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Research ArticleNew Research, Development

New Hippocampal Neurons Mature Rapidly in Response to Ketamine But Are Not Required for Its Acute Antidepressant Effects on Neophagia in Rats

Amelie Soumier, Rayna M. Carter, Timothy J. Schoenfeld and Heather A. Cameron
eNeuro 23 March 2016, 3 (2) ENEURO.0116-15.2016; DOI: https://doi.org/10.1523/ENEURO.0116-15.2016
Amelie Soumier
Section on Neuroplasticity, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892
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Rayna M. Carter
Section on Neuroplasticity, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892
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Timothy J. Schoenfeld
Section on Neuroplasticity, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892
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Heather A. Cameron
Section on Neuroplasticity, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892
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  • Figure 1.
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    Figure 1.

    Rapid and sustained behavioral effects of S-ketamine. A, Short-term S-ketamine (ket) treatment reduced the latency to eat in the novelty-suppressed feeding test (one-way ANOVA, F(3,14) = 6.61, p = 0.005; *Holm–Sidak test, 10 mg/ml vs saline, p = 0.004). B, In the repeated forced swim test, short-term administration of S-ketamine reduced the time spent immobile immediately and 21 d later, while fluoxetine had no effect (two-way repeated-measures ANOVA; treatment effect: F(2,9) = 31.65, p = 0.0001; time effect: F(1,9) = 31.47, p = 0.0003; treatment × time interaction: F(2,9) = 0.002, p =0.99; ***p < 0.001 vs saline in post hoc test). All bars represent mean ± standard error of the mean (SEM).

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    Figure 2.

    Examples of immunohistochemical markers. A, After kainate injection, all mature granule neurons and some BrdU-labeled 16-d-old NeuN+ neurons expressed zif268, indicating synaptic activation. GCL, granule cell layer B, Dividing cells (arrows) were identified using PCNA immunohistochemistry. C, Cells surviving 2-3 weeks (arrows) were identified with BrdU immunohistochemistry (gray-brown); immunonegative cells were stained with blue-purple counterstain.

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    Figure 3.

    Rapid effects of ketamine on granule cell maturation and proliferation. A, S-ketamine (ket) increased the proportion of 16-d-old BrdU+ cells colabeled with NeuN and zif268 (zif) 16 h later, relative to saline-treated controls (sal) (*t test, t(4) = 3.065, p =0.0375). All bars represent mean ± SEM. B, S-ketamine increased the number of PCNA+ (dividing) cells in the subgranular zone 16 h later (*t test, t(10) = 2.42, p = 0.0359). C, Animal treatment time course for short-term effects; ketamine injection was 10 mg/kg, i.p., in each experiment. D, The maturation effect was not seen in 7-d-old cells (t test, t(9) = 0.98, p = 0.35). E, Animal treatment time course for short-term effects in young cells. F, G, Increased zif/NeuN coexpression and strong NeuN expression were seen in 14-d-old cells within 2 h of ketamine treatment (zif: *t test, t(9) = 2.33, p = 0.0450; strong NeuN: *t test, t(9) = 3.55, p = 0.0062). H, Animal treatment time course for very rapid effects on maturation.

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    Figure 4.

    Effects of long-term ketamine treatment. A, B, Animal treatment time courses; all ketamine injections were 10 mg/kg, i.p. C, D, Long-term daily ketamine treatment for 14 d (C) or 21 d (D) increased the proportion of zif/NeuN+ BrdU+ granule cells (*14 d: t test, t(9) = 3.20, p = 0.0108; *21 d: t test, t(11) = 2.773, p = 0.0181). E, F, S-ketamine had no effect on cell proliferation when administered daily for 14 or 21 d (14 d: t(10) = 0.035, p = 0.973; 21 d: t(9) = 0.955, p = 0.365). G, H, BrdU+ cell survival was unaffected by 14 d of daily treatment with S-ketamine (t test, t(10) = 1.03, p = 0.33) but was decreased after 21 d (*t test, t(12) = 2.71, p = 0.0191). All bars represent the mean ± SEM (n = 6-7 per group).

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    Figure 5.

    Sustained effects of S-ketamine in a depression model. A, Ketamine given 32 d earlier increased zif/NeuN expression in 16-d-old cells regardless of long-term corticosterone exposure (main effect of CORT: F(1,17) = 0.00, p = 0.996; *main effect of ketamine: F(1,17) = 14.99, p = 0.0017; CORT × ketamine interaction: F(1,17) = 0.0005, p = 0.9821 by two-way ANOVA). B, S-ketamine increased the number of PCNA+ cells 32 d later and prevented the inhibition of proliferation by long-term corticosterone treatment (*main effect of ketamine: F(1, 23) = 7.44, p = 0.013; *main effect of CORT: F(1,23) = 8.35, p = 0.009; CORT × ketamine interaction: F(1,23) = 0.00, p = 0.988 by two-way ANOVA). C, Animal treatment time course for maturation and proliferation effects. D, A single S-ketamine injection prior to long-term CORT treatment prevented a decrease in sucrose preference (one-way ANOVA, F(2,15) = 6.98, p = 0.0072; *p < 0.05 vs saline in post hoc test). Values represent the mean ± SEM (n = 4-6 per group). E, Neither long-term exposure to CORT nor short-term ketamine exposure prior to CORT significantly altered new cell survival (F(2,15) = 1.12, p = 0.35 by one-way ANOVA). Values represent the mean ± SEM (n = 6-7 per group. F, Animal treatment time course for sucrose preference and survival effects.

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    Figure 6.

