Control and understanding of 5-HT1A/B signaling pathways and their involvement in anxiety behavior
Final Report Abstract
Anxiety related disorders are the most prevalent disorders in the modern world, affecting around one third of the human population. Anxiety is an emotional state of unpleasant arousal and often displayed with avoidance behavior. Several brain structures as the medial prefrontal cortex (mPFC) are involved in anxiety, as also the neurotransmitter serotonin. Besides other 5-HT receptors, the 5-HT1A receptor is highly expressed in the mPFC-dorsal raphe (DRN) circuitry, which is known to be affected in anxiety-related disorders. 5-HT1A(-/-) receptor knockout (ko) mice have an anxiety phenotype and show impaired serotonergic signaling. This project reveals, that increased anxiety in 5-HT1A(-/-) receptor ko mice is promoted by an elevated excitation/inhibition (E/I) ratio in the infralimbic region (IL) of the mPFC. Optogenetic activation of IL pyramidal neurons via Channelrhodopsin2 (ChR2) in Nex-Cre(-/-) mice is mimics this enhanced E/I ratio and increase anxiety levels during behavioral tasks. This shows, that the ratio between excitation/inhibition is crucial for a normal anxiety behavior, and that an overactivation of the IL region is sufficient to induce anxiety phenotypes. Contrary, the inhibition of IL pyramidal neurons via Archaerhodopsin (Arch) in Nex-Cre(-/-) mice did not affect anxiety levels, although a relief of anxiety was hypothesized. Probably anxiolytic effects are difficult to observe in mouse lines with low baseline anxiety levels, such as Nex-Cre(-/-). Surprisingly, activation of 5-HT1A receptor mediated signaling in IL pyramidal neurons increased anxiety levels in EPM and OF, and marginally in the NSF. It was expected, that an overactivation of 5-HT1A signaling pathways could have anxiolytic effects. But 1A-vLWO activation induced comparable anxiety phenotypes as seen in 5-HT1A(-/-) ko mice. This points to the importance of a balanced expression of 5-HT1A receptors. In sum, this project was able to reveal new details of the anxiety-network and the influence of serotonergic signaling on anxiety. Especially 5-HT1A receptor signaling in the IL region strongly affected anxiety phenotypes. This knowledge can now be transferred for the development of new therapeutic strategies to treat anxiety disorders.
Publications
- (2020) Optogenetic Manipulation of Neuronal Activity to Modulate Behavior in Freely Moving Mice. Journal of visualized experiments : JoVE (164) e61023
Berg, Laura; Gerdey, Jill; Masseck, Olivia A.
(See online at https://doi.org/10.3791/61023) - 2019. “Enhanced Activity of Pyramidal Neurons in the Infralimbic Cortex Drives Anxiety Behavior.” PLoS ONE 14(January): 1–19
Berg, L., J. Eckardt, and Masseck. O. A.
(See online at https://doi.org/10.1371/journal.pone.0210949) - 2019. “Imbalance of excitation and inhibition within the prefrontal cortex supports anxiety behavior.” University of Bochum, doctoral thesis
Berg, L.
