[Not] lost in translation : optogenetic and chemogenetic control of sensory circuits
Abstract/Contents
- Abstract
- This dissertation has two purposes: 1. To increase our ability to control the neural circuits that control pain perception, ideally in a way that can be applied to treat people with chronic pain disorders. 2. To improve our understanding of the spinal circuits required to process mechanical, thermal, and itch-related stimuli. Towards these ends, we performed three primary studies: 1. We initially asked whether optogenetic techniques (at the time used primarily in the brain) could be used to control peripheral pain circuits. We developed viral methods to specifically express stimulatory and inhibitory opsins in unmyelinated primary afferent neurons, and characterized the resulting transduction profile. We found that transdermal illumination could be used to non-invasively stimulate or inhibit pain perception. While blue light resulted in marked pain-related behavior in mice expressing channelrhodopsin-2 (ChR2), yellow light resulted in effective pain-suppression in mice expressing halorhodopsin (NpHR). Importantly pain inhibition could be maintained in mouse models of neuropathic pain --- pain thresholds under illumination could be restored to pre-injury levels. In a follow-up to this study, we found that optogenetically evoked pain-responses could be used to analyze analgesic drug efficacy. 2. In a second study, we addressed a major limitation of the first study --- that it enabled optogenetic inhibition of pain only through constant illumination, a major translational limitation. We devised two complementary strategies for sustained inhibition of pain perception over hour-long periods. In the first, we exploited innovations in opsin engineering to show that the step-function inhibitory channelrhodopsin (SwiChR), if expressed in primary afferent nociceptors, enabled long-term inhibition of pain perception with temporally sparse illumination. In the second, we expressed the inhibitory Gi coupled hM4D receptor in primary afferent neurons, and showed that activation of this designer receptor (DREADD) resulted in significant inhibition of pain thresholds. 3. Finally, we exploited innovations in light-delivery systems for optogenetic control of the spinal cord to examine the role of an excitatory interneuron population (somatostatin+ neurons) in mediating sensory perception. Using a combination of optogenetics, chemogenetics, and anatomical tracing, we examined the consequences of reversible bidirectional control over somatostatin+ interneurons, and identified a novel interaction between somatostatin+ neuron activity and itch-related behavior.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2016 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Iyer, Shrivats Mohan |
|---|---|
| Associated with | Stanford University, Department of Bioengineering. |
| Primary advisor | Delp, Scott |
| Thesis advisor | Delp, Scott |
| Thesis advisor | Clark, David |
| Thesis advisor | Deisseroth, Karl |
| Advisor | Clark, David |
| Advisor | Deisseroth, Karl |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Shrivats Mohan Iyer. |
|---|---|
| Note | Submitted to the Department of Bioengineering. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2016. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2016 by Shrivats Mohan Iyer
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