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The discovery of the involvement of alpha-synuclein (α-syn) in Parkinson's disease (PD) pathogenesis has resulted in the development and use of viral vector-mediated α-syn overexpression rodent models. The goal of these series of experiments was to characterize the neurodegeneration and functional deficits resulting from injection of recombinant adeno-associated virus (rAAV) serotype 2/5-expressing human wildtype α-syn in the rat substantia nigra (SN). Rats were unilaterally injected into two sites in the SN with either rAAV2/5-expressing green fluorescent protein (GFP, 1.2 x 10(13)) or varying titers (2.2 x 10(12), 1.0 x 10(13), 5.9 x 10(13), or 1.0 x 10(14)) of rAAV2/5-α-syn. Cohorts of rats were euthanized 4, 8, or 12 weeks following vector injection. The severity of tyrosine hydroxylase immunoreactive (THir) neuron death in the SN pars compacta (SNpc) was dependent on vector titer. An identical magnitude of nigrostriatal degeneration (60-70% SNpc THir neuron degeneration and 40-50% loss of striatal TH expression) was observed four weeks following 1.0 x 10(14) titer rAAV2/5-α-syn injection and 8 weeks following 1.0 x 10(13) titer rAAV2/5-α-syn injection. THir neuron degeneration was relatively uniform throughout the rostral-caudal axis of the SNpc. Despite equivalent nigrostriatal degeneration between the 1.0 x 10(13) and 1.0 x 10(14) rAAV2/5-α-syn groups, functional impairment in the cylinder test and the adjusting steps task was only observed in rats with the longer 8 week duration of α-syn expression. Motor impairment in the cylinder task was highly correlated to striatal TH loss. Further, 8 weeks following 5.9 x 10(13) rAAV2/5-α-syn injection deficits in ultrasonic vocalizations were observed. In conclusion, our rAAV2/5-α-syn overexpression model demonstrates robust nigrostriatal α-syn overexpression, induces significant nigrostriatal degeneration that is both vector and duration dependent and under specific parameters can result in motor impairment that directly relates to the level of striatal TH denervation.

Although individual differences in processing speed, working memory, intelligence, and other cognitive functions were found to explain individual differences in retrospective memory (RetM), much less is known about their relationship with prospective memory (ProM). Moreover, the studies that investigated the relationship between ProM and cognitive functions arrived to contradictory conclusions. The relationship between ProM, personality, and psychopathology is similarly unsettled. Meta-analytic reviews of the relationships of ProM with aging and personality suggest that the contradictory findings may be due to widespread methodological problems plaguing ProM research including the prevalent use of inefficient, unreliable binary measures; widespread ceiling effects; failure to distinguish between various ProM subdomains (e.g., episodic ProM versus vigilance/monitoring); various confounds; and, importantly, small sample sizes, resulting in insufficient statistical power. Accordingly, in a large scale study with nearly 1,200 participants, we investigated the relationship between episodic event-cued ProM, episodic RetM, and fundamental cognitive functions including intelligence, personality, and psychopathology, using reliable continuous measures of episodic event-cued ProM. Our findings show that (a) continuous measures of episodic event-cued ProM were much more reliable than binary measures, (b) episodic event-cued ProM was associated with measures of processing speed, working memory, crystallized and fluid intelligence, as well as RetM, and that such associations were similar for ProM and RetM, (c) personality factors did not improve prediction of neither ProM nor RetM beyond the variance predicted by cognitive ability, (d) symptoms of psychopathology did not improve the prediction of ProM although they slightly improved the prediction of RetM, and (e) participants' sex was not associated with ProM but showed small correlations with RetM. In addition to advancing our theoretical understanding of ProM, our findings highlight the need to avoid common pitfalls plaguing ProM research.

