Cellular and Molecular Neurobiology

, Volume 36, Issue 4, pp 553–563 | Cite as

Complexity of Compensatory Effects in Nrf1 Knockdown: Linking Undeveloped Anxiety-Like Behavior to Prevented Mitochondrial Dysfunction and Oxidative Stress

  • Solmaz Khalifeh
  • Shahrbanoo Oryan
  • Fariba Khodagholi
  • Hadi Digaleh
  • Fatemeh Shaerzadeh
  • Nader Maghsoudi
  • Mohammad-Reza Zarrindast
Original Research


Anxiety-related disorders are complex illnesses that underlying molecular mechanisms need to be understood. Mitochondria stand as an important link between energy metabolism, oxidative stress, and anxiety. The nuclear factor, erythroid-derived 2,-like 1(Nrf1) is a member of the cap “n” collar subfamily of basic region leucine zipper transcription factors and plays the major role in regulating the adaptive response to oxidants and electrophiles within the cell. Here, we injected small interfering RNA (siRNA) targeting Nrf1 in dorsal third ventricle of adult male albino Wistar rats and subsequently examined the effect of this silencing on anxiety-related behavior. We also evaluated apoptotic markers and mitochondrial biogenesis factors, along with electron transport chain activity in three brain regions: hippocampus, amygdala, and prefrontal cortex. Our data revealed that in the group that received Nrf1-siRNA, anxiety-related behavior did not show any significant changes compared to the control group. Caspase-3 did not increase in Nrf1-siRNA-injected rats even though Bax/Bcl2 ratio markedly elevated in Nrf1-knockdown rats in all three mentioned regions compared to control rats. Also, Nrf1 silencing of complex I and II–III did not alter, generally. In addition, Nrf1-knockdown affected mitochondrial biogenesis markers. The level of peroxisome proliferator-activated receptor gamma coactivator-1α and cytochrome-c increased, which indicates a possible role for mitochondrial biogenesis in anxiety.


Anxiety Nrf1 siRNA Electron transport chain PGC-1α 



This work was supported financially by the Iran National Science Foundation (INSF, grant number 91003013).

Compliance with Ethical Standards

Conflict of interest

All authors have no conflict of interest.

Animal Rights and Informed Consent

All procedures involving the care of animals were performed according to the guidelines for animal experimentation issued by the National Institutes of Health Publication (No. 80-23, revised 1996) and the Research and Ethics Committee of Shahid Beheshti University of Medical Sciences.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Solmaz Khalifeh
    • 1
    • 2
  • Shahrbanoo Oryan
    • 1
  • Fariba Khodagholi
    • 3
    • 4
  • Hadi Digaleh
    • 3
    • 4
  • Fatemeh Shaerzadeh
    • 5
  • Nader Maghsoudi
    • 3
    • 4
  • Mohammad-Reza Zarrindast
    • 2
    • 6
    • 7
    • 8
  1. 1.Department of Animal Physiology, Faculty of BiologyKharazmi UniversityTehranIran
  2. 2.Medical Genomics Research Center and School of Advanced Sciences in Medicine, Tehran Medical Sciences BranchIslamic Azad UniversityTehranIran
  3. 3.Neuroscience Research CenterShahid Beheshti University of Medical SciencesTehranIran
  4. 4.NeuroBiology Research CenterShahid Beheshti University of Medical SciencesTehranIran
  5. 5.Department of Physiology, Faculty of MedicineHormozgan University of Medical SciencesBandar AbbasIran
  6. 6.Department of Pharmacology, School of MedicineTehran University of Medical SciencesTehranIran
  7. 7.Institute for Cognitive Science Studies (ICSS)TehranIran
  8. 8.School of Cognitive SciencesInstitute for Research in Fundamental Sciences (IPM)TehranIran

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