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Theses Doctoral

Mechanisms of Basal Ganglia Development

Lieberman, Ori Jacob

Animals must respond to external cues and changes in internal state by modifying their behavior. The basal ganglia are a collection of subcortical nuclei that contribute to action selection by integrating sensorimotor, limbic and reward information to control motor output. In early life, however, animals display distinct behavioral responses to risk and reward and enhanced vulnerability to neuropsychiatric disease. This arises from the postnatal maturation of brain structures such as the striatum, the main input nucleus of the basal ganglia. Here, using biochemical, electrophysiological and behavioral approaches in transgenic mice, I have explored the molecular and circuit mechanisms that control striatal maturation.

In Chapter 1, I begin by reviewing the structure, physiology and function of the basal ganglia, with an emphasis on the striatum. I then describe the existing literature on the development and maturation of striatal neurons and their afferents. In Chapter 2, I review the molecular mechanisms of macroautophagy, a lysosomal degradation pathway that has recently been implicated in the regulation of neurotransmission, including its contribution to neuronal development, neurotransmitter release, and postsynaptic function.

The subsequent chapters can be split into two themes. In the first, encompassing chapters 3 and 4, I characterize the postnatal maturation of striatal physiology and define circuit mechanisms that control this process. In Chapter 3, I demonstrate that dopamine (DA) neurotransmission in the striatum initiates the maturation of striatal projection neuron (SPN) intrinsic excitability. I show that DA signaling leads to the maturation of SPN excitability via increased activity of the potassium channel, Kir2. Interestingly, introduction of DA beginning in adulthood could not rescue SPN hyperexcitability while it could during the juvenile period. In Chapter 4, I characterize the maturation of cholinergic interneurons (ChIs) in the striatum and describe the biophysical mechanisms that drive increases in spontaneous activity that occur in ChIs during postnatal development. Finally, I show that the functional maturation of ChIs leads to changes in DA release during the postnatal period.

The second theme includes Chapters 5 and 6, in which I explore the role of macroautophagy in striatal function and development. In chapter 5, I used biochemical approaches to show that autophagic flux is suppressed postnatally in the striatum due to increased signaling through the kinase activity of the mammalian target of rapamycin. In Chapter 6, I generated conditional knockouts of Atg7, a required macroautophagy gene, in different populations of SPNs and find that macroautophagy plays cell-type specific roles in SPN physiology. In one subtype of SPNs, macroautophagy regulates intrinsic excitability via degradation of Kir2 channels, which is the first demonstration of macroautophagic control of neuronal excitability.

Finally, in Chapter 7, I conclude with a general discussion, where I highlight themes in the molecular and circuit mechanisms of striatal maturation and their implication for neurodevelopmental disease.

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More About This Work

Academic Units
Neurobiology and Behavior
Thesis Advisors
Sulzer, David L.
Degree
Ph.D., Columbia University
Published Here
January 24, 2020