Florey Department of Neuroscience and Mental Health - Theses
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ItemThe Nature and Severity of Central Nervous System Dysfunction after Concussion in Contact Sport( 2019)Introduction. Traumatic brain injuries, including sports-related concussions, are a major public health concern. Although participation in sport brings with it many benefits, the potential risk of sustaining adverse injuries such as sports-related concussion is an escalating societal and ethical issue. The onset of short-lived impairment of central nervous system dysfunction in concussed athletes following a sport-related concussion can lead to complications if the condition is not recognised and removed from participation in sport in a timely manner. Rationale and Study aims. This series of studies aim to understand the nature and magnitude of head biomechanics, short-lived impairment of central nervous system (CNS) function, and clinical signs and symptoms associated with concussions and repetitive head impacts. More specifically, it is hypothesised that (i) the biomechanics of repetitive head impacts in amateur boxers, (ii) endorsement of symptoms, and performance on cognition and balance component scores immediately post-contest and, (iii) a decline in function on the King-Devick test, will be worse for boxers clinically classified with a concussion, be associated with high-risk for CNS injury circumstances, and be reflective of exposure to repetitive head impacts through exposure to repeat contests in the tournament. Method. Healthy male collegiate students (n = 376) between the ages of 18-34 years (M = 20.97, SD = 2.30) consented to participate in the Notre Dame Bengal Bouts amateur boxing tournament in 2012 and/or 2013. Boxers completed the Sports Concussion Assessment tool, Cogstate Brief Battery, and the King-Devick test prior to participation in any sparring and following each of the four elimination contests. A sample of boxers were also instrumented with X2 Biosystems headbands to monitor exposure to impacts during contests. Results. The results of this study support the hypothesis that in amateur boxers the number of head impacts, and the acceleration of those impacts are associated with the progress through the tournament, outcome of bouts, weight class, and concussion. However, there were no systematic differences in the number or magnitude of impacts between concussed and non-concussed boxers, although average rotational forces did show potential for the classification of concussed boxers. Symptom, cognition, and balance scores did not systematically change with multiple assessments nor with repeat exposure to head blows further into the tournament, however, symptom component scores were sensitive to and worse for boxers classified on performance factors representative of high-risk for CNS injury, such as sustaining a concussion, receiving a standing eight-count, and losing a contest. The cognitive component was successful in identifying concussed boxers from non-concussed boxers. But there were no meaningful differences on the balance component clinically relevant to the assessment of concussion-related changes. The King-Devick test was largely not sensitive to concussion in the context of amateur boxing and unable to appropriately classify most concussed boxers. Conclusion. This study offers guidance on the measures which provide the best predictive power for the classification of central nervous system dysfunction following a sport-related concussion and adds to the literature on repetitive head impacts. Though innovative, further study of the biomechanics of concussive head injury, amateur boxers, and the use of screening tools are warranted.
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ItemProbing white matter pathology in Alzheimer's disease using advanced diffusion MRI( 2019)Alzheimer’s disease is increasingly conceptualised as a disease of network dysfunction, which is likely underpinned by substantial white matter degeneration. Indeed, white matter is known to exhibit disruption in Alzheimer’s disease, both at microstructural and macroscopic levels, and has been reported in pathological and imaging studies. However, these white matter changes across the Alzheimer’s disease spectrum have been poorly described thus far, largely due to methodological limitations. In this thesis, advanced diffusion MRI methods were applied to investigate white matter changes in Alzheimer’s disease patients, as well as in mild cognitive impairment patients, who represent an at-risk cohort for developing Alzheimer’s disease. There were three major research questions for this thesis, which formed the basis of three major studies: (1) What are the specific white matter pathways that degenerate in mild cognitive impairment and Alzheimer’s disease? (2) To what extent does the degeneration of these fibre structures relate to cognitive decline? (3) What are the in vivo microstructural characteristics of white matter lesions in Alzheimer’s disease? To address the first research question, the first study utilised a novel method known as fixel-based analysis to investigate fibre tract-specific white matter degeneration in a cohort of Alzheimer’s disease, mild cognitive impairment, and healthy elderly control participants from the Australian, Imaging, Biomarkers and Lifestyle (AIBL) study. Using this approach, specific fibre pathways that exhibited degeneration in Alzheimer’s disease subjects compared to control subjects were identified. Of these fibre pathways, only select fibre tracts exhibited degeneration in mild cognitive impairment patients, and this degeneration did not appear to be associated with high amyloid accumulation. The findings supported a structural basis to theories of network-wide disruption in Alzheimer’s disease. In a related second study, the associations between tract-specific degeneration and decline across a number of cognitive domains were then investigated, in a similar cohort of Alzheimer’s disease, mild cognitive impairment, and healthy elderly control participants. Tract-specific degeneration was closely associated to cognitive impairment across all cognitive domains, and interestingly, certain pathways in particular (namely, the posterior cingulum and inferior fronto-occipital fasciculus) appeared to be most closely associated with all domains. This suggested that network-wide dysfunction is mediated by degeneration of specific fibre structures. Finally, the third study in this thesis aimed to investigate white matter lesions, which are commonly reported in elderly individuals, but are increased in Alzheimer’s disease. By applying novel diffusion MRI methods to characterise the diffusion profile of lesions, microstructural heterogeneity could be observed within these macroscopic lesions, which has previously been reported in post-mortem studies but has not been described in vivo. Different lesion classes were shown to exhibit distinct diffusional properties, and the findings of this work highlighted the need to account for microstructural heterogeneity when investigating the relevance of lesions to disease. The overall findings of this thesis offer disease-specific insight that highlights the crucial importance of white matter degeneration in Alzheimer’s disease. Moreover, the findings demonstrate the ability of advanced diffusion MRI to non-invasively investigate white matter changes in vivo, thus providing the potential to further our understanding of this disease in the future.