    Neurogenesis is not required for the S-ketamine effect on novelty-suppressed feeding. A, Animal treatment time course showing valganciclovir to inhibit neurogenesis, the injection of saline (sal) or ketamine (ket; 10 mg/kg), and NSF testing. B, Photographs show DCX-expressing young granule neurons (green) in the dentate gyrus of valganciclovir (VGCV)-treated wild-type rats (WT), but not in GFAP-TK (TK) rats. Blue counterstain shows cell nuclei. C, Higher magnification of granule cell layer showing DCX staining. D, Quantification shows near-complete absence of DCX+ new neurons in GFAP-TK rats and no effect of short-term S-ketamine treatment on DCX+ cell number. (*main effect of genotype: F(1,20) = 183.6, p < 0.0001; main effect of ketamine: F(1,20) = 1.471, p = 0.2392; genotype × ketamine interaction: F(1,20) = 1.418, p = 0.2477, all by two-way ANOVA) E, In the NSF test, the latency to eat in a novel arena was decreased by S-ketamine in both wild-type and GFAP-TK rats (*main effect of genotype: F(1,20) = 0.2827, p = 0.6008; main effect of ketamine: F(1,20) = 13.24, p = 0.0016; genotype × ketamine interaction: F(1,20) = 0.3756, p = 0.5469, all by two-way ANOVA). All bars represent mean ± SEM.

Tables

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    Table 1:

    Statistical table

    FigureDescriptionData structureType of testPower
    a1ALatency to eat in NSFNormal distributionANOVAp = 0.0052
    b1ALatency to eat in NSF (0 vs 10 mg/kg)Normal distributionHolm–Sidak post hoc testp = 0.0042
    c1BImmobility, main effect of treatmentNormal distribution2-way repeated measures ANOVAp < 0.0001
    d1BImmobility, main effect of timeNormal distribution2-way repeated measures ANOVAp = 0.0003
    e1BImmobility, treatment × time interactionNormal distribution2-way repeated measures ANOVAp = 0.9980
    f1BImmobility, ketamine vs salineNormal distributionHolm–Sidak post hoc testp < 0.0001
    g3AShort-term effects on cell maturationNormal distributiont testp = 0.0375
    h3BProliferation effectsNormal distributiont testp = 0.0359
    i3DMaturation effects in younger cellsNormal distributiont testp = 0.3548
    j3FVery rapid maturation effectsNormal distributiont testp = 0.0450
    k3GStrong NeuN expressionNormal distributiont testp = 0.0062
    l4CLong-term 14 d maturation effectsNormal distributiont testp = 0.0108
    m4DLong-term 21 d maturation effectsNormal distributiont testp = 0.0181
    n4ELong-term 14 d proliferation effectsNormal distributiont testp = 0.9726
    o4FLong-term 21 d proliferation effectsNormal distributiont testp = 0.365
    p4GLong-term 14 d survival effectsNormal distributiont testp = 0.3280
    q4HLong-term 21 d survival effectsNormal distributiont testp = 0.0191
    r5ASustained maturation, main effect of CORTNormal distribution2-way ANOVAp = 0.9964
    s5ASustained maturation, main effect of ketamineNormal distribution2-way ANOVA p = 0.0017
    t5ASustained maturation, CORT × ketamine interactionNormal distribution2-way ANOVAp = 0.9821
    u5BProliferation, main effect of ketamineNormal distribution2-way ANOVAp = 0.0130
    v5BProliferation, main effect of CORTNormal distribution2-way ANOVA p = 0.0091
    w5BProliferation, CORT × ketamine interactionNormal distribution2-way ANOVAp = 0.9883
    x5DSucrose preferenceNormal distributionANOVAp = 0.0072
    y5DSucrose preference, vehicle/saline vs CORT/salineNormal distributionHolm-Sidak post hoc testp = 0.0074
    z5DSucrose preference, CORT/saline vs CORT/ketamineNormal distributionHolm-Sidak post hoc testp = 0.0405
    aa5ESurvivalNormal distributionANOVAp = 0.3512
    bb6DDCX+ cell number, main effect of genotypeNormal distribution2-way ANOVAp < 0.0001
    cc6DDCX+ cell number, main effect of ketamineNormal distribution2-way ANOVAp = 0.2393
    dd6DDCX+ cell number, genotype × ketamine interactionNormal distribution2-way ANOVAp = 0.2477
    ee6ELatency to eat in NSF, main effect of genotypeNormal distribution2-way ANOVAp = 0.6008
    ff6ELatency to eat in NSF, main effect of ketamineNormal distribution2-way ANOVAp = 0.0016
    ee6ELatency to eat in NSF, genotype × ketamine interaction Normal distribution2-way ANOVAp = 0.5469
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New Hippocampal Neurons Mature Rapidly in Response to Ketamine But Are Not Required for Its Acute Antidepressant Effects on Neophagia in Rats
Amelie Soumier, Rayna M. Carter, Timothy J. Schoenfeld, Heather A. Cameron
eNeuro 23 March 2016, 3 (2) ENEURO.0116-15.2016; DOI: 10.1523/ENEURO.0116-15.2016

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New Hippocampal Neurons Mature Rapidly in Response to Ketamine But Are Not Required for Its Acute Antidepressant Effects on Neophagia in Rats
Amelie Soumier, Rayna M. Carter, Timothy J. Schoenfeld, Heather A. Cameron
eNeuro 23 March 2016, 3 (2) ENEURO.0116-15.2016; DOI: 10.1523/ENEURO.0116-15.2016
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Keywords

  • antidepressive agents
  • cell proliferation
  • dentate gyrus
  • mood disorders
  • neurogenesis
  • neuronal maturation

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