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Research ArticleResearch Article: New Research, Cognition and Behavior

Dorsomedial Striatum (DMS) CB1R Signaling Promotes Pavlovian Devaluation Sensitivity in Male Long Evans Rats and Reduces DMS Inhibitory Synaptic Transmission in Both Sexes

Catherine A. Stapf, Sara E. Keefer, Jessica M. McInerney, Joseph F. Cheer and Donna J. Calu
eNeuro 2 January 2025, 12 (1) ENEURO.0341-24.2024; https://doi.org/10.1523/ENEURO.0341-24.2024
Catherine A. Stapf
1Program in Neuroscience, University of Maryland Baltimore, Baltimore, Maryland 21201
2Department of Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201
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Sara E. Keefer
2Department of Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201
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Jessica M. McInerney
1Program in Neuroscience, University of Maryland Baltimore, Baltimore, Maryland 21201
2Department of Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201
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Joseph F. Cheer
1Program in Neuroscience, University of Maryland Baltimore, Baltimore, Maryland 21201
2Department of Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201
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Donna J. Calu
1Program in Neuroscience, University of Maryland Baltimore, Baltimore, Maryland 21201
2Department of Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201
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  • Figure 1.
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    Figure 1.

    Acquisition of a pavlovian conditioned approach differs by tracking and sex. A, PavCA index (mean ± SEM) split by ST and GT/INT groups (collapsed on sex). *Main effect of session. %Significant session × tracking interaction. B, PavCA index (mean ± SEM) split by male and female rats (collapsed on tracking). *Main effect of session. %Significant session × sex interaction.

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    Figure 2.

    Intra-DMS CB1R signaling inhibition impairs pavlovian devaluation sensitivity, which differs by sex. Data represented as within-subject individual data (lines) and group data (bars; mean ± SEM). Rats received intra-DMS injections of either vehicle (left) or rimonabant (right) 10 min prior to the probe test. A, All rats’ total behavior (sum of lever and food cup contacts) in outcome devaluation probe test. Under vehicle conditions, the rats show lower responding for devalued relative to valued conditions, and this is blocked by intra-DMS rimonabant infusions (significant outcome value × treatment interaction). B, Coronal sections (in millimeters relative to bregma) depicting the location of DMS injector tips for intracranial infusions. C, GT/INT rats’ total behavior in the outcome devaluation probe test is lower for devalued relative to valued conditions, and this is blocked by intra-DMS rimonabant infusions (significant outcome value × treatment interaction). D, ST rats’ total behavior in outcome devaluation probe test, during which there were no significant main effects or interactions when collapsed across sex. E, Male rats’ total behavior in the outcome devaluation probe test is lower for devalued relative to valued conditions, and this is blocked by intra-DMS rimonabant infusions (significant outcome value × treatment interaction). F, Female rats’ total behavior in outcome devaluation probe test, during which there were no significant main effects or interactions when collapsed across tracking. Post hoc comparisons: #p = 0.051, **p < 0.025.

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    Figure 3.

    Male, but not female, rats are sensitive to pavlovian outcome devaluation, and this sensitivity is blocked by intra-DMS rimonabant regardless of the tracking group. Data represented as within-subject individual data (lines) and group data (bars; mean ± SEM). A, B, In ST rats, we observe a significant outcome value × treatment × sex interaction on total behavior. In male ST rats, we observed a significant outcome value × treatment interaction. Post hocs confirm that male ST rats were sensitive to devaluation with lower responding for devalued relative to valued conditions, while all other post hocs were not significant. C, D, In GT/INT rats, we observed an outcome value × treatment interaction, but no interaction with sex. Post hoc comparisons: #p = 0.055, **p < 0.025. See Extended Data Figure 3-1 for an analysis of lever contacts and Extended Data Figure 3-2 for an analysis of food cup contacts.

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    Figure 4.

    Consumption in postdevaluation choice test and conditioned responding in nonsated probe tests are unaffected by intra-DMS rimonabant. Data represented as group data (bars; mean ± SEM). A, B, In a post-outcome devaluation probe choice test, we gave rats 30 min of access to both outcomes, and they consumed less of the outcome they were stated on compared with nonsated outcome (*significant main effect of outcome), and there were no effects of CB1R inhibition on consumption regardless of tracking or sex. C, D, Intra-DMS rimonabant does not affect pavlovian conditioned approach in nonsated, nonreinforced PLA sessions. Total behavior for GT/INT rats and ST rats during a nonsated probe test identical in duration to the sated tests. There were no effects of CB1R inhibition on total behavior, regardless of tracking or sex. E, F, Intra-DMS rimonabant does not affect pavlovian conditioned approach in nonsated, reinforced PLA sessions. All rats received an intracranial infusion of vehicle or rimonabant (1, 2 µg/µl) 10 min prior to the start of the reinforced PLA sessions. E, No effects of intra-DMS rimonabant dose on reinforced behavior for total contacts, lever, or food cup contacts and no interactions between dose or other factors. F, We observed a main effect of sex on lever contacts but no effect of intra-DMS rimonabant dose. Main effect: *p = 0.05. Main effect: *p < 0.05. Post hoc comparisons: ***p < 0.01.

