Role of anterior insula cortex in context-induced relapse of nicotine-seeking
- Department of Pharmacology, Medical University of Innsbruck, Austria
- Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Anatomy & Neurosciences, Netherlands
- Amsterdam Neuroscience, Compulsivity Impulsivity and Attention, Netherlands
- Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit, Netherlands
- School of Psychology, University of New South Wales, Australia
Figures
Figure 1
Context-induced relapse of punished nicotine-seeking is associated with selective activation of BLA → aIC and contralateral aIC → aIC projections.
(A) Outline of the experimental procedure (n = 19 females). Mean ± standard error of the mean (SEM) active and inactive nose-pokes, and nicotine infusions, during nicotine self-administration in context A (B), punishment in context B (C), and the context-induced nicotine-relapse test in context B or A (D). (E) Representative plots of the spread of CTb injections for the three groups. (F) Representative images of CTb injection in aIC, and CTb + Fos in BLA. Data are mean ± SEM number of Fos or CTb neurons per mm2, and percentage Ctb + Fos neurons, in the IC hemisphere ipsilateral to CTb injection (G), insular cortex (IC) hemisphere contralateral to the CTb injection (H), or BLA ipsilateral to the CTb injection (I). *p < 0.05; aIC, anterior insula cortex; mIC, middle insula cortex; pIC, posterior insula cortex; BLA, basolateral amygdala; FR, fixed-ratio.
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Figure 1—source data 1
Figure 1 - raw data.
- https://cdn.elifesciences.org/articles/75609/elife-75609-fig1-data1-v2.xlsx
Figure 2 with 2 supplements
Photometry reveals nicotine and punishment-associated activity in anterior insula cortex (aIC).
(A) Outline of the experimental procedure (n = 7 female). (B) Representative images of jGCaMP7f expression and fiber implant in aIC. Mean ± standard error of the mean (SEM) nicotine infusions, inactive nose-pokes, and nonreinforced active nose-pokes during nicotine self-administration in context A (C), punishment in context B (D), and the context-induced nicotine-seeking tests (E). (F) Ca2+ traces around the nose-poke in aIC self-administration in context A (Reinforced active [Nic]: n = 751; Nonreinforced active: n = 838; Inactive: n = 588). (G) Ca2+ traces around the nose-poke in aIC during punishment in context B (Reinforced active [Nic]: n = 89; Nonreinforced active: n = 366; Inactive: n = 318; Punish: n = 137). (H) Ca2+ traces around the nose-poke in aIC during context-induced relapse test in context A (Active + Nic CS: n = 95; Active nonreinforced: n = 187; Inactive: n = 80). For all photometry traces, bars at bottom of graph indicate significant deviations from baseline (dF/F ≠ 0), or significant differences between the specific events (Nicotine infusion, nonreinforced active nose-poke, inactive nose-poke, Punishment, or Nicotine CS), determined via bootstrapped confidence intervals (95% CIs), and permutation tests with alpha 0.008 and 0.01 for comparisons between punishment sessions, and self-administration and tests, respectively. Vertical dashed line indicates nose-poke, horizontal line indicates baseline (dF/F = 0).
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Figure 2—source data 1
Figure 2 - raw data and statistical outputs.
- https://cdn.elifesciences.org/articles/75609/elife-75609-fig2-data1-v2.xlsx
Figure 2—figure supplement 1
Additional photometry analysis across phases.
(A) Ca2+ traces around the nose-poke in anterior insula cortex (aIC) self-administration during FR1 (left; Reinforced active [Nic]: n = 213, Inactive: n = 151), FR2 (middle; Reinforced active [Nic]: n = 156; Nonreinforced active: n = 150; Inactive: n = 114), and FR3 (right; Reinforced active [Nic]: n = 382; Nonreinforced active: n = 685; Inactive: n = 323). (B) Ca2+ traces around the nose-poke in aIC during the first punishment session (Reinforced active [Nic]: n = 17; Nonreinforced active: n = 85; Inactive: n = 54; Punish: n = 25). (C) Ca2+ traces around the nose-poke in aIC during context-induced relapse test in context A during test day 1 (left; Reinforced active [Nic]: n = 42; Nonreinforced active: n = 88; Inactive: n = 40) and test day 2 (right; Reinforced active [Nic]: n = 53; Nonreinforced active: n = 99; Inactive: n = 40). For all photometry traces, bars at bottom of graph indicate significant deviations from baseline (dF/F ≠ 0) determined via bootstrapped confidence intervals (95% CI), or significant differences between the specific events (Nicotine infusion, nonreinforced active nose-poke, inactive nose-poke, Punishment, or Nicotine CS), determined by permutation tests with alpha 0.008 and 0.01 for comparisons between punishment sessions, and self-administration and tests, respectively. Vertical dashed line indicates nose-poke, horizontal line indicates baseline (z-dF/F=0).
