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Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behavior

  1. Ronald S. Duman a , 1
  1. aLaboratory of Molecular Psychiatry, Center for Genes and Behavior, Departments of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, CT 06519; and
  2. bFishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029

  1. Edited* by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved December 28, 2009 (received for review September 16, 2009)

  1. Fig. 1.
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    Fig. 1.

    Effects of stress and NF-κB inhibitors on hippocampal neurogenesis in rats. (A) Schematic depicting the experimental procedures for acute stress (aSTR). After 8–10 days of recovery and handling, rats were infused (i.c.v.) with the NF-κB inhibitors JSH or SC or with vehicle (DMSO) before immobilization and were then killed (sac) 2 h after BrdU administration. injt., injection. (B) aSTR decreased the number of BrdU+ cells in the DG of the hippocampus. The effect of aSTR was blocked by either JSH or SC (one-way ANOVA: F 3,26 = 3.527, P < 0.05; n = 7–8 per group). Dividing BrdU+ cells (black arrowheads) in the DG of acute-stressed (C) and JSH-infused stressed (D) rats. GCL, granular cell layer. (Scale bar: 100 μm.) (E) Schematic for CUS. Rats were implanted with a cannula (i.c.v.) and minipump (s.c.), were exposed to two stressors per day for 21 days, received BrdU daily for the last 4 CUS days, and were killed 14 days later. JSH blocked the effects of CUS on BrdU+ cells (F 3,19 = 5.013, P < 0.05; n = 5–6 per group) (F), and immature neurons were measured as the number of BrdU+ (red) DCX+ (green) double-labeled cells per hippocampal DG (F 3,12 = 6.250, P < 0.01; n = 4 per group) (G and H). (Scale bar: 25 μm.) By one-way ANOVA followed by the Fisher’s PLSD test, *P < 0.05 and **P < 0.01 compared with control (DMSO) and #, P < 0.05 and ##, P < 0.01 compared with stressed animals.

  2. Fig. 2.
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    Fig. 2.

    Role of NF-κB signaling in the regulation of NSC and ANP cell proliferation in acute stress. (A) Representative photograph of proliferating NSCs [GFAP+ (red) SOX2+ (blue) BrdU+ (green) cells] in the SGZ. (B) Acute stress decreased the proliferation of total progenitors (SOX2+ BrdU+ cells), and there was no significant effect in CUS animals receiving JSH (F 2,11 = 4.215, P < 0.05; n = 4–5 per group). aSTR, acute stress; CTRL, control. Stress-induced impairment of NSC (F 2,11 = 5.814, P < 0.05) (C) but not ANP (F 2,11 = 0.852, P = n.s.) (D) proliferation was blocked by JSH. (Scale bar: 25 μm.) By the Fisher’s PLSD test, *, P < 0.05 compared with CTRL group and # , P < 0.05 compared with aSTR group.

  3. Fig. 3.
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    Fig. 3.

    Acute stress effects on NF-κB reporter expression in the hippocampus in NF-κB/LacZ reporter mice. (A–D) Most hippocampal progenitors [∼94%; BrdU+ (red), SOX2+ (blue), white arrows] did not express the NF-κB reporter [β-gal+ (green), yellow arrowheads]. (Scale bar: 50 μm.) (E–H) Expression of NF-κB reporter in NSCs [β-gal+ (F, green) SOX2+ (G, blue) GFAP+ (H, red)]. (Scale bar: 50 μm.) (I) Enlarged view of NSCs from E (Inset). (J) NF-κB/β-gal was observed in ANPs (β-gal+ SOX2+ GFAP−) as well as NSCs in the SGZ. Immature [β-gal+ DCX+ (red)] (K) and mature [β-gal+ NeuN+ (red)] (I) neurons also expressed the NF-κB reporter. (M–P) Acute immobilization stress (aSTR) resulted in more NF-κB activation (β-gal+) in NSCs but not in ANPs or in total progenitors compared with control (CTRL) [NSCs, F 2,9 = 11.381, P < 0.01 (M); ANPs, F 2,9 = 0.134, P = n.s. (N); total progenitors, F 2,9 = 2.994, P = n.s. (O); n = 4 per group]. (Scale bar: 25 μm.) By the Fisher’s PLSD test, **, P < 0.01 compared with CTRL and ## , P < 0.01 compared with aSTR group.

  4. Fig. 4.
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    Fig. 4.

    Effects of CUS on depressive-like behaviors in NIH and sucrose consumption test (SCT) in mice. (A) Experimental procedures for CUS in mice. Mice were exposed to two or three stressors per day for 28 days and received BrdU daily for the last 4 days of CUS. On days 21 and 28, NIH and the SCT, respectively, were conducted. Mice were killed (sac) 24 h after the last BrdU administration. (B) CUS significantly increased latency to drink, and this effect was blocked by continuous administration of SC (F 2,38 = 3.748, P < 0.05; n = 13–15 per group). CTRL, control. (C) SC administration also blocked the effect of CUS on sucrose consumption (F 2,21 = 3.497, P < 0.05; n = 5–13 per group). By the Fisher’s PLSD test, *, P < 0.05 compared with CTRL and # , P < 0.05 compared with CUS.

  5. Fig. 5.
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    Fig. 5.

    Analysis of IL-1β signaling in cultured AHPs. (A and B) Representative images of proliferating AHPs [BrdU+ (red) nestin+ (green)] in the presence of IL-1β (10 ng/mL) ± JSH (25 μM). (C) Coincubation with IL-1Ra (Ra, 100 ng/mL) or JSH blocked the effect of IL-1β on the ratio of BrdU+ to nestin+ compared with control (CTRL) (F 5,16 = 11.174, P < 0.001; n = 3–4 per group). By the Fisher’s PLSD test, **, P < 0.01 and ***, P < 0.001 compared with CTRL and ## , P < 0.01 and ### , P < 0.001 compared with IL-1β. (Scale bar: 50 μm.)

  6. Fig. 6.
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    Fig. 6.

    Model of stress-induced impairment of NSC proliferation in the hippocampus. Stress activates IL-1β/NF-κB signaling, resulting in impairment of hippocampal neurogenesis and thereby contributing to depressive-like behaviors. Notably, the results demonstrate that acute stress decreases NSC proliferation and that this effect is mediated by IL-1β/NF-κB signaling. In contrast, antidepressant treatment increases neurogenesis by inducing NSC [electroconvulsive seizure (ECS)] or ANP (chronic fluoxetine) proliferation.

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