due to an impaired capacity to appropriately encode or recall fear associated memories with specificity during times of stress. Deficits in associative fear learning and memory, particularly contextual fear processing, are thought to lie at the core of fear-based anxiety disorders (Grillon, 2002; Milad et al., 2009; Maren, Phan & Liberzon, 2013). Therefore, investigating the neurobiological mechanisms underlying contextual fear learning and memory may provide insight into the systems that mediate sex differences in fear related pathologies. Furthermore, anxiety disorders are distributed broadly across the lifespan, yet they typically manifest prior to adulthood (US National Survey of Children's Health, 2020). Despite this, most studies in rodent models of fear have been conducted in adult subjects. This paucity of basic research on the biological development of fear learning and memory neural systems and its neural circuitry, represents an important gap in the study of context fear conditioning (CFC) and its relationship to anxiety and stress-related disorders. The chapters in this dissertation seek to elucidate the basic learning and neurobiological processes underlying sex differences in CFC and their biological development through four primary aims, which are preceded by a review of the neuro-behavioral processes underlying context fear conditioning its ontogeny and sex differences (Chapter 1). First, to identify learning and brain processes that underlie sex differences, I characterize patterns of neural activation within the fear circuit under different levels of context fear processing and retrieval in both male and female adult rodents (chapter 2). We observed greater activation of the dorsal hippocampal CA1 of adult male mice during both acquisition and retrieval of context fear memories compared to females. Second, to identify learning processes during development, I characterize CFC in juvenile, adolescent, and adult, male and female rodents (chapter 3). We found sex differences in context fear learning emerge prior to puberty; but only under specific parameters involving contextual cues and limited learning trials– sex differences are not observed at any age to auditory fear or when multiple shocks are administered. Third, to determine the contributions of gonadal hormones in shaping CFC in male and female rodents, I remove the source of these hormones at key developmental periods and test their contributions to context fear learning (chapter 4). We report that the presence or absence of gonadal hormone exposure during early development also influences fear learning and memory. Removal of estrogens in females and androgens in males on the day of birth inversely affected learning in males and females, such that males display reduced learning and females display enhanced learning when fear is conditioned as adults. Removal of gonadal hormones just prior to adolescence diminished context fear learning in males only. Removal of circulating gonadal hormones early in development does not impact estimated relative number of neurons within the adult PL or BLA. Last, to expand upon brain processes that underlie sex differences in development, I characterize freezing behavior across development as well as Fos immunoreactivity within the hippocampus, BLA, and mPFC. In a subset of these animals, the neuroanatomical development of context fear associated neural projections was qualitatively assessed through injections of the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHA-L) within the PL and ventral CA1 of juvenile and adult, male and female rats and describe the distribution of labelled axonal fibers within the boundaries of the BLA complex (chapter 5). We identified sex-and region-specific maturation of fear circuit structures underly the emergence of sex differences in behavior prior to puberty. We observed that juvenile females specifically engaged both PL and dCA1, juvenile males preferentially engaged PL, adult males preferentially engaged the dCA1, and adult females appeared to engaged PL when retrieving context fear memories. We confirmed the projection status of PL and vCA1 neurons to the BLA in males and females at both the juvenile and adult time points. In the final chapter (chapter 6) I discuss the overall findings of this dissertation, which, in short, is that males and females rely on developmentally distinct recruitment of fear circuit structures based on enhanced Fos-ir expression, and the broader impact of this work. Characterizing both male and female development in parallel will broaden our understanding of mechanisms that contribute to sex differences in contextual fear conditioning and the neuroanatomical substrates that support the emergence and continued development of this form of learning. Additionally, these findings may generate novel insights into mechanisms that underlie differential incidence and expression of anxiety and stress-related disorders that can be used to develop sex-specific treatment strategies for developing populations.

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