Cerebellar modulation of anxiety: serotonergic involvement examined via a new 5-HT sensor
Cerebellar involvement in anxiety and anxiety-related behavior is supported by numerous clinical and animal studies (Behav. Brain Res. 112:107). Because the neuromodulator serotonin (5-HT) is well-known to play a role in anxiety (Nature 537:97) and serotonergic axons are amongst the most abundant fi...
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sg-ntu-dr.10356-1620632022-11-17T06:00:40Z Cerebellar modulation of anxiety: serotonergic involvement examined via a new 5-HT sensor Chin, Pei Wern Wan, Jinxia Li, Yulong Augustine, George James Interdisciplinary Graduate School (IGS) Lee Kong Chian School of Medicine (LKCMedicine) Neuroscience 2022 School of Life Sciences, Peking University PKU-IDG/McGovern Inst. for Brain Res, Peking University Peking-Tsinghua Ctr. for Life Sciences, Acad. for Advanced Interdisciplinary Studies, Peking University Chinese Institute for Brain Research (CIBR) Science::Biological sciences::Zoology::Animal behavior Science::Medicine::Biosensors Cerebellum Anxiety Serotonin Cerebellar involvement in anxiety and anxiety-related behavior is supported by numerous clinical and animal studies (Behav. Brain Res. 112:107). Because the neuromodulator serotonin (5-HT) is well-known to play a role in anxiety (Nature 537:97) and serotonergic axons are amongst the most abundant fibers in the cerebellar cortex (Neuroscience 462:106), we determined whether cerebellar 5-HT is involved in anxiety. We first identified a locus for anxiety within the mouse cerebellum. We found that photostimulation of lobule VII in transgenic mice expressing channelrhodopsin in molecular layer interneurons (Cell Rep. 7:1601) caused a 67% decrease in time spent in the open quadrants of an elevated-zero maze (EZM; n = 8), indicating an anxiogenic effect. This is consistent with a previous observation that inhibiting lobule VII interneurons decreases anxiety (eLife 7: e36401) and indicates that lobule VII output is important for anxiety. To measure 5-HT levels in lobule VII, we expressed a novel fluorescent 5-HT indicator (GRAB5HT2h) with improved sensitivity to 5-HT compared to previous sensors (Nat. Neurosci. 24:746). GRAB5HT2h fiber photometry revealed higher 5-HT levels when mice were in open quadrants of the EZM, compared to the closed quadrants, indicating that 5-HT is higher during a low-anxiety state. To determine whether 5-HT levels affect anxiety, we optogenetically controlled the activity of serotonergic axons in lobule VII of a transgenic mouse line expressing channelrhodopsin or archaerhodopsin in serotonergic neurons (PNAS 102:16472). Photostimulation of 5-HT fibers caused a 106% increase in the amount of time spent in open quadrants of the EZM (n = 8), indicating an anxiolytic effect. Conversely, photoinhibition of 5-HT fibers produced an 81% decrease in the time spent in the open quadrants (n = 4), indicating an anxiogenic effect. Collectively, these results support the hypothesis that 5-HT levels in cerebellar lobule VII regulate anxiety, with higher 5-HT reducing anxiety. Ministry of Education (MOE) Grant/Other Support: : Ministry of Education, Singapore, MOE AcRF Tier 3 Award MOE2017-T3-1-002, MOE AcRF Tier 2 Award MOE2016-T2-1-097 and Interdisciplinary Graduate School bench fees. 2022-11-17T06:00:40Z 2022-11-17T06:00:40Z 2022 Conference Paper Chin, P. W., Wan, J., Li, Y. & Augustine, G. J. (2022). Cerebellar modulation of anxiety: serotonergic involvement examined via a new 5-HT sensor. Neuroscience 2022. https://hdl.handle.net/10356/162063 en MOE2017-T3-1-002 MOE2016-T2-1-097 © 2022 Society for Neuroscience. All rights reserved. |
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Science::Biological sciences::Zoology::Animal behavior Science::Medicine::Biosensors Cerebellum Anxiety Serotonin Chin, Pei Wern Wan, Jinxia Li, Yulong Augustine, George James Cerebellar modulation of anxiety: serotonergic involvement examined via a new 5-HT sensor |
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Cerebellar involvement in anxiety and anxiety-related behavior is supported by numerous clinical and animal studies (Behav. Brain Res. 112:107). Because the neuromodulator serotonin (5-HT) is well-known to play a role in anxiety (Nature 537:97) and serotonergic axons are amongst the most abundant fibers in the cerebellar cortex (Neuroscience 462:106), we determined whether cerebellar 5-HT is involved in anxiety. We first identified a locus for anxiety within the mouse cerebellum. We found that photostimulation of lobule VII in transgenic mice expressing channelrhodopsin in molecular layer interneurons (Cell Rep. 7:1601) caused a 67% decrease in time spent in the open quadrants of an elevated-zero maze (EZM; n = 8), indicating an anxiogenic effect. This is consistent with a previous observation that inhibiting lobule VII interneurons decreases anxiety (eLife 7: e36401) and indicates that lobule VII output is important for anxiety. To measure 5-HT levels in lobule VII, we expressed a novel fluorescent 5-HT indicator (GRAB5HT2h) with improved sensitivity to 5-HT compared to previous sensors (Nat. Neurosci. 24:746). GRAB5HT2h fiber photometry revealed higher 5-HT levels when mice were in open quadrants of the EZM, compared to the closed quadrants, indicating that 5-HT is higher during a low-anxiety state. To determine whether 5-HT levels affect anxiety, we optogenetically controlled the activity of serotonergic axons in lobule VII of a transgenic mouse line expressing channelrhodopsin or archaerhodopsin in serotonergic neurons (PNAS 102:16472). Photostimulation of 5-HT fibers caused a 106% increase in the amount of time spent in open quadrants of the EZM (n = 8), indicating an anxiolytic effect. Conversely, photoinhibition of 5-HT fibers produced an 81% decrease in the time spent in the open quadrants (n = 4), indicating an anxiogenic effect. Collectively, these results support the hypothesis that 5-HT levels in cerebellar lobule VII regulate anxiety, with higher 5-HT reducing anxiety. |
author2 |
Interdisciplinary Graduate School (IGS) |
author_facet |
Interdisciplinary Graduate School (IGS) Chin, Pei Wern Wan, Jinxia Li, Yulong Augustine, George James |
format |
Conference or Workshop Item |
author |
Chin, Pei Wern Wan, Jinxia Li, Yulong Augustine, George James |
author_sort |
Chin, Pei Wern |
title |
Cerebellar modulation of anxiety: serotonergic involvement examined via a new 5-HT sensor |
title_short |
Cerebellar modulation of anxiety: serotonergic involvement examined via a new 5-HT sensor |
title_full |
Cerebellar modulation of anxiety: serotonergic involvement examined via a new 5-HT sensor |
title_fullStr |
Cerebellar modulation of anxiety: serotonergic involvement examined via a new 5-HT sensor |
title_full_unstemmed |
Cerebellar modulation of anxiety: serotonergic involvement examined via a new 5-HT sensor |
title_sort |
cerebellar modulation of anxiety: serotonergic involvement examined via a new 5-ht sensor |
publishDate |
2022 |
url |
https://hdl.handle.net/10356/162063 |
_version_ |
1751548487535689728 |