Nicotinic cholinergic signaling plays key roles in the mammalian nervous system. Nicotinic acetylcholine receptors mediate excitatory signaling between neurons as post-synaptic receptors and, from extrasynaptic sites, modulate neurotransmitter release at diverse synapse types across virtually every area of the brain and spinal cord. Alterations in nicotinic cholinergic signaling are associated with a number of debilitating neurological disorders including Alzheimer's disease, schizophrenia and certain forms of epilepsy. Moreover, nicotine binding to nicotinic receptors in the nervous system initiates the cellular and molecular cascade that results in nicotine addiction. Despite the clear importance of nicotinic signaling in normal brain physiology and neuronal dysfunction, there are major gaps in our understanding of the molecular mechanisms by which nicotinic signaling is achieved, and the regulatory pathways that impact cholinergic signaling in the nervous system remain poorly defined. This proposal employs a highly tractable model system, the nematode C. elegans, to investigate the molecular details of cholinergic signaling in a defined nervous system. Our preliminary data show that nicotinic receptors play key roles in regulating the excitability of motor neurons in a well-characterized C. elegans motor circuit.
In Aim 1, we will test the hypothesis that the expression and localization of specific receptor types are restricted to subsets of motor neurons, determine the molecular nature of pathways important for proper localization of nicotinic receptors on neurons, and test the roles of specific receptor types in the control of C. elegans behavior.
In Aim 2, we will use patch clamp electrophysiology to directly measure cholinergic currents from motor neurons and assess the roles of these receptors in motor neuron physiology.
In Aim 3, we will use a powerful genetic approach to uncover components of novel molecular pathways that regulate cholinergic signaling onto neurons. We expect that our studies will provide fundamental insights into the mechanisms of nicotinic receptor function in the central nervous system. Additionally, the identification and functional characterization of genetic pathways that regulate synapse formation and function in our experiments will ultimately yield novel drug targets for therapeutic strategies designed to treat neurological disorders involving cholinergic signaling.

Public Health Relevance

Cellular communication in the nervous system requires the neurotransmitter acetylcholine and alterations in acetylcholine-mediated signaling are a hallmark of a wide variety of degenerative neurological disorders and nicotine addiction, yet we know very little about the molecular pathways that regulate this process in the nervous system. This proposal will explore the mechanisms by which acetylcholine transmits information between cells of the nervous system and uncover new genes required in this process. Our work will provide fundamental insights into the mechanisms of acetylcholine-mediated signaling and is expected to lead to the development of new therapies for the treatment of disorders arising from deficits in this process.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Stewart, Randall R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
Schools of Medicine
United States
Zip Code
Philbrook, Alison; Ramachandran, Shankar; Lambert, Christopher M et al. (2018) Neurexin directs partner-specific synaptic connectivity in C. elegans. Elife 7:
Barbagallo, Belinda; Philbrook, Alison; Touroutine, Denis et al. (2017) Excitatory neurons sculpt GABAergic neuronal connectivity in the C. elegans motor circuit. Development 144:1807-1819
Francis, Michael M; Freeman, Marc R (2016) Dendrites actively restrain axon outgrowth and regeneration. Proc Natl Acad Sci U S A 113:5465-6
He, Siwei; Philbrook, Alison; McWhirter, Rebecca et al. (2015) Transcriptional Control of Synaptic Remodeling through Regulated Expression of an Immunoglobulin Superfamily Protein. Curr Biol 25:2541-8
Kowalski, Jennifer R; Dube, Hitesh; Touroutine, Denis et al. (2014) The Anaphase-Promoting Complex (APC) ubiquitin ligase regulates GABA transmission at the C. elegans neuromuscular junction. Mol Cell Neurosci 58:62-75
Bhattacharya, Raja; Touroutine, Denis; Barbagallo, Belinda et al. (2014) A conserved dopamine-cholecystokinin signaling pathway shapes context-dependent Caenorhabditis elegans behavior. PLoS Genet 10:e1004584
Donnelly, Jamie L; Clark, Christopher M; Leifer, Andrew M et al. (2013) Monoaminergic orchestration of motor programs in a complex C. elegans behavior. PLoS Biol 11:e1001529
Philbrook, Alison; Barbagallo, Belinda; Francis, Michael M (2013) A tale of two receptors: Dual roles for ionotropic acetylcholine receptors in regulating motor neuron excitation and inhibition. Worm 2:e25765
Petrash, Hilary A; Philbrook, Alison; Haburcak, Marian et al. (2013) ACR-12 ionotropic acetylcholine receptor complexes regulate inhibitory motor neuron activity in Caenorhabditis elegans. J Neurosci 33:5524-32
Jensen, Michael; Hoerndli, Frederic J; Brockie, Penelope J et al. (2012) Wnt signaling regulates acetylcholine receptor translocation and synaptic plasticity in the adult nervous system. Cell 149:173-87

Showing the most recent 10 out of 11 publications