The striatum is central to motivated behaviors and goal-directed actions. Neuromodulation by acetylcholine (ACh) plays a major role in regulating striatal circuits and resulting behaviors. ACh levels within the striatum are the highest in the CNS. Cholinergic transmission is involved in multiple basal ganglia based functions including the control of voluntary movement, motor and associative learning, as well as reward. Dysfunctions in acetylcholine (ACh) signaling in the striatum are associated with a variety of neurological movement disorders including Parkinson?s disease, Huntington?s disease, and dystonia. Identifying how these dysfunctions occur is limited by a lack of understanding of the basic mechanisms of cholinergic transmission. While both nicotinic and muscarinic receptors are expressed in the striatum, ACh does not directly evoke post-synaptic events at most synapses that can be detected with conventional electrophysiological approaches. Instead cholinergic receptors modulate striatal inputs or indirectly alter the excitability of post-synaptic neurons through multistep intracellular cascades. This proposal will examine the dynamics of ACh at muscarinic synapses using the viral expression of GIRK channels that was developed in the last funding period. The dynamics of ACh will be compared in control and disease states following loss of dopamine. The proposed studies are expected to be significant in that they have to potential to determine specific mechanisms that regulate cholinergic transmission and identify the dysregulations that occur in an animal model of Parkinson?s disease.

Public Health Relevance

Neuromodulation by acetylcholine (ACh) plays a major role in regulating striatal circuits and downstream resulting behaviors. Alterations in cholinergic transmission in the striatum underlie numerous neurological diseases. A better understanding of the events linking acetylcholine release to its physiological actions will be significant as it has the potential to direct new strategies for the treatment of movement based neurological disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Churn, Severn Borden
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
Schools of Medicine
United States
Zip Code
Gulati, Sahil; Jin, Hui; Masuho, Ikuo et al. (2018) Targeting G protein-coupled receptor signaling at the G protein level with a selective nanobody inhibitor. Nat Commun 9:1996
Mulvey, Bernard; Bhatti, Dionnet L; Gyawali, Sandeep et al. (2018) Molecular and Functional Sex Differences of Noradrenergic Neurons in the Mouse Locus Coeruleus. Cell Rep 23:2225-2235
Marcott, Pamela F; Gong, Sheng; Donthamsetti, Prashant et al. (2018) Regional Heterogeneity of D2-Receptor Signaling in the Dorsal Striatum and Nucleus Accumbens. Neuron 98:575-587.e4
Mamaligas, Aphroditi A; Cai, Yuan; Ford, Christopher P (2016) Nicotinic and opioid receptor regulation of striatal dopamine D2-receptor mediated transmission. Sci Rep 6:37834
Mamaligas, Aphroditi A; Ford, Christopher P (2016) Spontaneous Synaptic Activation of Muscarinic Receptors by Striatal Cholinergic Neuron Firing. Neuron 91:574-86
Courtney, Nicholas A; Ford, Christopher P (2016) Mechanisms of 5-HT1A receptor-mediated transmission in dorsal raphe serotonin neurons. J Physiol 594:953-65