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Complexity of Compensatory Effects in Nrf1 Knockdown: Linking Undeveloped Anxiety-Like Behavior to Prevented
Solmaz Khalifeh1,2, Shahrbanoo Oryan3, Fariba Khodagholi4,5
1Department of Animal Physiology, Faculty of Biology, Kharazmi University, P.O. Box: 15614, Tehran, Iran. soolmaz25kh@yahoo.com.
Abstract:
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.
Insights
Silencing nuclear factor Nrf1 in rats did not alter anxiety behaviors. However, it affected mitochondrial biogenesis markers, suggesting a potential role for mitochondria in anxiety disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Anxiety-related disorders are complex, requiring understanding of molecular mechanisms.
- Mitochondria are crucial in energy metabolism, oxidative stress, and anxiety.
- Nuclear factor erythroid-derived 2-like 1 (Nrf1) regulates cellular adaptive responses to oxidants.
Purpose of the Study:
- To investigate the effect of Nrf1 silencing on anxiety-related behavior in rats.
- To evaluate the impact of Nrf1 knockdown on apoptotic markers and mitochondrial biogenesis factors.
- To assess changes in electron transport chain activity in response to Nrf1 silencing.
Main Methods:
- Small interfering RNA (siRNA) targeting Nrf1 was injected into the dorsal third ventricle of adult male Wistar rats.
- Anxiety-related behaviors were assessed.
- Apoptotic markers (Caspase-3, Bax/Bcl2 ratio), mitochondrial biogenesis factors (PGC-1α, cytochrome-c), and electron transport chain activity (Complex I, II-III) were measured in the hippocampus, amygdala, and prefrontal cortex.
Main Results:
- Nrf1-siRNA injection did not significantly alter anxiety-related behaviors compared to controls.
- The Bax/Bcl2 ratio increased in Nrf1-knockdown rats, but Caspase-3 levels remained unchanged.
- Nrf1 silencing led to increased levels of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and cytochrome-c, indicating altered mitochondrial biogenesis.
Conclusions:
- Nrf1 knockdown does not directly influence anxiety-related behaviors in this rat model.
- Despite no change in anxiety, Nrf1 silencing impacts apoptotic markers and significantly affects mitochondrial biogenesis factors.
- The observed alterations in mitochondrial biogenesis suggest a potential role for mitochondrial function in the pathophysiology of anxiety.
