Mechanisms underlying dopaminergic modulation of striatal firing and learning




Damodaran, Sriraman

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This dissertation investigates the mechanisms underlying the changes in firing, oscillations and synaptic plasticity after dopamine depletion in order to identify potential therapeutic targets for Parkinson's disease. Dopamine depletion leads to an imbalance in the activation of the two classes of MSNs and aberrant oscillations in β-band frequencies observed in the basal ganglia output nuclei. Therefore, understanding the mechanisms underlying balanced firing in the control condition, and mechanisms controlling oscillations and synchrony in the dopamine depleted condition, can help us understand how to restore normal activity in Parkinson's disease. In order to investigate these mechanisms, we used a detailed computational model of striatal medium spiny neurons (MSN), and a striatal network model consisting of MSNs and fast spiking interneurons (FSI). I first investigate the mechanisms that modulate striatal firing by analyzing the firing frequency of direct (D1 MSN) and indirect (D2 MSN) pathway neurons in response to excitatory synaptic input in a network of 1049 neurons. I show that though D2 MSNs are significantly more excitable than D1 MSN in response to current injection both neuron classes fire at similar frequencies in the network. Simulations also reveal that the synchronized firing of FSIs is critical in producing this balance and the removal of gap junctions between FSIs was sufficient to eliminate the balance in firing. I extend this work by investigating whether the striatum can be the source of the aberrant β-band oscillations observed in the basal ganglia output nuclei after dopamine depletion. I modeled the dopamine depleted striatal network by implementing changes to cellular and network properties that have been reported to occur after dopamine depletion. Simulations reveal that these changes are sufficient to produce increased β-band oscillations and imbalanced firing in the MSNs. Simulations also reveal that reducing the synchronicity between FSIs by blocking gap junctions is sufficient to restore oscillations and balance in firing in the dopamine depleted network to control levels. I then begin to investigate learning by the striatal network in response to realistic in vivo input by developing a calcium-based synaptic plasticity rule to investigate mechanisms whereby dopamine contributes to cortico-striatal plasticity. The plasticity rule is implemented in a MSN with sophisticated model of calcium diffusion, buffering, and pump extrusion, tuned to match experimentally reported post-synaptic calcium dynamics during timed plasticity protocols. Using this model I show that a calcium-based plasticity rule is sufficient to predict the direction of plasticity in both D1 and D2 MSNs in response to several different STDP protocols. In conclusion, this dissertation presents insights about striatal physiology that helps us better understand diseased states involving the basal ganglia, and that will potentially lead to novel therapeutic targets.



Neurosciences, Fast spiking interneurons, Gap junctions, Medium Spiny Neurons, Parkinson' disease, Striatum