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    Figure 5.

    sIPSCs in DMS cells show reduced frequency and greater interevent intervals in males compared to females. A, Representative sIPSC traces from DMS cells in aCSF bath from male (blue; 1–2 cells per rat; n = 8 cells) and female (purple; 1–2 cells per rat; n = 9 cells) Long Evans rats. Scale bars: 20 pA and 1 s. Data presented as mean ± SEM. B, Mean amplitude. C, Mean frequency. D, Cumulative frequency of interevent interval of sIPSCs. **p < 0.025.

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    Figure 6.

    Activation of CB1R by WIN reduces sIPSC frequency and increases sIPSC interevent interval, regardless of sex. A, Representative sIPSC traces from DMS cells pre- (blue) and post-WIN (light blue) bath application from Long Evans rats (1–2 cells per rat; n = 21 cells). Scale bars: 20 pA and 1 s. Data presented as mean ± SEM. B, Mean amplitude with individual data for males (blue lines) and females (purple lines). C, Mean frequency with individual data for males and females. D, Cumulative frequency of interevent interval of sIPSCs. **p < 0.025.

Extended Data

  • Figures
  • Figure 3-1

    Male ST rats are sensitive to Pavlovian outcome devaluation for lever contacts, which is blocked by intra-DMS Rimonabant. Data represented as within-subject individual data (lines) and group data (bars; mean ± SEM). Across all rats, we observed a significant Outcome Value X Treatment X Tracking X Sex interaction for lever contact. A,B, In ST rats, we observe a significant Outcome Value X Treatment X Sex interaction on lever contact. Post hocs confirm that male ST rats were sensitive to devaluation with lower lever contacts for devalued relative to valued conditions, while all other post hocs were not significant. C,D In GT/INT rats, we did not observe any significant main effects or interactions. Post hoc comparisons: *p < 0.05. See Figure 3 for analysis of total approach. Download Figure 3-1, TIF file.

  • Figure 3-2

    Male GT/INT rats are sensitive to Pavlovian outcome devaluation for food cup responding, which is differentially affected by intra-DMS Treatment. Data represented as within-subject individual data (lines) and group data (bars; mean ± SEM). For all rats, we observed a significant Outcome Value X Treatment interaction and main effects of Sex and Tracking. A, B, In ST rats, we did not observe any significant main effects or interactions. C, D In GT/INT rats, we observe an Outcome Value X Treatment interaction, and a main effect of Sex. C, In male GT/INT rats, we observed a significant Outcome Value X Treatment interaction (%p = 0.021) but post hocs were not significant. D, In female GT/INTs, we did not observe any significant main effects or interactions. See Figure 3 for analysis of total approach. Download Figure 3-2, TIF file.

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Dorsomedial Striatum (DMS) CB1R Signaling Promotes Pavlovian Devaluation Sensitivity in Male Long Evans Rats and Reduces DMS Inhibitory Synaptic Transmission in Both Sexes
Catherine A. Stapf, Sara E. Keefer, Jessica M. McInerney, Joseph F. Cheer, Donna J. Calu
eNeuro 2 January 2025, 12 (1) ENEURO.0341-24.2024; DOI: 10.1523/ENEURO.0341-24.2024

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Dorsomedial Striatum (DMS) CB1R Signaling Promotes Pavlovian Devaluation Sensitivity in Male Long Evans Rats and Reduces DMS Inhibitory Synaptic Transmission in Both Sexes
Catherine A. Stapf, Sara E. Keefer, Jessica M. McInerney, Joseph F. Cheer, Donna J. Calu
eNeuro 2 January 2025, 12 (1) ENEURO.0341-24.2024; DOI: 10.1523/ENEURO.0341-24.2024
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Keywords

  • devaluation
  • dorsal striatum
  • endocannabinoids
  • pavlovian conditioning
  • sex differences

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