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Abstract |
The mammalian brain is a remarkable organ that continues to fascinate biologists with its ability to undergo experience-dependent adaptations, and this property is preserved throughout the life. Brain plasticity on the molecular and cellular level within neurons is thought to occur in response to neuronal activity, continuously changing the strength of synapses and thus influencing the connections between neurons. Synapses are weakened or strengthened in response to specific patterns of neuronal activity. The underlying mechanism of synaptic plasticity is thought to consist of the regulated release of neurotransmitters (chemical mediators of neuronal communication) from the presynaptic side, and changes in the expression levels and availability of corresponding receptors located predominantly on the postsynaptic side of the synapse. Numerous studies over the past three decades have focused on elucidating the molecular basis of synaptic plasticity, with the goal of better understanding the link between transient changes in neuronal activity in response to experience, and short- and long-term changes in brain circuitry that underlie learning, memory and adaptive behavior. However, many key questions remain unresolved. The results of research efforts presented in this dissertation represent a modest contribution to our increasing knowledge of experience-dependent brain plasticity and its relevance to human health.; Naturally, the most dramatic changes in the complexity and functionality of any brain region happen during development, when a single sheet of precursor cells gives rise to a complex organ with multiple types of neurons, communicating through billions of connections and using different types of chemical messengers, the neurotransmitters. At the other end of life, during aging and the neurodegenerative processes, the brain undergoes a different kind of plasticity, a dynamic process that effectively breaks connections between neurons, and severely impairs numerous brain functions. Looking from the outside, these two periods of life seem to initiate the most dramatic and highly dynamic of all the changes in the brain as they are evident through striking changes in behavior or by the gain or the loss of functions. However, throughout the healthy adult life, more subtle, yet important plastic changes happen in the brain at both the molecular and cellular level, enabling animals and humans to learn new motor skills or a new language and remember places and people they meet. Emerging new research suggests that dynamics in the brain go beyond learning processes. Accumulating evidence supports the hypothesis that daily experiences, stress, physical activity, diet, and lifestyle changes are all factors that cause subtle plastic changes in the brain, bringing both positive and negative consequences to overall brain function. In this dissertation, I investigated adult brain plasticity in health and disease. For my research I used the MPTP mouse model of Parkinson’s disease. This animal model enabled me to investigate plastic changes in the brain on the molecular and cellular level and also provided me with a simple model of behavioral changes. The first study of this dissertation was designed to investigate the plasticity in the serotonin system in different brain regions following a neurotoxic brain injury resulting in severe loss of dopamine (presented in Chapter 2).; Serotonin is a chemical used by different brain regions for communication between neurons. Through its signaling in the frontal cortex, amygdala and midbrain, serotonin controls complex behaviors such as fear response and memory formation, and its imbalance is closely linked to human psychiatric conditions such as depression and anxiety. In the study presented in Chapter 2, severe dopamine depletion caused loss of serotonin in multiple brain regions in the mice treated with MPTP, and this neurotransmitter imbalance caused memory impairments, but not depression and anxiety-like behaviors. Three other studies in this dissertation focused on investigating experience-driven neuroplasticity in the adult mouse brain. Specifically, in Chapter 3, my studies focused on plastic changes in expression of dopamine receptor D2 in the striatum of mice lesioned with MPTP and exposed to daily treadmill exercise. Dopamine receptors are gates of dopamine signaling in the brain and without them the neurotransmitter cannot be used for communication between neurons. Results presented in Chapter 3 indicate that daily treadmill exercise for 6 weeks increases expression of dopamine receptor D2 in the striatum of mice. This finding was also confirmed using in vivo positron emission tomography (PET) imaging of live mice. Using the same experimental model in Chapter 4, I examined the plastic changes of medium spiny neurons (MSNs), the principal neurons in the striatum, focusing on the analysis of their complex morphology. The analysis showed that 6 weeks of treadmill exercise increased the spine density on MSNs in the dorsolateral striatum, and this increase was observed in both control and MPTP-lesioned mice but was more pronounced in the lesioned mice. This finding was supported by electron microscopy analysis of synapse number, which showed significant increase in response to treadmill exercise.; I investigated this phenomenon further in Chapter 5 by focusing on a subset of MSNs, those that are part of the striatal indirect pathway and predominantly express dopamine D2 receptors. This study used a transgenic mouse model that was engineered to allow direct visualization of the indirect pathway MSNs in the mouse brain using the fluorescent microscope. Results of this study showed that spine density changes on MSNs in response to exercise occur in indirect pathway neurons and future analysis will investigate if these changes are restricted to this striatal pathway or if they also occur in direct pathway MSNs. Analysis of glutamate AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) receptor composition in indirect pathway MSNs showed that treadmill exercise increased expression levels of the GluR2 subunit of this receptor in both control and MPTP lesioned mice. Electrophysiological recordings support these findings. Subunit composition of glutamate AMPA receptors is critical for experience-dependent synaptic plasticity in multiple brain regions, including the striatum. Modulation of AMPA receptor subunit composition through treadmill exercise training could be a part of the molecular mechanisms responsible for the benefits of exercise on the brain in both healthy individuals and people affected with PD.; Taken together, the results of the studies presented in this dissertation contribute to our knowledge and understanding of adult brain plasticity in health and disease. In addition, studies in this dissertation contribute to our better understanding of animal models of human diseases. |
University of Southern California Dissertations and Theses
