GUO-DISSERTATION-2022.pdf (11.7 MB)
Lateral Habenula Astrocyte Activation in Paclitaxel-Induced Peripheral Neuropathy
thesis
posted on 2022-08-01, 00:00 authored by Xiao GuoThe painful neuropathy induced by paclitaxel (PIPN) significantly impacts the quality of life for cancer
patients and may lead to the cessation of the chemotherapy and poor clinical outcomes. The importance
of spinal glia pathophysiology to the etiology of chronic pain has been investigated in multiple pain
models; however, less is understood regarding its regulation at the supraspinal level. The lateral
habenula (LHb), which is responsible for coding aversion signals, has emerged as a key region of pain
signal processing. Whether activated astrocytes in LHb are responsible for pain signaling is not yet
understood. In the current study, we investigated the astrocyte activation in LHb, evoked
hypersensitivity, spontaneous pain and comorbid anxiety-like behaviors in a mouse model of PIPN.
We first demonstrated the existence of astrocyte activation in LHb during the late phase of PIPN, as
indicated by the enhanced immunoreactivity of GFAP and cellular hypertrophy. We then inhibited LHb
astrocyte activation by microinjections of L-a-aminoadipic acid (L-a-AA), an astrocyte-specific
cellular toxin. L-a-AA selectively attenuated the spontaneous pain but not the evoked hyperalgesia in a
lateralized manner, supporting the hypothesis that the activated astrocytes contribute differently to
sensory and affective pain in PIPN. Furthermore, we induced PIPN-like behaviors in naive mice by
transplantation of activated astrocytes treated by paclitaxel and by in vivo chemogenetic activation of
astrocytes through AAV-GFAP-hM3Dq. Taken together, our results showed the contributions of
astrocyte activation in LHb to the development of pain and associated affective changes and its
unilateral regulation of spontaneous pain, deepening our understanding of the functional asymmetry of
LHb.
History
Advisor
Wang, Zaijie JimChair
Wang, Zaijie JimDepartment
Pharmaceutical ScienceDegree Grantor
University of Illinois at ChicagoDegree Level
- Doctoral
Degree name
PhD, Doctor of PhilosophyCommittee Member
Lee, Seung Young Glover, Elizabeth Park, Thomas Rasenick, MarkSubmitted date
August 2022Thesis type
application/pdfLanguage
- en