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ItemThe role of neuroligin 3 in cognitive function( 2018)Neuroligins (NLGNs) are members of trans-synaptic protein complexes that mediate synaptic transmission and plasticity, both of which are critical for information processing and cognition. Genetic risk factors for a range of neurodevelopmental disorders disproportionately converge upon synaptic genes, including NLGNs. Although mutations in NLGN3 are linked to ASD, a condition with characteristic cognitive impairments, little is known about the impact of a loss of function of NLGN3 on cognitive processing. This thesis describes the impact of a loss of function of Nlgn3 on a range of distinct cognitive functions in mice, using rodent touchscreen technology. In Chapter 2, we assessed Nlgn3 KO mice on a battery of cognitive tests to explore the involvement of Nlgn3 in operant learning, associative learning, behavioural flexibility, response inhibition and motivation. We found that loss of function of Nlgn3 did not impact operant learning, discrimination learning, extinction learning or appetitive motivation, but had striking impacts on behavioural flexibility indexed by perseverative incorrect responding as well as performance on a reversal learning task. In Chapter 3 we extended the characterisation of Nlgn3 KO mice to probe working memory, pattern separation, signal detection and sustained attention. We found that Nlgn3 KO mice displayed normal pattern separation and a subtle but significant impairment in working memory, suggestive of a shift in the balance between stability and flexibility. Loss of Nlgn3 additionally resulted in robust improvements in measures of sustained attention and signal detection, implicating Nlgn3 in processes underlying allocation of attention. However, performance of Nlgn3 KO mice was also more severely impacted by increasing demands on perceptual or attentional processing, suggesting a reduced ability to scale up the allocation of processing resources under challenging conditions. In Chapter 4 we examined relational memory and flexibility by adapting a novel version of the touchscreen transitive inference task. After validating that WT mice were able to perform our adapted version of the touchscreen transitive inference test, we assessed both Nlgn3 KO and Nlgn3 R451C mice to compare two different models of Nlgn3 dysfunction on relational memory. We show that both Nlgn3 KO and Nlgn3 R451C mice display intact relational memory. However, both Nlgn3 mutant mice exhibited elevated behavioural flexibility, consistent with our results from Chapter 2. Across all chapters, our results indicate Nlgn3 KO mice exhibit longer response times than WT mice across tests that require discrimination of complex stimuli, strongly implicating Nlgn3 in processes underlying perceptual processing. Collectively, the findings from this thesis show that Nlgn3 is involved in aspects of behavioural flexibility, attention and perceptual processing. These studies contribute to our understanding of the function of Nlgn3, and more broadly the impact of synaptic gene dysfunction in aspects of cognition relevant to neurodevelopmental disorders.
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ItemUndetected preclinical neurodegenerative disease in models of normal cognitive aging( 2018)With population aging, understanding cognitive changes that occur in late life is vital to support these increasing numbers of older adults to maintain their wellbeing and independence. Furthermore, accurate estimates of age-related cognitive change will enable the differentiation of early stage neurodegenerative disease from normal aging. Current cognitive aging models describe a pattern of progressive decline in memory,executive function, and processing speed abilities, and retention of experience-based knowledge, with increasing age. However, given that many older adults show signs of neurodegenerative disease, despite not meeting clinical criteria for dementia, it is possible that cognitive aging studies may have over-estimated the nature and magnitude of age-related cognitive decline. The aim of this thesis was to determine the extent to which undetected preclinical neurodegenerative disease could influence models of cognitive aging. Age-related change in cognition was examined in cognitively normal healthy older adults who underwent repeated clinical and neuropsychological assessments, as well as biomarker assessment for neurodegenerative disease. The influence of progression to mild cognitive impairment (MCI) and dementia was also considered. Results indicated that estimates of age-related cognitive decline were inflated by undetected disease. This was also found when the data were reconceptualised as intelligence factors and was confirmed across two cohorts and utilizing a range of analytic methods. Notably, in the absence of disease, increasing age was associated with stability of performance in episodic and working memory, and an attenuated rate of decline in some processing speed and executive functions. Together these results indicate that current expectations about cognitive loss in aging are biased by unrecognized neurodegenerative disease.