Parkinson disease (PD) compromises oropharyngeal swallowing, which negatively affects quality of life and contributes to aspiration pneumonia. Dysphagia often begins early in the disease process, and does not improve with standard therapies. As a result, swallowing deficits are undertreated in the PD population. The Pink1 −/− rat is used to model PD, and demonstrates widespread brainstem neuropathology in combination with early-onset sensorimotor dysfunction; however, to date, swallowing behaviors have not been evaluated. To test the hypothesis that Pink1 −/− rats demonstrate early-onset differences in swallowing, we analyzed within-subject oropharyngeal swallowing using videofluoroscopy. Pink1 −/− and wildtype (WT) controls at 4 (Pink1 −/− n = 16, WT = 16) and 8 (Pink1 −/− n = 12, WT = 12) months of age were tested. The average and maximum bolus size was significantly increased in Pink1 −/− rats at both 4 and 8 months. Bolus average velocity was increased at 8 months for all animals; yet, Pink1 −/− animals had significantly increased velocities compared to WT at 8 months. The data show a significant reduction in mastication rate for Pink1 −/− rats at 8 months suggesting the onset of oromotor dysfunction begins at this time point. Relationships among swallowing variables and neuropathological findings, such as increased alpha-synuclein protein in the nucleus ambiguus and reductions in noradrenergic cells in the locus coeruleus in the Pink1 −/− rats, were determined. The presence of early oropharyngeal swallowing deficits and relationships to brainstem pathology in Pink1−/− rat models of PD indicate that this may be a useful model of early swallowing deficits and their mechanisms. These findings suggest clinical implications for early detection and management of dysphagia in PD.

Voice and communication are significantly impaired in Parkinson disease (PD), frequently manifesting early in the disease process and negatively impacting social interactions and quality of life. Voice deficits are refractory to pharmacological and surgical therapies aimed at treating the primary disease pathology of nigrostriatal dopamine depletion. This suggests that alternative, non-dopaminergic, mechanisms contribute to these early-onset vocal deficits. Germane to this issue, loss of norepinephrine (NE) in brainstem regions critical to neuromodulation, sensorimotor, and cognitive functions also occurs early in the disease progression in humans with PD and has been implicated in the manifestation and treatment of other refractory deficits. Consistent with what is observed in humans, vocal communication and NE are compromised in transgenic mouse and genetic rat models of PD, indicating that NE loss may contribute to the manifestation of vocal communication deficits in these models. However, in each of these models, there were other pathologies that could be contributing to these vocal deficits. Importantly, the contribution of NE in normal vocal control and in PD related voice deficits has not been well established. The present work employed a rat model to address these gaps in knowledge. In Chapter 2 we establish that NE depletion following the administration of the neurotoxin DSP-4 is sufficient to disrupt pertinent vocal communication parameters. In Chapter 3 we used NE adrenoceptor agonists and antagonists to quantify the contribution of specific NE receptors to pertinent vocalization parameters. This work is significant because results confirm the involvement of NE in vocal control and point to potential pharmacological targets for treating voice deficits in PD.

The discovery of the involvement of alpha-synuclein ( alpha -syn) in Parkinson's disease (PD) pathogenesis has resulted in the development and use of viral vector-mediated alpha -syn overexpression rodent models. The goal of these series of experiments was to characterize the neurodegeneration and functional deficits resulting from injection of recombinant adeno-associated virus (rAAV) serotype 2/5-expressing human wildtype alpha -syn in the rat substantia nigra (SN). Rats were unilaterally injected into two sites in the SN with either rAAV2/5-expressing green fluorescent protein (GFP, 1.2 x 1013) or varying titers (2.2 x 1012, 1.0 x 1013, 5.9 x 1013, or 1.0 x 1014) of rAAV2/5- alpha -syn. Cohorts of rats were euthanized 4, 8, or 12 weeks following vector injection. The severity of tyrosine hydroxylase immunoreactive (THir) neuron death in the SN pars compacta (SNpc) was dependent on vector titer. An identical magnitude of nigrostriatal degeneration (60-70% SNpc THir neuron degeneration and 40-50% loss of striatal TH expression) was observed four weeks following 1.0 x 1014 titer rAAV2/5- alpha -syn injection and 8 weeks following 1.0 x 1013 titer rAAV2/5- alpha -syn injection. THir neuron degeneration was relatively uniform throughout the rostral-caudal axis of the SNpc. Despite equivalent nigrostriatal degeneration between the 1.0 x 1013 and 1.0 x 1014 rAAV2/5- alpha -syn groups, functional impairment in the cylinder test and the adjusting steps task was only observed in rats with the longer 8 week duration of alpha -syn expression. Motor impairment in the cylinder task was highly correlated to striatal TH loss. Further, 8 weeks following 5.9 x 1013 rAAV2/5- alpha -syn injection deficits in ultrasonic vocalizations were observed. In conclusion, our rAAV2/5- alpha -syn overexpression model demonstrates robust nigrostriatal alpha -syn overexpression, induces significant nigrostriatal degeneration that is both vector and duration dependent and under specific parameters can result in motor impairment that directly relates to the level of striatal TH denervation.