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Figure 2—figure supplement 1—source data 1
Figure 2 - figure supplement 1 statistical outputs.
- https://cdn.elifesciences.org/articles/75609/elife-75609-fig2-figsupp1-data1-v2.xlsx
Figure 2—figure supplement 2
Mean df/f analysis of the photometry data.
(A) Mean df/f for the different response types during nicotine self-administration. (B) Mean df/f for the different response types during nicotine punishment. (C) Mean df/f for the different response types during the context-induced relapse tests in context A. *p < 0.05; **p < 0.01.
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Figure 2—figure supplement 2—source data 1
Figure 2 - figure supplement 2 raw data.
- https://cdn.elifesciences.org/articles/75609/elife-75609-fig2-figsupp2-data1-v2.xlsx
Figure 3
Validation of chemogenetic inhibition of anterior insula cortex (aIC) neurons expressing hM4Di by clozapine.
(A) The virus injection location. (B) Example trace of inward current demonstrating clear clozapine-induced hyperpolarization of the hM4Di expressing neurons. (C) The average hyperpolarization induced by clozapine for the n = 6 neurons recorded (left) and the mean hyperpolarization (right) for these neurons.
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Figure 3—source data 1
Figure 3 - raw data.
- https://cdn.elifesciences.org/articles/75609/elife-75609-fig3-data1-v2.xlsx
Figure 4 with 1 supplement
Effect of chemogenetic inhibition of anterior insula cortex (aIC) on context-induced relapse of punished nicotine-seeking.
(A) Outline of the experimental procedure (n = 15 females, 13 males). (B) Mean ± standard error of the mean (SEM) nicotine infusions, active, inactive nose-pokes during nicotine self-administration in context A. (C) Mean ± SEM nicotine infusions, active, inactive nose-pokes during punishment in context B. (D) Mean ± SEM nose-pokes during the context-induced relapse tests. Individual data also plotted, triangles = female, circles = male. (E) Representative plots of the spread of GFP (left) and hM4Di (middle) in aIC of rats in experiment 4. Right top shows an example section of a rat showing GFP expression in aIC, and right bottom shows an example of hM4Di expression. *p < 0.05; CLZ, clozapine; FR, fixed-ratio.
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Figure 4—source data 1
Figure 4 - raw data.
- https://cdn.elifesciences.org/articles/75609/elife-75609-fig4-data1-v2.xlsx
Figure 4—figure supplement 1
Effect of chemogenetic inhibition of anterior insula cortex (aIC) on latency to the first nose-poke during context-induced relapse tests.
Mean ± standard error of the mean (SEM) time (in seconds) for the first response to be made both the active and inactive nose-pokes during the test sessions of experiment 4. (A) Test in the punishment context (context B); (B) test in the nicotine context (context A).
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Figure 4—figure supplement 1—source data 1
Figure 4 - figure supplement 1 raw data.
- https://cdn.elifesciences.org/articles/75609/elife-75609-fig4-figsupp1-data1-v2.xlsx
Figure 5 with 1 supplement
Effect of chemogenetic inhibition of anterior insula cortex (aIC) on context-induced relapse of extinguished nicotine-seeking.
(A) Outline of the experimental procedure (n = 18 females, 13 males). (B) Mean ± standard error of the mean (SEM) nicotine infusions, active, inactive nose-pokes during nicotine self-administration in context A. (C) Mean ± SEM active, inactive nose-pokes during extinction in context B. (D) Mean ± SEM nose-pokes during the context-induced relapse tests. Individual data also plotted, triangles = female, circles = male. (E) Representative plots of the spread of GFP (left) and hM4Di (middle) in aIC of rats in experiment 5. Right top shows an example section of a rat showing GFP expression in aIC, and right bottom shows an example of hM4Di expression. CLZ, clozapine; FR, fixed-ratio.
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Figure 5—source data 1
Figure 5 - raw data.
- https://cdn.elifesciences.org/articles/75609/elife-75609-fig5-data1-v2.xlsx
Figure 5—figure supplement 1
Effect of chemogenetic inhibition of anterior insula cortex (aIC) on latency to the first nose-poke during context-induced relapse tests.
Mean ± standard error of the mean (SEM) time (in seconds) for the first response to be made both the active and inactive nose-pokes during the test sessions of experiment 5. (A) Test in the extinction context (context B); (B) test in the nicotine context (context A).
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Figure 5—figure supplement 1—source data 1
Figure 5 - figure supplement 1 raw data.
- https://cdn.elifesciences.org/articles/75609/elife-75609-fig5-figsupp1-data1-v2.xlsx
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Role of anterior insula cortex in context-induced relapse of nicotine-seeking
eLife 11:e75609.
https://doi.org/10.7554/eLife.75609