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ItemDissociating therapeutic effects of exercise and environmental enrichment in mouse models of serotonergic dysfunction( 2017)Serotonergic (5-HTergic) signaling is implicated in the manifestation of psychiatric disorders and regulates hippocampus-dependent cognitive and emotional processing that can underpin them. Clinical evidence indicates that serotonin 1A receptor (5-HT1AR) and serotonin transporter (5-HTT) gene polymorphisms are associated with anxiety disorders and deficits in cognition. In animal models, exercise and environmental enrichment (EE) can change emotionality-related behaviours as well as enhance some aspects of cognition. We aimed to determine the therapeutic effects of exercise versus EE (which does not include running wheels) on constitutive 5-HT1AR and 5-HTT knock-out (KO) mice phenotypes. 5-HT1AR KO mice have an anxiety-like phenotype as well as hippocampus-dependent learning and memory deficits. In addition to increased anxiety-like behaviour, 5-HTT KO mice also have a depression-like phenotype. The Morris water maze (MWM) is one of the most widely cited behavioural tasks in neuroscience. It measures the capability of the hippocampus to create a viewpoint invariant cognitive map of a distal cue array to find a hidden platform escape goal. Using a Matlab classification algorithm of the search strategy utilised to find the escape during MWM spatial learning, we have shown that increases in the odds of more hippocampus-dependent (allocentric) strategy selection is the key measure indicating the formation of this map to the escape location. Furthermore, using this measure we demonstrated a novel cognitive enhancement due to exercise (but not EE) for the first time. We also showed that 5-HT1AR KO mice had a significant reduction in the likelihood of an allocentric strategy selection. This deficit provides a novel explanation for their impaired long-term memory on the MWM retention probe. Strikingly, we found that these increases in spatial strategy selection through exercise corrected the long-term spatial memory deficits displayed by the 5-HT1AR KO mice. Assessing emotionality-related behaviours in both models dissociated further therapeutic effects of exercise from EE. Exercise (but not EE) had an antidepressant-like effect in 5-HTT KO mice, rescuing their deficit on the forced-swim test. In contrast, our EE paradigm (but not exercise access) reduced anxiety-like behaviours in both 5-HT1AR and 5-HTT KO mice. Furthermore, we report that 5-HTT KO mice had impaired synaptic plasticity by measuring long term potentiation (LTP) in the hippocampus and exercise also rescued this deficit. Exercise elicited robust increases in adult-born cell survival in wild-type (WT) mice. Exercising 5-HTT KO mice did also have increased adult-born cell survival but had a 3-fold decrease in the level compared to exercising WT mice. LTP and adult neurogenesis are both hypothesised to contribute to antidepressant effects, so our study adds support to the hypothesis that LTP and neurogenesis changes drive the antidepressant-like effect of exercise in 5-HTT KO mice. Surprisingly, in 5-HTT HET mice exercise induced a deficit in LTP compared to WT control mice and there were no exercise-induced increases in adult-born cell survival. 5-HTT HET mice in the standard-housing condition displayed enhanced cognitive flexibility and this behaviour was not present in exercising 5-HTT HET mice. Prevalent 5-HT1AR or 5-HTT targeted drugs are established treatments in various psychiatric disorders. Functional polymorphisms in both the 5-HT1AR and the 5-HTT genes are associated with increased risk of developing various psychiatric disorders as well as with increased insensitivity to their unique sets of targeted pharmacology. Unfortunately, for this and for other reasons, not all patients have efficacious responses to these established interventions, so novel therapies are required. The therapeutic effects of exercise and EE we uncovered do not seem to require one of either the 5-HT1AR or the 5-HTT, although further mechanistic studies are required to substantiate that conclusion. Therefore, the preclinical evidence contained herein adds support for clinically employing analogous environmental manipulations, such as brief durations of cognitive-behavioural therapy and/or exercise regimes, as viable therapeutic alternatives for such patients.
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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.