Theta-burst LTP in the Dorsal Striatum: Its Development and Use to Illuminate Striatal Dynamics Underlying Skill Learning, and the Aberrant Learning behind Addiction

THETA-BURST LTP IN THE DORSAL STRIATUM: ITS DEVELOPMENTS AND USE TO ILLUMINATE STRIATAL DYNAMICS UNDERLYING SKILL LEARNING, AND THE ABERRANT LEARNING BEHIND ADDICTION. Sarah Louise Hawes, PhD George Mason University, 2015 Dissertation Director: Dr. Kim Blackwell Corticostriatal plasticity facilitates action selection and skill learning through dynamic enhancement (“long term potentiation” or LTP) and reduction (“long term depression” or LTD) in communication strength between neurons. Striatal primary neurons are divided into two classes: motor-enhancing “direct” and motor-suppressing “indirect” pathway neurons. The regulation of plasticity in these two classes is critical because pathway imbalance is a noted feature in Parkinson’s disease, and strong classspecific plasticity accompanies exposure to drugs of abuse. Thus, it is important to understand striatal plasticity not only to identify neural learning mechanisms, but also because dysregulation of plasticity processes serving learning contributes to disease states. Dorsal striatal LTP has been difficult to induce in brain slices without resorting to unrealistic electrical or chemical treatments. The first research aim is to develop a striatal LTP induction paradigm that resembles brain activity observed during learning behavior. I achieve this by developing a theta-burst stimulation (TBS) protocol modeled after in vivo striatal activity during learning. I show the evoked LTP is indeed reliant on kinases and neurotransmitter receptors implicated in learning. This is a powerful tool for any researcher interested in recreating naturalistic striatal plasticity in acute brain slice. The second research aim within this dissertation is to clarify the relationship between striatal plasticity and learning behavior. Prior works show a transition in the engaged dorsal striatal subregion as skill performance shifts from an attentive phase to a more habitual phase. In addition, increased striatal activity in one hemisphere is known to generate contralateral turning behavior. Thus, I analyze striatal subregional plasticity at different time points as animals learn to execute a consistently rewarded T-maze turn, and further characterize lateralized striatal plasticity as animals are trained to turn. I find that modifications in evoked plasticity and in intrinsic neuronal excitability differ between hemispheres relative to the direction of the trained turn. More significantly, I find that striatal LTP and LTD are independently modulated during learning rather than reciprocally related as previously suggested. Finally, analysis of neuronal morphology reveals novel dendritic pruning in trained animals, without a change in spine density. This dendritic pruning may enhance signal to noise ratio of information transmission through the striatum. The third research aim within this dissertation is to identify the striatal pathway(s) expressing LTP, and neuromodulatory roles in induction. Direct and indirect pathway neurons co-release distinct neuropeptides, including opioids known to influence motivational and addictive states. Whether LTP is naturally expressed in both pathways is not known, and little is known about potential intra-striatal pathway interaction via the co-released neuropeptides. Recordings from single striatal neurons suggest that both pathways express LTP. By genetically expressing channel rhodopsin in either pathway to elevate pathway-specific co-release during TBS LTP induction, we identify a mechanism whereby direct pathway neurons suppress corticostriatal LTP, possibly via reduced intrastriatal dopamine release. In summary, the work comprising this dissertation furthers the field of striatal learning and plasticity by supplying a robust, physiological LTP induction method, and by using this new method to demonstrate altered striatal plasticity consequent to striatal dependent learning. Finally, revealing LTP modulation by endogenous opioids has major implications for understanding the aberrant learning involved in addiction to drugs of abuse.