Cytotoxic chemotherapy-induced side effects, including nausea and vomiting, impose a severe physical and emotional burden on cancer patients, which can limit the use of dose-dense curative cancer therapy. Although the exact mechanisms for these adverse effects remain obscure, current theories suggest that vagal sensory signals from the gastrointestinal (GI) tract play a critical role. Until now, it has been impossible to test the function of defined vagal afferent population signaling in these responses to chemotherapy because peripheral neurons could not be selectively, and reversibly, silenced or activated; the optogenetic approach potentially removes this barrier. Here, we propose to use a small animal model for emesis testing (musk shrew) as a platform to assess modulation of GI vagal signaling. Unlike rodents, the musk shrew (a mouse-sized mammal) has a vomiting reflex and is an efficient alternative to ferrets, cats, and dogs for the study of chemotherapy-induced emesis. Our central hypothesis states that vagal afferent neurons can be optogenetically controlled to produce emesis or inhibit chemotherapy-induced emesis. We plan to test this hypothesis by pursuing two specific aims: (1) test the specificity of transport of viral vectors containing light-sensitive opsins, halorhodopsin (for inhibition) and channelrhodopsin-2 (for excitation) in GI vagal afferent populations; and, (2) determine the effects of optical modulation of vagal signaling on emesis. Adeno- associated viruses (AAVs) will be injected into specific stomach regions to infect vagal sub- populations. AAVs will also contain fluorescent reporters to permit the histological examination of sub- sets of nodose ganglia neurons. Specific wavelengths of light applied to AAV loaded vagal fibers will be used to stimulate and inhibit emesis (produced by chemotherapy) in our established in vivo electrophysiology preparation. These experiments will confirm the use of optogenetic methods to modulate vagal sensory transmission. The results of this project with be valuable in the control and testing of emetic mechanisms; similarly, optogenetic methods may be applied to assessing the role of vagal signaling in other diseases affecting cancer patients, including obesity, diabetes, and inflammation.
We seek to establish the use of optogenetic modulation of vagal afferent neurons to investigate the mechanisms responsible for cytotoxic chemotherapy-induced nausea and vomiting. Our work could lead to innovative strategies to make high-dose cancer chemotherapy more tolerable for patients and potentially improve treatment outcomes by permitting dose-dense curative chemotherapy.
