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Research ArticleNew Research, Cognition and Behavior

Anterior Cingulate Cortex Contributes to Alcohol Withdrawal- Induced and Socially Transferred Hyperalgesia

Monique L. Smith, Andre. T. Walcott, Mary M. Heinricher and Andrey E. Ryabinin
eNeuro 24 July 2017, 4 (4) ENEURO.0087-17.2017; https://doi.org/10.1523/ENEURO.0087-17.2017
Monique L. Smith
1Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239
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Andre. T. Walcott
1Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239
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Mary M. Heinricher
1Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239
2Department of Neurological Surgery, Oregon Health & Science University, OR 97239
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Andrey E. Ryabinin
1Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239
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    Figure 1.

    Differentially enhanced Fos in primary and bystander mice. A, Timeline of data collection. Blue bar represents bystander and control mice, black bar represents primary mice, with corresponding EtOH concentration at different times (% v/v); VF and orange arrows represent von Frey testing at the end of the WD period. B, Primary (n = 6) and bystander (n = 6) mice demonstrate significant decreases in mechanical thresholds compared to separately housed controls (n = 7; F(2,16) = 9.68, p = 0.002). Fos-positive cell counts in three brain regions revealed significant differences among groups, the ACC (C; bregma 1.1-0.5), INS (D; bregma 1.1-0.5), and the DMH (E; bregma -1.4 to -0.94). Brain regions are shown schematically in the top left of each panel, with representative photomicrographs of each treatment group in corresponding order on the right (bystander, black bar/top right; primary, white bar/middle right; control, striped bar/bottom right; scale bar, 100 μm). Bystander mice displayed an increase in the number of c-Fos cells in the ACC (F(2,14) = 4.8, p = 0.026), and in INS (F(2,15) = 3.8, p = 0.046) compared to the controls. By contrast, the primary group displayed enhanced Fos-ir in the DMH (F(2,16) = 4.8, p = 0.007). *p < 0.05 compared to the control group based on Fishers LSD.

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    Figure 2.

    Inhibition of ACC, but not somatosensory cortex reverses hyperalgesia in primary and bystander mice. A, Timeline of data collection and experimental manipulation: Sfx refers to surgery, which took place 7-14 d before beginning of experiments. Blue bar represents bystander and control mice, black bar represents primary mice, with corresponding EtOH % (v/v); VF and orange arrows represent von Frey testing at end of 24-h abstinence; WD represents withdrawal from alcohol; black syringe represents CNO injection (20 min before the second mechanical test). B, C, Overlapping pattern of viral expression (blue) for each treatment group in the ACC and SI. Representative photomicrographs of hM4Di viral expression, within the (D) ACC (orange) with DAPI in blue (E) SI (orange) and DAPI in blue. Left panels: scale bars, 100 μm; right panels: scale bars, 20 μm. F, Animals in which DREADDs were expressed in ACC and given Veh (n = 5, primary; n = 5, bystander) showed a significant decrease in threshold compared to Veh-treated separately housed control animals (n = 8). By contrast, animals given CNO before testing (n = 6, primary; n = 6, bystander) showed no hyperalgesia compared to CNO-treated controls (n = 6). According to ANOVA, this led to a significant difference of treatment (F(1,30) = 4.79, p = 0.037), as well as a significant interaction (F(2,30) = 3.37, p = 0.048). CNO groups were no longer significantly different from separately housed controls according to Fishers LSD. G, Bystander (n = 5-7/group) and primary (n = 6/group) mice bilaterally transfected with the hM4Di DREADD virus in SI demonstrated significant decreases in mechanical thresholds on the second WD session compared to separately housed controls (n = 5-6), leading to significant differences between groups (F(2,29) = 14.88, p < 0.0001), but no significant effects of CNO treatment or an interaction, indicating that inactivation of SI had no effect on hypersensitivity. Mean basal responses of all groups represented by dotted line (—). *p < 0.05 compared to controls receiving the same treatment, according to Fishers LSD.

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    Table 1.