A cure for HIV-1 remains unattainable as only one case has been reported, a decade ago 1 , 2 . The individual—who is known as the ‘Berlin patient’—underwent two allogeneic haematopoietic stem-cell transplantation (HSCT) procedures using a donor with a homozygous mutation in the HIV coreceptor CCR5 (CCR5Δ32/Δ32) to treat his acute myeloid leukaemia. Total body irradiation was given with each HSCT. Notably, it is unclear which treatment or patient parameters contributed to this case of long-term HIV remission. Here we show that HIV-1 remission may be possible with a less aggressive and toxic approach. An adult infected with HIV-1 underwent allogeneic HSCT for Hodgkin’s lymphoma using cells from a CCR5Δ32/Δ32 donor. He experienced mild gut graft-versus-host disease. Antiretroviral therapy was interrupted 16 months after transplantation. HIV-1 remission has been maintained over a further 18 months. Plasma HIV-1 RNA has been undetectable at less than one copy per millilitre along with undetectable HIV-1 DNA in peripheral CD4 T lymphocytes. Quantitative viral outgrowth assays from peripheral CD4 T lymphocytes show no reactivatable virus using a total of 24 million resting CD4 T cells. CCR5-tropic, but not CXCR4-tropic, viruses were identified in HIV-1 DNA from CD4 T cells of the patient before the transplant. CD4 T cells isolated from peripheral blood after transplantation did not express CCR5 and were susceptible only to CXCR4-tropic virus ex vivo. HIV-1 Gag-specific CD4 and CD8 T cell responses were lost after transplantation, whereas cytomegalovirus-specific responses were detectable. Similarly, HIV-1-specific antibodies and avidities fell to levels comparable to those in the Berlin patient following transplantation. Although at 18 months after the interruption of treatment it is premature to conclude that this patient has been cured, these data suggest that a single allogeneic HSCT with homozygous CCR5Δ32 donor cells may be sufficient to achieve HIV-1 remission with reduced intensity conditioning and no irradiation, and the findings provide further support for the development of HIV-1 remission strategies based on preventing CCR5 expression. An adult infected with HIV-1 who underwent allogeneic haematopoietic stem-cell transplantation for Hodgkin’s lymphoma using cells from a CCR5Δ32/Δ32 donor achieved full remission of HIV-1 for 18 months after transplantation and 16 months after cessation of antiretroviral therapy.

Circadian (∼24-hour) timing systems pervade all kingdoms of life and temporally optimize behavior and physiology in humans. Relatively recent changes to our environments, such as the introduction of artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behavior and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these, too, are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioral and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important.

Significance The conventional parametric approach to modeling relies on hypothesized equations to approximate mechanistic processes. Although there are known limitations in using an assumed set of equations, parametric models remain widely used to test for interactions, make predictions, and guide management decisions. Here, we show that these objectives are better addressed using an alternative equation-free approach, empirical dynamic modeling (EDM). Applied to Fraser River sockeye salmon, EDM models ( i ) recover the mechanistic relationship between the environment and population biology that fisheries models dismiss as insignificant, ( ii ) produce significantly better forecasts compared with contemporary fisheries models, and ( iii ) explicitly link control parameters (spawning abundance) and ecosystem objectives (future recruitment), producing models that are suitable for current management frameworks. It is well known that current equilibrium-based models fall short as predictive descriptions of natural ecosystems, and particularly of fisheries systems that exhibit nonlinear dynamics. For example, model parameters assumed to be fixed constants may actually vary in time, models may fit well to existing data but lack out-of-sample predictive skill, and key driving variables may be misidentified due to transient (mirage) correlations that are common in nonlinear systems. With these frailties, it is somewhat surprising that static equilibrium models continue to be widely used. Here, we examine empirical dynamic modeling (EDM) as an alternative to imposed model equations and that accommodates both nonequilibrium dynamics and nonlinearity. Using time series from nine stocks of sockeye salmon ( Oncorhynchus nerka ) from the Fraser River system in British Columbia, Canada, we perform, for the the first time to our knowledge, real-data comparison of contemporary fisheries models with equivalent EDM formulations that explicitly use spawning stock and environmental variables to forecast recruitment. We find that EDM models produce more accurate and precise forecasts, and unlike extensions of the classic Ricker spawner–recruit equation, they show significant improvements when environmental factors are included. Our analysis demonstrates the strategic utility of EDM for incorporating environmental influences into fisheries forecasts and, more generally, for providing insight into how environmental factors can operate in forecast models, thus paving the way for equation-free mechanistic forecasting to be applied in management contexts.