Theses Doctoral

Postnatal Development of the Striatal Cholinergic Interneuron

McGuirt, Avery Fisher

The early postnatal period is marked by the rapid acquisition of sensorimotor processing capabilities. Initially responding to a limited set of environmental stimuli with a restricted repertoire of behaviors, mammals exhibit a remarkable proliferation of sensorimotor abilities in the early postnatal period. Central to action selection, reinforcement, and contingency learning are a subcortical set of evolutionarily conserved nuclei called the basal ganglia. The striatum, which is the primary input nucleus of the basal ganglia, receives afferent innervation from throughout the CNS. Its projection neurons (SPNs) integrate these diverse inputs, regulating movement and encoding salient cue-outcome contingencies. Here, using electrophysiological, electrochemical, imaging, and behavioral approaches in mice, I will explore the postnatal maturation of the striatal cholinergic interneuron (ChI), a critical modulator of dopamine signaling, afferent excitation, and SPN excitability.

In Chapter 1, I will set the stage for this exploration by reviewing the current literature on striatal postnatal development, including cellular physiology, axonal elaboration and synapse formation, and plasticity expression. I will survey striatal deficits observed in clinical neurodevelopmental conditions such as autism, ADHD, tic disorders, and substance use disorders. I will additionally summarize evidence that the striatum is uniquely vulnerable to physiological and immunological insult, as well as early life adversity.

In Chapter 2, I turn my focus specifically to the striatal ChI, uncovering fundamental cell-intrinsic changes that occur postnatally in this population. I will also elaborate on the postnatal maturation of dopamine release properties and regulation thereof by cholinergic signaling from the ChI. In Chapter 3, I investigate the circuit connectivity and circuit-driven firing dynamics of ChIs as they mature postnatally. I utilize a brain slice preparation retaining thalmostriatal afferents in order to assay the ChI pause, a synchronized transient quiescence in ChIs thought to facilitate cue learning and behavioral flexibility. I find that the ChI pause is refined postnatally, dependent on developmental changes in thalamic input strength and the cell- intrinsic expression of specific ionic conductances.

Finally, in Chapter 4, I present preliminary evidence that ChI circuit maturation as defined in preceding chapters is delayed by chronic stress exposure postnatally. Following the maternal separation model of early life stress, ChI intrinsic characteristics mature normally, but they retain heightened thalamic innervation and thalamus-driven pause expression.


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More About This Work

Academic Units
Neurobiology and Behavior
Thesis Advisors
Sulzer, David
Ph.D., Columbia University
Published Here
April 13, 2022