    Statistical analyses

    Data structureType of testCIData structureType of testCI
    Table 2, row 1; Fig. 1CAutomated quantification of Fos+ cells in CG1 from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA with significant main effect of group followed by Fishers LSD n = 5-7 *p < 0.05CTRL: (119.9-193.3) primary: (147.1-294.4) bystander: (195.9-308.0) Table 2, row 14Manual quantification of Fos+ cells in posteromedial cortical amygdaloid from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-6 p > 0.05CTRL: (5.040-14.10) primary: (4.533-10.61) bystander: (7.170-10.27)
    Table 2, row 2Automated quantification of Fos+ cells in CG2 from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-7 p > 0.05CTRL: (62.64-86.59) primary: (23.61-126.7) bystander: 41.03-113.6) Table 2, row 15Manual quantification of Fos+ cells in basolateral amygdala from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-6 p > 0.05CTRL: (6.156-19.07) primary: (5.469-18.79) bystander: (5.186-30.38)
    Table 2, row 3Automated quantification of Fos+ cells in GI from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-7 p > 0.05CTRL: (12.35-25.82) primary: (16.69-30.81) bystander: (8.518-40.40) Table 2, row 16Manual quantification of Fos+ cells in central nucleus of the amygdala from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-6 p > 0.05CTRL: (5.992-12.13) primary: (2.869-8.797) bystander: (3.828-16.21)
    Table 2, row 4; Fig. 1DAutomated quantification of Fos+ cells in INS from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA with significant main effect of group followed by Fishers LSD n = 5-6 *p < 0.05CTRL: (25.97-45.22) primary: (27.64-74.08) bystander: (29.72-116.3) Table 2, row 17Manual quantification of Fos+ cells in paraventricular nucleus from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-6 p > 0.05CTRL: (1.755-8.645) primary: (7.872-12.30) bystander: (0.972-25.83)
    Table 2, row 5Automated quantification of Fos+ cells in S1 from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-6 p > 0.05CTRL: (432.5-651.8) primary: (191.4-1128) bystander: (262.4-636.9) Table 2, row 18Quantification of Fos+ cells in the DMH from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA with significant main effect followed by Fishers LSD n = 6-7 **p = 0.007CTRL: (10.64-21.66) primary: (17.37-43.81) bystander: (15.25-26.22)
    Table 2, row 6Manual quantification of Fos+ cells in dorsal lateral septum from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-6 p > 0.05CTRL: (3.120-10.67) primary: (1.763-12.15) bystander: (3.195-9.805) Table 2, row 19Manual quantification of Fos+ cells in the centrally projecting Edinger Westphal from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-6 p > 0.05CTRL: (4.866-11.11) primary: (4.261-20.06) bystander: (6.974-15.78)
    Table 2, row 7Manual quantification of Fos+ cells in intermediate lateral septum from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-6 p > 0.05CTRL: (18.13-29.51) primary: (12.99-25.89) bystander: (20.04-27.38) Table 2, row 20Manual quantification of Fos+ cells in periaqueductal gray from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-6 p > 0.05CTRL: (27.73-62.22) primary: (30.75-129.2) bystander: (42.31-85.50)
    Table 2, row 8Manual quantification of Fos+ cells in ventral lateral septum from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-6 p > 0.05CTRL: (11.23-16.07) primary: (5.770-22.95) bystander: (5.559-18.98) Table 2, row 21Manual quantification of Fos+ cells in substantia nigra from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-6 p > 0.05CTRL: (-0.945-10.30) primary: (1.372-14.46) bystander: (2.184-10.03)
    Table 2, row 9Manual quantification of Fos+ cells in nucleus accumbens from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-6 p > 0.05CTRL: (5.400-37.91) primary: (10.44-41.08) bystander: (15.03-31.01) Table 2, row 22Manual quantification of Fos+ cells in ventral tegmental Area from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-6 p > 0.05CTRL: (-1.562-8.729) primary: (-4.473-20.07) bystander: (-9.419-31.42)
    Table 2, row 10Manual quantification of Fos+ cells in anterior bed nucleus of the stria terminalis from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-6 p > 0.05CTRL: (25.51-36.28) primary: (19.48-76.52) bystander: (25.76-52.53) Fig. 1BComparison of mechanical thresholds of each group over 3 test sessionsTwo-way RM ANOVA, significant for test session n = 6-7 *p < 0.05CTRL: (1.521-2.143) primary: (-0.255-2.787) bystander: (0.031-2.950)
    Table 2, row 11Manual quantification of Fos+ cells in posterior bed nucleus of the stria terminalis from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-6 p > 0.05CTRL: (-1.066-17.96) primary: (0.4374-5.382) bystander: (1.829-7.948) Fig. 2FComparison of mechanical thresholds of each group following treatment with Veh or CNO on the second test session (inhibition of the ACC)Two-way ANOVA, significant main effect of treatment and significant interaction followed by Fishers LSD n = 5-7 *p < 0.05CTRL/Veh: (0.76-1.68) CTRL/CNO: (0.70-1.54) bystander/VEH: (0.31-0.76) bystander/CNO: (0.39-1.85) primary/Veh: (0.16-0.65) primary/CNO:(0.36-2.14)
    Table 2, row 12Manual quantification of Fos+ cells in dentate gyrus from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-6 p > 0.05CTRL: (24.09-29.40) primary: (22.46-55.44) bystander: (28.60-38.16) Fig. 2GComparison of mechanical thresholds of each group following treatment with Veh or CNO on the second test session (inhibition of S1)Two-way ANOVA, significant main effect of group, no interaction n = 5-7 *p < 0.0001CTRL/Veh: (-7.73-11.46) CTRL/CNO: (0.368-2.32) bystander/VEH: (-0.088-1.23) bystander/CNO: (-4.63-6.18) primary/Veh: (-0.62-1.91) primary/CNO:(-0.80-3.36)
    Table 2, row 13Manual quantification of Fos+ cells in posterolateral cortical amygdaloid from two separate reactions. Counts were averaged between the 2 runs, with 2-4 slices for each region per mouse per batch (average of 4-8 slices per mouse)One-way ANOVA n = 5-6 p > 0.05CTRL: (18.99-30.39) primary: (8.949-25.65) bystander: (13.75-19.45)
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    Table 2.

