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Neurotrophic factor-α1 prevents stress-induced depression through enhancement of neurogenesis and is activated by rosiglitazone.

Publication ,  Journal Article
Cheng, Y; Rodriguiz, RM; Murthy, SRK; Senatorov, V; Thouennon, E; Cawley, NX; Aryal, DK; Ahn, S; Lecka-Czernik, B; Wetsel, WC; Loh, YP
Published in: Mol Psychiatry
June 2015

Major depressive disorder is often linked to stress. Although short-term stress is without effect in mice, prolonged stress leads to depressive-like behavior, indicating that an allostatic mechanism exists in this difference. Here we demonstrate that mice after short-term (1 h per day for 7 days) chronic restraint stress (CRS), do not display depressive-like behavior. Analysis of the hippocampus of these mice showed increased levels of neurotrophic factor-α1 (NF-α1; also known as carboxypeptidase E, CPE), concomitant with enhanced fibroblast growth factor 2 (FGF2) expression, and an increase in neurogenesis in the dentate gyrus. In contrast, after prolonged (6 h per day for 21 days) CRS, mice show decreased hippocampal NF-α1 and FGF2 levels and depressive-like responses. In NF-α1-knockout mice, hippocampal FGF2 levels and neurogenesis are reduced. These mice exhibit depressive-like behavior that is reversed by FGF2 administration. Indeed, studies in cultured hippocampal neurons reveal that NF-α1 treatment directly upregulates FGF2 expression through extracellular signal-regulated kinase-Sp1 signaling. Thus, during short-term CRS, hippocampal NF-α1 expression is upregulated and has a key role in preventing the onset of depressive-like behavior through enhanced FGF2-mediated neurogenesis. To evaluate the therapeutic potential of this pathway, we examined, rosiglitazone (Rosi), a PPARγ agonist, which has been shown to have antidepressant activity in rodents and humans. Rosi upregulates FGF2 expression in a NF-α1-dependent manner in hippocampal neurons. Mice fed Rosi show increased hippocampal NF-α1 levels and neurogenesis compared with controls, thereby indicating the antidepressant action of this drug. Development of drugs that activate the NF-α1/FGF2/neurogenesis pathway can offer a new approach to depression therapy.

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Published In

Mol Psychiatry

DOI

EISSN

1476-5578

Publication Date

June 2015

Volume

20

Issue

6

Start / End Page

744 / 754

Location

England

Related Subject Headings

  • Up-Regulation
  • Thiazolidinediones
  • Swimming
  • Sweetening Agents
  • Sucrose
  • Stress, Psychological
  • Rosiglitazone
  • Psychiatry
  • Neuropeptides
  • Neurogenesis
 

Citation

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Cheng, Y., Rodriguiz, R. M., Murthy, S. R. K., Senatorov, V., Thouennon, E., Cawley, N. X., … Loh, Y. P. (2015). Neurotrophic factor-α1 prevents stress-induced depression through enhancement of neurogenesis and is activated by rosiglitazone. Mol Psychiatry, 20(6), 744–754. https://doi.org/10.1038/mp.2014.136
Cheng, Y., R. M. Rodriguiz, S. R. K. Murthy, V. Senatorov, E. Thouennon, N. X. Cawley, D. K. Aryal, et al. “Neurotrophic factor-α1 prevents stress-induced depression through enhancement of neurogenesis and is activated by rosiglitazone.Mol Psychiatry 20, no. 6 (June 2015): 744–54. https://doi.org/10.1038/mp.2014.136.
Cheng Y, Rodriguiz RM, Murthy SRK, Senatorov V, Thouennon E, Cawley NX, et al. Neurotrophic factor-α1 prevents stress-induced depression through enhancement of neurogenesis and is activated by rosiglitazone. Mol Psychiatry. 2015 Jun;20(6):744–54.
Cheng, Y., et al. “Neurotrophic factor-α1 prevents stress-induced depression through enhancement of neurogenesis and is activated by rosiglitazone.Mol Psychiatry, vol. 20, no. 6, June 2015, pp. 744–54. Pubmed, doi:10.1038/mp.2014.136.
Cheng Y, Rodriguiz RM, Murthy SRK, Senatorov V, Thouennon E, Cawley NX, Aryal DK, Ahn S, Lecka-Czernik B, Wetsel WC, Loh YP. Neurotrophic factor-α1 prevents stress-induced depression through enhancement of neurogenesis and is activated by rosiglitazone. Mol Psychiatry. 2015 Jun;20(6):744–754.

Published In

Mol Psychiatry

DOI

EISSN

1476-5578

Publication Date

June 2015

Volume

20

Issue

6

Start / End Page

744 / 754

Location

England

Related Subject Headings

  • Up-Regulation
  • Thiazolidinediones
  • Swimming
  • Sweetening Agents
  • Sucrose
  • Stress, Psychological
  • Rosiglitazone
  • Psychiatry
  • Neuropeptides
  • Neurogenesis