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Research ArticleResearch Article: New Research, Disorders of the Nervous System

Unique Effects of Social Defeat Stress in Adolescent Male Mice on the Netrin-1/DCC Pathway, Prefrontal Cortex Dopamine and Cognition

Philip Vassilev, Andrea Haree Pantoja-Urban, Michel Giroux, Dominique Nouel, Giovanni Hernandez, Taylor Orsini and Cecilia Flores
eNeuro 22 February 2021, 8 (2) ENEURO.0045-21.2021; https://doi.org/10.1523/ENEURO.0045-21.2021
Philip Vassilev
1Department of Psychiatry and Department of Neurology and Neurosurgery
3Douglas Mental Health University Institute, Montreal, Quebec, H4H 1R3, Canada
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Andrea Haree Pantoja-Urban
2Integrated Program in Neuroscience, McGill University, Montréal, Quebec, H3A 2B4, Canada
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Michel Giroux
3Douglas Mental Health University Institute, Montreal, Quebec, H4H 1R3, Canada
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Dominique Nouel
3Douglas Mental Health University Institute, Montreal, Quebec, H4H 1R3, Canada
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Giovanni Hernandez
3Douglas Mental Health University Institute, Montreal, Quebec, H4H 1R3, Canada
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Taylor Orsini
3Douglas Mental Health University Institute, Montreal, Quebec, H4H 1R3, Canada
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Cecilia Flores
1Department of Psychiatry and Department of Neurology and Neurosurgery
3Douglas Mental Health University Institute, Montreal, Quebec, H4H 1R3, Canada
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  • Figure 1.
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    Figure 1.

    Differences in the resilience to AcSD stress in adolescence versus adulthood. The SIT data were pooled together from all experiments. A, Experimental timeline. For AcSD in adolescence, CD-1 mice underwent two phases of priming and screening before the actual AcSD procedure. B, Diagram representing the AcSD procedure. Only for AcSD in adolescence, CD-1 mice were primed with an adult C57BL/6 mouse for aggressiveness before each defeat session. C, Behavior during the SIT after AcSD in adolescence. IZ, interaction zone; *** significantly different, p < 0.001. D, SIT behavior following AcSD in adulthood; *** significantly different, p < .001; ** significantly different, p < 0.01; * significantly different, p < 0.05. E, The majority of mice exposed to AcSD in adolescence are resilient, but (F) the majority of mice exposed to AcSD in adulthood are susceptible. G, Following AcSD in adolescence, resilient mice spent more time in the open arms of the EPM, *** significantly different, p < 0.001. (H), AcSD in adulthood does not lead to changes in the EPM test. I, the time spent in the open arms of the EPM and the time spent in the IZ during the SIT correlate significantly after AcSD in adolescence. J, there is no correlation between the time spent in the open arms of the EPM and the time spent in the IZ after AcSD in adulthood. All data are shown as mean ± SEM.

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    Figure 2.

    AcSD in adolescence, but not adulthood, dysregulates the Netrin-1/DCC pathway in the mesolimbic DA system. A, Experimental timeline. B, AcSD in adolescence leads to downregulation of Dcc mRNA expression in the VTA of both resilient and susceptible mice, while Netrin-1 protein levels in the NAcc are upregulated only in the susceptible group; ** significantly different, p < 0.01; * significantly different, p < 0.05. C, AcSD in adulthood does not lead to changes in Dcc mRNA expression in the VTA or Netrin-1 protein levels in the NAcc. All data are shown as mean ± SEM.

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    Figure 3.

    Exposure to AcSD in adolescence leads to altered mPFC DA connectivity in adulthood. A, Experimental timeline. B, Coronal sections containing the sampled PrL and IL mPFC subregions. The photomicrographs show TH-immunolabeled DA axons in deep PrL and IL layers (5×, 20×, and 100× magnifications). White arrows indicate examples of TH+ varicosities. C, AcSD in adolescence leads to increased expanse of the DA innervation to the PrL cortex of resilient mice; ** significantly different, p < 0.01; and to (D) increased total number of DA varicosities in the PrL cortex of susceptible mice; ** significantly different, p < 0.01. All data are shown as mean ± SEM.

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    Figure 4.

    AcSD in adolescence, but not adulthood, leads to deficits in inhibitory control in adulthood. A, Experimental timeline. B, Go/No-Go task. C, AcSD in adolescence leads to an increase in proportion of commission errors in defeated mice, regardless of behavioral phenotype shown in the SIT (Fig. 1); & significant main effect of phenotype, p < 0.05. D, AcSD in adulthood does not alter inhibitory control six weeks later. E, Correct response rate representing the proportion of total rewards acquired from both Go and No-Go trials. AcSD in adolescence leads to decreased correct response rate in resilient and susceptible mice relative to controls; * significantly different, p < 0.05. F, AcSD in adulthood does not alter correct response rate. There are no significant differences in hits between groups following AcSD (G) in adolescence (H) or in adulthood.

Extended Data

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  • Extended Data Figure 1-1

    A, Proportion of resilient and adolescent animals as a proportion of all adult and adolescent cohorts (as in Fig. 1). B, The proportions of resilient and susceptible animals following AcSD in adulthood or adolescence did not change significantly after adjusting the number of attacks. The majority of mice exposed to AcSD in adolescence were resilient even after increasing the number of attacks received. The majority of mice exposed to AcSD in adulthood were susceptible even after reducing the number of attacks received. C, There were no significant correlations between the average number of attacks received and the time spent in the interaction zone during the SIT. Download Figure 1-1, EPS file.

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Unique Effects of Social Defeat Stress in Adolescent Male Mice on the Netrin-1/DCC Pathway, Prefrontal Cortex Dopamine and Cognition
Philip Vassilev, Andrea Haree Pantoja-Urban, Michel Giroux, Dominique Nouel, Giovanni Hernandez, Taylor Orsini, Cecilia Flores
eNeuro 22 February 2021, 8 (2) ENEURO.0045-21.2021; DOI: 10.1523/ENEURO.0045-21.2021

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Unique Effects of Social Defeat Stress in Adolescent Male Mice on the Netrin-1/DCC Pathway, Prefrontal Cortex Dopamine and Cognition
Philip Vassilev, Andrea Haree Pantoja-Urban, Michel Giroux, Dominique Nouel, Giovanni Hernandez, Taylor Orsini, Cecilia Flores
eNeuro 22 February 2021, 8 (2) ENEURO.0045-21.2021; DOI: 10.1523/ENEURO.0045-21.2021
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Keywords

  • adolescence
  • developmental biology
  • dopamine
  • guidance cues
  • prefrontal cortex
  • social defeat stress

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