    Fos-ir in primary and bystander mice

    Brain areaControlPrimaryBystanderANOVA
    Anterior cingulate (CG1)156.6 ± 14.28220.8 ± 28.66251.9 ± 20.18*F(2,14) = 4.77
    Anterior cingulate (CG2)73.56 ± 5.6575.14 ± 20.0577.33 ± 14.12F(2,15) = 0.017
    GranularInsula (GI)19.08 ± 2.75223.89 ± 2.69524.46 ± 6.201F(2,16) = 0.547
    Agranular insula (INS)36.1 ± 3.7350.86 ± 9.03273.02 ± 15.59*F(2,15) = 3.779
    Somatosensory542.1 ± 44.79659.8 ± 168.7449.6 ± 76.52F(2,16) = 1.147
    Dorsal lateral septum6.893 ± 1.5426.958 ± 2.0216.5 ± 1.351F(2,17) = 0.023
    Intermediate lateral septum23.82 ± 2.32623.71 ± 1.42919.44 ± 2.637F(2,17) = 1.250
    Ventral lateral septum13.65 ± 0.99114.36 ± 3.34212.27 ± 2.743F(2,17) = 0.183
    Nucleus accumbens21.65 ± 6.32325.76 ± 5.95923.02 ± 3.265F(2,16) = 0.155
    Bed nucleus of the stria terminalis (anterior)30.89 ± 2.248 ± 11.139.14 ± 5.47F(2,17) = 1.561
    Bed nucleus of the stria terminalis (posterior)20.53 ± 8.44425.45 ± 2.9123.33 ± 4.889F(2,15) = 1.472
    Dentate gyrus36.19 ± 5.33739.14 ± 6.74431.27 ± 6.609F(2,17) = 0.4011
    Posterolateral cortical amygdaloid24.69 ± 2.32817.3 ± 3.41216.6 ± 1.027F(2,16) = 2.845
    Posteromedial cortical amygdaloid9.571 ± 1.8527.571 ± 1.2428.722 ± 0.604F(2,17) = 0.5452
    Basolateral amygdala12.61 ± 12.6112.13 ± 2.59217.78 ± 4.901F(2,15) = 0.7956
    Central nucleus of the amygdala9.063 ± 1.1945.833 ± 1.15310.02 ± 2.409F(2,15) = 1.687
    Paraventricular nucleus3.4 ± 0.7511.17 ± 3.5512.13 ± 3.29F(2,12) = 2.584
    Dorsal medial hypothalamus16.15 ± 2.25130.59 ± 5.143**20.73 ± 2.242F(2,16) = 4.842
    Centrally projecting Edinger Westphal7.988 ± 1.27612.16 ± 3.07311.38 ± 1.799F(2,17) = 1.150
    Periaqueductal gray44.98 ± 7.04979.96 ± 19.1463.9 ± 8.827F(2,17) = 2.073
    Substantia nigra4.679 ± 2.2987.917 ± 2.5466.107 ± 1.603F(2,17) = 0.5495
    Ventral tegmental area2.93 ± 1.024.88 ± 2.549.43 ± 4.66F(2,15) = 1.115
    • Mean (±SEM) c-Fos-positive cell counts for experimental each group per brain area examined. ANOVA values are presented in the right column, with significant main effects of group in bold. *p < 0.05 contrast to controls, Fishers LSD.

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Anterior Cingulate Cortex Contributes to Alcohol Withdrawal- Induced and Socially Transferred Hyperalgesia
Monique L. Smith, Andre. T. Walcott, Mary M. Heinricher, Andrey E. Ryabinin
eNeuro 24 July 2017, 4 (4) ENEURO.0087-17.2017; DOI: 10.1523/ENEURO.0087-17.2017

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Anterior Cingulate Cortex Contributes to Alcohol Withdrawal- Induced and Socially Transferred Hyperalgesia
Monique L. Smith, Andre. T. Walcott, Mary M. Heinricher, Andrey E. Ryabinin
eNeuro 24 July 2017, 4 (4) ENEURO.0087-17.2017; DOI: 10.1523/ENEURO.0087-17.2017
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