zed below were obtained in collaborative studies: Accumulating evidence suggests that the regulation of airway diameter and body weight are intertwined. Studies with different mutant mouse models demonstrated that leptin increased airway diameter by decreasing parasympathetic signaling through M3 mAChRs expressed by airway smooth muscle cells. Moreover, reduction of parasympathetic tone inhibited bronchoconstriction and normalized lung function in obese mice regardless of bronchial inflammation. These findings are of potential clinical relevance for the treatment of obesity-associated asthma. (Arteaga-Solis E, et al. Inhibition of leptin regulation of parasympathetic signaling as a cause of extreme body weight-associated asthma. Cell Metab 17, 35-48, 2013) Chronic obstructive pulmonary disease (COPD) is characterized by an increase in parasympathetic cholinergic tone. Recent data suggest that ACh also plays a role in mediating airway inflammation. To identify the nature of the mAChR subtypes involved in this activity, M1, M2, and M3 mAChR KO mice and WT control mice were exposed to cigarette smoke for several days. Interestingly, the outcome of mouse phenotyping studies indicated that the M3 mAChR has a pro-inflammatory role in cigarette smoke-induced neutrophilia and cytokine release, whereas the M1 and M3 mAChRs exert anti-inflammatory effects in this animal model. These findings are highly relevant for the development of novel muscarinic drugs useful for the treatment of COPD. (Kistemaker LE, et al. Muscarinic receptor subtype-specific effects on cigarette smoke-induced inflammation in mice. Eur Respir J Feb 8, 2013 Epub ahead of print) Cholinergic neurons in the laterodorsal tegmental (LDT) and peduncolopontine tegmental (PPT) nuclei regulate reward, arousal, and sensory gating via major projections to midbrain dopamine regions and other areas of the brain. It is well known that the activity of these cholinergic neurons is modulated by muscarinic agonists. To identify the nature of the mAChR subtypes involved in this activty, various mAChR KO strains were subjected to electrophysiological and calcium imaging studies. These experiments demonstrated that multiple mAChRs coordinate cholinergic outflow from the LDT in an unexpectedly complex manner. (Kohlmeier KA, et al. Knockouts reveal overlapping functions of M2 and M4 muscarinic receptors and evidence for a local glutamatergic circuit within the laterodorsal tegmental nucleus. J Neurophysiol 108, 2751-66, 2012) We recently generated an M3 mAChR-based designer GPCR that selectively activates the stimulatory G protein, Gs (Guettier et al., PNAS 106, 19197-202, 2009). This designer receptor, which we refer to as 'Rs', is unable to bind ACh, the endogenous mAChR ligand, but can be selectively activated by an exogenously administered drug that is otherwise pharmacologically inert (clozapine-N-oxide or short CNO). To explore the behavioral roles of Gs signaling in striatopallidal medium spiny neurons (MSNs), studies were carried out with transgenic mice selectively expressing the Rs construct in these neurons. Following CNO treatment, the Rs mutant mice showed reduced spontaneous and novelty-induced locomotor activity and failed to display behavioral sensitization to amphetamine. These findings demonstrate that the Rs receptor, an M3 mAChR-based designer GPCR, represents an excellent novel tool for elucidating the behavioral consequences of activating Gs signaling in striatopallidal MSNs. (Farrell MS, et al. A Gαs DREADD mouse for selective modulation of cAMP production in striatopallidal neurons. Neuropsychopharmacology 38, 854-62, 2013) The dorsal striatum plays a role in reward-based decision making, but the importance of specific striatal circuits in these processes remains unclear. By using neuron-specific viral vectors, the Rs receptor (see previous paragraph), an M3 mAChR-based designer GPCR that is selectively coupled to Gs, was expressed in direct-pathway (striatonigral) neurons of the dorsomedial striatum of the rat. CNO-mediated activation of the Rs designer receptor significantly improved the retention of task strategies used to maximize reward obtainment during subsequent preference testing. These data demonstrate that Gs signaling in direct-pathway striatal neurons plays a well-defined role in reward-related behavior. (Ferguson SM, et al. Direct-pathway striatal neurons regulate the retention of decision-making strategies. J Neurosci 133, 11668-76, 2013)

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$530,931
Indirect Cost
City
State
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Shen, Weixing; Plotkin, Joshua L; Francardo, Veronica et al. (2015) M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia. Neuron 88:762-73
Kistemaker, Loes E M; van Os, Ronald P; Dethmers-Ausema, Albertina et al. (2015) Muscarinic M3 receptors on structural cells regulate cigarette smoke-induced neutrophilic airway inflammation in mice. Am J Physiol Lung Cell Mol Physiol 308:L96-103
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Gericke, Adrian; Steege, Andreas; Manicam, Caroline et al. (2014) Role of the M3 muscarinic acetylcholine receptor subtype in murine ophthalmic arteries after endothelial removal. Invest Ophthalmol Vis Sci 55:625-31
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