Dissertation
LJA5: a novel population of pain and itch suppressing brainstem neurons
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2021
DOI: 10.17077/etd.005802
Abstract
Chronic pain and itch afflict millions of patients, and current treatments are largely ineffective. The neural control of pain and itch are not fully elucidated, and this limits the development of therapies targeting the underlying neural circuitry. Sensory information is transmitted from peripheral nerves, to the spinal cord, and up to the brain (“bottom up” pathway), but may be modulated by “top-down” projections from the brain to the spinal cord. However, the neurons mediating top-down inhibition of pain are not fully elucidated, nor has any such pathway been identified for itch sensation.
Here we identify a novel population of GABAergic neurons in the ventral brainstem, distinguished by prodynorphin expression. We named the neurons LJA5 to describe their location in the lateral pons, juxta the A5 cell group. LJA5 neurons provides the only known inhibitory projection to the spinal cord selectively targeting lamina I, which exclusively transmits pain, temperature, and itch information up to the brain. Through this work, we sought to investigate the role of LJA5 neurons in sensation.
The first set up experiments were designed to more fully characterize LJA5 neurons. We first identified the gene expression pattern in mouse, and then we looked to identify these neurons in human brains. We then fully explored the input and output connections of LJA5 neurons in mouse using anterograde and retrograde tracers. These neurons demonstrate the first inhibitory projection specifically targeting lamina I of the spinal cord. This finding, along with projections to other sensory regions in the brainstem, suggested that LJA5 neurons directly inhibit noxious sensory information. Furthermore, we show that LJA5 neurons receive input from forebrain structures implicated in stress and sensory detection.In the second set of experiments, we tested the function of LJA5 neurons through chemogenetic activation during behavioral tests. We knew that LJA5 neurons projected to many known sensory regions including lamina I of the spinal cord, so we hypothesized that LJA5 neurons could modulate itch, pain, or temperature sensations. Chemogenetically activating LJA5 neurons reduced capsaicin-induced pain and histamine-induced itch.
Together, our findings identify and characterize a novel nucleus in the brainstem with the first described inhibitory projection specifically targeting lamina I of the spinal cord. Additionally, this is the first identified descending projection that reduces both pain and itch. This new top-down pathway updates current sensory models and opens new treatment opportunities for refractory pain and pruritis.
Details
- Title: Subtitle
- LJA5: a novel population of pain and itch suppressing brainstem neurons
- Creators
- Lindsay J Agostinelli
- Contributors
- Alexander G Bassuk (Advisor)Marco Hefti (Committee Member)Yuriy Usachev (Committee Member)Joseph Glykys (Committee Member)Martin Cassell (Committee Member)Polly Ferguson (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Neuroscience
- Date degree season
- Spring 2021
- DOI
- 10.17077/etd.005802
- Publisher
- University of Iowa
- Number of pages
- xiii, 110 pages
- Copyright
- Copyright 2021 Lindsay J. Agostinelli
- Comment
- This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: https://www.lib.uiowa.edu/sc/contact/
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 100-110)
- Public Abstract (ETD)
Chronic pain and itch afflict millions of patients, and current treatments are largely ineffective. The neural control of pain and itch are not fully understood, and this limits the development of therapies targeting the underlying neural circuitry. Pain and itch sensory information are transmitted from the skin to the spinal cord and up to the brain (the bottom-up pathway), but how the brain controls pain and itch in a top-down fashion remains unknown. However, we recently discovered a group of neurons (named LJA5) with the only known inhibitory projection from the brain specifically to the sensory region of the spinal cord (lamina I). We investigated the expression pattern of these dynorphinergic LJA5 neurons in both mouse and human brains. Chemogenetic activation of these neurons reduces both pain and itch sensation. Identification of this new top-down pathway opens new treatment opportunities for chronic, refractory pain and itch.
- Academic Unit
- Interdisciplinary Graduate Program in Neuroscience
- Record Identifier
- 9984097168702771
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