Dissertations, Theses, and Capstone Projects

Date of Degree

9-2025

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy

Program

Psychology

Advisor

Andreas H. Kottmann

Committee Members

Peter Balsam

Jeff Beeler

Andrew Delamater

Jonathan Javitch

Nicolas Tritsch

Subject Categories

Behavioral Neurobiology | Cell Biology | Molecular and Cellular Neuroscience | Molecular Biology

Keywords

Sonic Hedgehog, Cholinergic Interneurons, Striatum, Dopamine, Acetylcholine, Smoothened

Abstract

The striatum is a central node in action selection and associative learning, integrating cortical, thalamic, and neuromodulatory input. Among its principal modulators, dopamine (DA) and acetylcholine (ACh) are known for their temporally coordinated yet mechanistically distinct influences on striatal output. However, the upstream signals that regulate their dynamic interplay, particularly within cholinergic interneurons (CINs)—the primary source of striatal ACh—remain incompletely characterized. This dissertation investigates the role of Smoothened (Smo), a G protein-coupled receptor (GPCR) effector of Sonic Hedgehog (Shh) signaling, in modulating ACh signaling dynamics in the striatum.

Building on evidence that midbrain DA neurons co-release Shh and that CINs express its signaling machinery, we use genetic, pharmacological, and behavioral tools to dissect how Smo activity shapes CIN physiology and basal ganglia output. We suggest that Smo signaling acutely opposes dopamine receptor 2 (D2)-mediated inhibition of CINs, modulates the temporal coordination between ACh and DA release, and offer a mechanism by which it might constrain pathological ACh dynamics implicated in L-DOPA-induced dyskinesias (LIDs). Notably, we show that Smo activation counteracts features of CIN physiology associated with D2 receptor signaling, a molecular pathway we also implicate here in the formation of LIDs.

Beyond its real-time effects on neuromodulatory output, Smo also regulates cellular stress responses in CINs, supporting their long-term viability. These findings suggest that the same signaling mechanisms enabling moment-to-moment modulation of ACh dynamics may also underlie the trophic support required for CIN survival. In this view, Smo-mediated regulation of CIN physiology represents a continuum, linking acute functional modulation to long-term cellular resilience. Together, these findings identify Shh-Smo signaling as a critical mechanism for fine-tuning striatal ACh signaling and restoring DA-ACh balance in disease states marked by neuromodulatory dysfunction.

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