Florey Department of Neuroscience and Mental Health - Theses
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ItemPrefrontal dopaminergic mechanisms of adolescent cue extinction learning( 2016)Addiction and anxiety disorders represent the most prevalent mental illnesses in young people worldwide. Unfortunately, adolescents attain poorer outcomes following extinction-based treatment for these disorders compared to adults. Cue extinction learning involves dopamine signaling via the dopamine 1 receptor (D1R) and dopamine 2 receptor (D2R) in the medial prefrontal cortex. In particular, the infralimbic cortex, a subregion of the medial prefrontal cortex, has been implicated in extinction learning in both adolescent and adult rodents. The prefrontal dopamine system changes dramatically during adolescence. However, the role of prefrontal dopamine in adolescent cue extinction learning is poorly understood. Therefore, this thesis aimed to elucidate the role of prefrontal dopamine in adolescent cue extinction, using cocaine self-administration and fear conditioning in rats. My first study examined cocaine self-administration and cocaine-associated cue extinction in adolescent versus adult rats. Adolescents displayed a deficit in cocaine-cue extinction learning compared to adults (postnatal day [P]53 and P88 on cue extinction day, respectively). A single infusion of the full D2R agonist quinpirole into the infralimbic cortex prior to extinction enhanced adolescent cue extinction to reduce relapse-like behavior the next day. This effect was recapitulated by a systemic injection of the partial D2R agonist aripiprazole, an FDA-approved drug for the treatment of psychosis with strong translational potential. My second study examined fear conditioning and extinction in adolescent and adult rats. I first aimed to optimize behavior in late adolescent (P53) and adult (P88) rats during the dark phase of their 12-hour light-dark cycle, to remain consistent with conditions of the previous chapter. However, this produced unreliable behavioral results. In contrast, adolescent rats (P35) consistently display a deficit in long-term fear extinction compared to adults (P88) during the light phase. Infusion of the D1R agonist SKF-81297 into the infralimbic cortex prior to fear extinction had no effect for either age group. However, infusion of quinpirole into the infralimbic cortex significantly enhanced long-term fear extinction in adolescents, whereas it delayed within-session extinction in adults. Interestingly, an acute systemic injection of aripiprazole improved long-term fear extinction in adults. My final experiments measured prefrontal gene expression for D1R, D2R, and D1R relative to D2R (D1R/D2R ratio) in naïve rats across adolescent development, or following cocaine-cue, or fear extinction. There were no significant differences in prefrontal dopamine receptor gene expression across naïve rats age P35, P53, and P88. Following cocaine-cue extinction, prefrontal D1R gene expression was upregulated in adults but not adolescents. By comparison, following fear conditioning, adolescents showed higher D1R and D1R/D2R ratio gene expression compared to adults. D1R/D2R ratio was modulated in opposite directions following fear extinction learning during adolescence versus adulthood. These findings show that adolescents are impaired in extinction of emotionally salient cues across both appetitive (drug) and aversive (fear) learning domains. Functional and molecular data provide novel evidence for divergent involvement of prefrontal dopamine in cue extinction learning across adolescent development. Results not only extend understandings of extinction learning in general, but represent an exciting step towards finding new therapeutic targets to facilitate exposure-based therapy in the clinic.
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ItemThe role of CRFR1 in addiction and anxiety disorders( 2016)Addiction and anxiety disorders are highly co-morbid, and represent a huge burden on society. The central role of stress-reactivity in the pathogenesis and maintenance of both of these diseases has led to the identification of corticotropin-releasing factor (CRF) signalling as a key factor in these effects. The focus of this thesis was the ventral tegmental area (VTA), as it is a site where reward- and fear- related circuitry converge and can be modulated by CRF. The broad aims of this thesis were to examine the role of VTA CRF receptor 1 (CRFR1) in animal models of reward-seeking and conditioned fear to understand how these systems can become dysregulated in addiction and anxiety disorders. To this end, chapter 3 of this thesis validated a technique for the viral-mediated downregulation of CRFR1 within the VTA, and chapter 4 established a novel model of stress-induced reinstatement of cocaine-seeking in mice. These techniques were then implemented to examine the effects of VTA CRFR1 knockdown on the acquisition, extinction, and reinstatement behaviours. Chapters 5 and 6 are two separate publications demonstrating that VTA CRFR1 signalling is differentially involved in various components of cocaine-seeking and conditioned fear. In chapter 5, knockdown of CRFR1 in the VTA blocked stress-induced reinstatement of cocaine-seeking and attenuated cued cocaine-seeking, without any effects on self-administration or extinction responding. This was a specific effect on drug-related behaviours, as there were no changes to operant responding for sucrose rewards. In chapter 6, VTA CRFR1 knockdown enhanced the expression of conditioned fear, but had no effects on fear extinction or reinstatement. This evidence suggests that CRFR1 participates in distinct subcircuits within the VTA which mediate fear and reward-seeking.