Florey Department of Neuroscience and Mental Health - Theses
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ItemThe effect of sex hormones on cognition and psychosis-like behaviour with relevance to schizophrenia( 2017)There is undeniable necessity for a novel pharmacological treatment for schizophrenia. Current treatment for the disorder, antipsychotics, are associated with several side effects and do not effectively treat the entire array of symptoms. The sex hormone, 17β-estradiol (17β), has demonstrated therapeutic effects in preclinical and clinical studies of schizophrenia. Unfortunately, long-term 17β treatment is associated with potential health risks and feminising side effects in men. The Selective Estrogen Receptor Modulator (SERM), raloxifene (RAL), is a feasible alternative to 17β, having demonstrated a beneficial effect in all schizophrenia symptom domains and in both sexes, albeit inconsistently between laboratory groups. Further, given their promising neuroprotective and cognitive-enhancing effects, the SERM, tamoxifen (TAM), and brain-synthesised estrogen, 17α-estradiol (17α), may also be feasible alternatives, however these compounds require validation in established animal models for psychosis. Thus, this thesis explored the effect of 17β, 17α, RAL, and TAM on schizophrenia-like behaviour in rats, using acute pharmacological models and the neurodevelopmental maternal immune activation (MIA) poly(I:C) model of schizophrenia. In the first experiment (Chapter 3), we assessed two psychosis-like behaviours, psychotomimetic drug-induced prepulse inhibition (PPI) deficits and locomotor hyperactivity, using the dopamine D1/D2 receptor agonist, apomorphine, the indirect dopamine releaser, methamphetamine, and the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. Long Evans rats were ovariectomised to reduce endogenous hormones, which resulted in an impairment of baseline PPI, and all estrogenic compounds were able to successfully reverse this impairment. 17β treatment in OVX rats successfully attenuated dopaminergic drug-induced PPI disruption and locomotor hyperactivity, while RAL and TAM-treated OVX rats showed limited actions against psychosis-like behaviours, with TAM successfully attenuating both methamphetamine and apomorphine-induced disruption of PPI, and RAL only protecting against the latter. 17α, however, showed no protective effect in either assay. None of the estrogenic compounds significantly modulated NMDA receptor-mediated psychosis-like behaviour. These findings show that 17β, RAL, and TAM effectively modulate behavioural effects of dopaminergic stimulation, a key neurotransmitter system implicated in schizophrenia. To further explore these estrogenic compounds, we used the neurodevelopmental poly(I:C) model (Chapter 4). Pregnant dams were treated with saline or viral mimic, poly(I:C), at mid-late gestation, and adult offspring were tested in psychosis-like behaviours. Both male and female poly(I:C) offspring exhibited a baseline PPI deficit, and RAL and 17β treatment in intact female rats successfully reversed this deficit, however 17α had no significant effect. PPI in poly(I:C) offspring was significantly disrupted by apomorphine and MK-801 to a similar level of disruption as seen in the control offspring. Following methamphetamine, however, control offspring demonstrated an expected PPI impairment, while poly(I:C) offspring showed no disruption at all, suggesting an altered dopaminergic system. Male poly(I:C) offspring exhibited increased drug-induced locomotor hyperactivity (Chapter 5), however, female poly(I:C) offspring did not differ from control offspring. Regardless of condition, RAL and 17β treatment in intact female rats increased methamphetamine-induced hyperactivity, while 17α had no significant effect, and the effect of 17β in methamphetamine-induced hyperactivity was in contrast to its effect in OVX rats in Chapter 3, which we theorise is due to endogenous hormone profile. For the first time, the effect of OVX and estrous cycle was explored on performance in the rodent touchscreen apparatus. Using the Trial-Unique Nonmatching-to-Location (TUNL) task to test spatial working memory, results showed that OVX impaired (Chapter 6), and phase of estrous cycle altered performance (Chapter 7). Our findings highlight the importance of endogenous hormone profile for normal working memory performance. Further, using the touchscreen TUNL task, we found that male poly(I:C) offspring, but not female, exhibited a spatial working memory deficit. However, performance did not differ between conditions in pairwise discrimination and reversal learning, a task measuring cognitive flexibility. To summarise, this research found sex-specific alterations in psychosis-like behaviour and cognition in the poly(I:C) model of schizophrenia. Further, three estrogenic compounds, 17α, RAL, and TAM, had limited action on psychosis-like behaviour in both pharmacological and neurodevelopmental MIA models of schizophrenia. Ultimately, RAL exerted promising effects requiring exploration in future research, however, 17β exerted the most potent antipsychotic-like effect.
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ItemThe role of steroid hormones in schizophrenia: unravelling the mechanism of 17-beta estradiol and raloxifene on cognitive function( 2016)The glycoprotein reelin is integral for brain development and maintaining synaptic plasticity, and its expression is reduced in schizophrenia brains. Whether stress, a risk factor for schizophrenia, is mediated by altered reelin levels is unknown. Here, we showed that adolescent treatment with corticosterone (CORT), the major stress hormone, in a reelin heterozygous mouse model, induced hippocampal-dependent cognitive deficits in both male and female mice. Interestingly, female mice showed sex-specific molecular changes in the dorsal hippocampus after CORT treatment. This suggests a significant role of estrogens in mediating stress responses and cognition. One mechanism through which estrogens, particularly 17β-estradiol (E2), the most potent of the estrogens, may regulate cognitive function is through its ability to affect the number of parvalbumin (PV)-containing GABAergic interneurons. PV-interneurons are reduced in the brain of schizophrenia patients. In our previous study, ovariectomy (OVX) in mice reduced the number of hippocampal PV-interneurons which was accompanied by hippocampus-dependent memory impairment. Both neuron reduction and cognitive deficits were prevented by simultaneous E2 replacement after OVX. Due to the significant role of PV-interneurons in generating neuronal oscillations in the gamma frequency range, a vital component required for cognition, we investigated whether E2 can mediate gamma oscillations which would explain its influence on cognition. We further scrutinized whether raloxifene, a selective estrogen receptor modulator, has a similar effect on cognition as E2. Raloxifene has been shown to improve cognitive performance in schizophrenia patients and constitutes a safer treatment option as opposed to E2 due to its absence of peripheral side effects. We recorded electrical brain activities in the dorsal hippocampus of control, OVX mice or OVX mice with E2 or raloxifene implants both at baseline and during Y-maze, a hippocampal-dependent spatial memory task. While gamma-band oscillations were significantly increased in the control mice when placed in a novel environment (Y-maze), this increase was absent in OVX mice. E2 as well as raloxifene replacement prevented this deficit. This indicates that both E2 and raloxifene can regulate gamma oscillations in the dorsal hippocampus during exploration of a novel space. Moreover, OVX mice showed a significant reduction in gamma oscillations, specifically during decision making, which was accompanied by a significant deficit in short-term memory. E2 and raloxifene replacement rescued these deficits. This suggests that both E2 and raloxifene regulate spatial memory via specifically regulating hippocampal gamma oscillations during decision making. In agreement with this data we further demonstrated that raloxifene was able to recover gamma oscillations during decision making in the Polyinositic:polycitidylic acid (poly(I:C))-induced maternal immune activation mouse model of schizophrenia. Overall, these results suggest that raloxifene modulates hippocampus-dependent memory via preserving gamma oscillations through its conservation of PV-interneurons; a mechanism that most likely explains the beneficial effect of raloxifene on cognitive performance in schizophrenia patients. This aids understanding the mechanisms underlying the cognitive aspect of schizophrenia, but more importantly, strengthens the case of raloxifene as an adjunctive therapeutic option in this disorder.