Florey Department of Neuroscience and Mental Health - Theses
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ItemEarly life stress and the extinction of conditioned fear in the developing rat( 2021)Early life stress is a known antecedent to anxiety- and fear-related disorders. It may disrupt the ability to regulate fear and act to trigger the development of an anxiety- or fear-related disorder. Hence, in this thesis, I examined the link between early life stress and fear regulation across development. To do this, I used Pavlovian fear extinction as a model of fear regulation to assess the effects of infancy and peri-adolescent stress in rats. In Chapter 2, I examined whether a chronic infancy stressor altered fear extinction in juvenile rats. This series of experiments utilized the limited bedding and nesting model of chronic infancy stress. I found that chronic infancy stress resulted in the precocious emergence of relapse-prone fear in male juvenile rats. However, chronic infancy stress had little effect on extinction behavior in female juvenile rats, as they exhibited relapse-prone fear regardless of stress condition. In Chapter 3, I investigated whether chronic peri-adolescent stress altered fear extinction in adolescence and adulthood. This series of experiments utilized social isolation as a model of chronic peri-adolescent stress. Peri-adolescent stress had a sex-specific effect on fear extinction. In males, peri-adolescent stress resulted in impairments in extinction recall in adolescent and adult male rats. However, in females, peri-adolescent stress had no effect on fear extinction behavior. In Chapter 4, I explored the interplay between peri-adolescent stress and physical activity on fear extinction in adolescence. Peri-adolescent stress, as modelled by social isolation, impaired extinction recall in male adolescents, but this effect was prevented by increased physical activity. Extinction recall in female adolescents was again unaffected by peri-adolescent stress. Surprisingly, increased physical activity was disruptive to extinction recall in peri-adolescent stressed females. Pharmacological suppression of cellular proliferation in peri-adolescent stressed adolescents blocked the effect of physical activity on extinction recall in both sexes. This suggests that peri-adolescent born cells mediate the interplay between peri-adolescent stress and physical activity effects on extinction behavior. Together, these findings highlight sex-specific outcomes of peri-adolescent stress and physical activity on adolescent brain and behavior. In the final Chapter, I propose the Variable Speed Stress model to interpret the effects of stress in infancy and peri-adolescence. Further, I outline potential reasons for the sex effects and possible avenues for future research. Overall, the findings in this thesis contribute to our understanding of how early life stress affects fear extinction throughout development. It suggests that after early life adversity, stress-induced changes to extinction learning development in males may contribute to a reduction in treatment efficacy for exposure-based anxiety disorder therapies.
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ItemAge related dopamine 1 and dopamine 2 receptor expression in addiction-related behaviours( 2020)Methamphetamine (meth) is a significant social and public health concern worldwide, and a growing problem in Australia. One factor contributing to meth use disorder is the lasting memory of its rewarding experience, which can lead to persistent use in vulnerable individuals. Epidemiological data show that adolescence is a period of heightened vulnerability for developing meth use disorder. Furthermore, sex differences exist in numerous aspects of meth use motivations, behaviours, and consequences. Despite this, few studies have investigated age and sex effects of meth on brain and behaviour. A unified neural mechanism by which substances of abuse, including meth, produce their addictive properties is by increasing dopaminergic transmission throughout the mesocorticolimbic dopamine system. Although dopamine binds to and activates several subclasses of receptor in brain regions implicated in reward processing, the dopamine receptors 1 (D1) and 2 (D2) have been reported to be particularly important for drug-affected behaviour. Importantly, levels of D1 and D2 have been shown to fluctuate throughout development. D1 and D2 signalling may therefore be important mediators of adolescent vulnerability to substance use. However, there are numerous inconsistencies in the literature that describe developmental changes in D1 and D2 expression. Systematic characterisation of these changes is therefore critical for a full understanding of how changes to the dopamine system may affect susceptibility to meth (and other substance) use disorder. As such, the first aim of my thesis was to investigate the postnatal developmental trajectory of D1 and D2 in addiction-related brain regions. This was achieved using D1- and D2-green fluorescent protein (GFP) transgenic mice, starting from the juvenile period through to adulthood. The results showed region-specific changes in D1 and D2 expression occur across development, with the insular cortex (insula) showing the most dramatic changes. In particular, the density of D1 compared to D2 expressing neurons (D1:D2 ratio) in the insula substantially increased from adolescence to adulthood in males. Since substance use disorders are male dominant disorders which often have an adolescent onset, this reduced D1:D2 ratio may be relevant in understanding the neurobiological basis of substance use disorders. The second aim of my thesis was to investigate the role of insula D1 and D2 in potential age and sex differences in meth conditioned place preference (CPP) and aversion (CPA). Although no age or sex differences were observed in CPP to 0.1 or 3 mg/kg meth at a group level, analysis of individual data revealed females were less likely to form a place aversion compared to males, and adolescents formed more of a place preference to 0.1 mg/kg meth compared to adults. Conditioning with 3 mg/kg meth led to age differences in insula D1:D2 ratio in males, reduced age differences in insula D1:D2 ratio in females, and increased the activation of insula D2 expressing cells in adults compared to adolescents. Insula activity and expression of D1 and D2 did not correlate with place preference behaviour. Taken together, these findings suggest distinct sex differences in D1 and D2 expression across development in addiction-related cortical and striatal brain regions may underly age- and sex-associated vulnerability to meth-related behaviours.
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ItemSex differences in fear learning in juvenile rats( 2020)The present thesis examined the sex differences in fear learning in the developing rat. Traditionally, it has been widely assumed that pre-pubertal sex differences are negligible in developmental studies. However, epidemiological studies and sexual dimorphism in the brain prior to puberty, indicate that sex differences in fear learning may emerge early in life. In chapter 2, I assessed renewal, reinstatement and spontaneous recovery of extinguished fear (i.e. relapse of extinguished fear) in juvenile male and female rats. I found that P18 females showed all three fear relapse behaviors while P18 males did not. This finding implied that P18 female rats were able to form the contextual memories while P18 males could not. However, whether the ability to form a context-shock association contributes to fear extinction in juvenile rats, has not been explicitly tested. Therefore in chapter 3a and 3b, I directly compared renewal with context fear, using identical fear conditioning parameters in the developing rats. In chapter 3a, I found that P18 male rats did not show renewal while P25 male rats did. P18 and P25 male rats displayed comparable contextual freezing immediately after conditioning and after 24 hours delay. In chapter 3b, both P18 and P25 female rats displayed renewal. I also found that P18 female rats displayed a developmental deficit in context fear learning compared to P25 female rats. Together, findings from chapter 2, 3a and 3b strongly suggested that the emergence of context memory may be sex-dependent, where context-specific extinction emerges earlier in females while context fear learning emerges first in males. Given the critical role of the hippocampus in context-dependent learning, I thought the sex differences in the hippocampal function may underlie the observed sex differences in fear learning. In chapter 4, I examined the role of dHPC and vHPC in fear extinction in P18 male and female rats. I showed that temporary inactivation of the dHPC prior to extinction accelerated extinction acquisition in both male and female rats. I also showed that pre extinction inactivation of the vHPC reduced freezing during extinction and impaired extinction recall, regardless of sex. Collectively, these findings strongly suggest sexually dimorphism in fear learning emerges early in life and emphasize the importance of sex as a factor in the field of developmental learning and memory.