The Distribution and Interplay of Corticotropin Releasing Factor in Pathological Aggression
By Cuong-Alexander To, Pharm.D Candidate 2020; Marco Bortolato, MD Ph.D; Gabriele Floris, Ph.DAbstract The contemporary principle of elucidating antisocial behavior’s (ASB), such as pathological aggression, ontology has mediated by studying complicated gene x environment interactions (GxEi). A well-studied GxEi of pathological aggression occurs between the interplay of low-activity (hypomorphic) alleles of monoamine oxidase A (MAO-A) and childhood maltreatment (early stressors). This study’s aim is to further develop the understanding of the neurobiological mechanisms that contribute to the above mentioned GxEi of pathological aggression for future considerations on innovative targets. As part of ongoing researched on ASB, our research developed a mouse model of GxEi of pathological aggression known as MAO-ANeo Mice: MAO-A hypomorphic transgenic male mice subjected to a semi-random early-life stressor regimen for the first week of life. MAO-ANeo Mice developed overt ASB (aggression, social deficits, and stress response abnormalities), low resting heart rate (an accepted premorbid ASB sign), and significant up-regulation of serotonin receptors 2A (5-HT2aR) in the prefrontal cortex (contributing to the association between stress and serotonergic activity). Corticotrophin releasing factor (CRF) is another neurotransmitter implicated in the role of the GxEi of pathological aggression as it furthers serotonergic activity via decoupling the negative feedback mechanism of 5-HT2aR activation and internalization. Thus, the observation that CRF expression in stressed mice groups were elevated in the prefrontal cortex to evidence that CRF activity may drive 5-HT2aR’s role in the neurobiological mechanism in the GxEi of pathological aggression.
Very interesting. Having been involved with the Foster Care system, I have seen these behaviors first hand and the stresses they have. Thank you.
Thank you for your insight. One of my favorite things about this project was getting to look closer at the mechanisms that drives antisocial behaviors. For example, it is a known observation that those who get abused children have a higher risk of becoming an abuser compared to non-abused children. Now, I have a better explanation on why those occur to help my patients understand why.
Alex, very nice poster and work! This looks like a very interesting hypothesis and potential therapeutic target. One question I have is whether you looked at CRF levels in other brain regions and, also, at later developmental timepoints, such as in adulthood when the ASB is apparent?
Hi Dr. Keefe,
Thank you for your praise, it is much appreciated. We originally planned to look at CRF concentrations in two other tissues: nucleus accumbens and hypothalamus because its role in modulating behavior and the stress response. However, we could not get the data from those tissues mainly due to problems with raising the colony of MAO-ANeo Mice. So, we are going forward with only the PFC data for now, and may explore other tissue types in the future. As of now, we did not have any plans to observe CRF concentrations in different developmental time points. We did not look at later time points because we intended to further develop the findings of a previous study (Godar SC, et al 2019). This study observed that exposure to early stressors in the first week of life (PND 1-7) was able to yield significantly more aggressive behaviors compared MAO-ANeo not exposed to any early stressors, while exposure to early stressors in the second week of life (PND 8-14) did not yield significant increases in aggression. Although, these findings do not rule out the need to observe brain tissues at different time points.
Godar SC, et al 2019 – Godar SC, Mosher LJ, Scheggi S, et al. Gene-environment interactions in antisocial behavior are mediated by early-life 5-HT2A receptor activation. Neuropharmacology. 2019. doi:https://doi.org/10.1016/j.neuropharm.2019.01.028
Those are compelling results, and I think that future therapy targeting this pathway will be beneficial for this condition.
Thank you for visiting my poster. I also think that these are good results in the context of other studies. However, I think it is still important to highlight some limitations with mouse models translating to human applications. For instance, I learned about the anthropomorphic bias, which is about the inherent limitation of animal models to study behavioral features because certain aspects of human society cannot be captured such as societal norms, responsibilities, and deceitfulness.
Very interesting work. What are the next steps?
Hi Dr. Lim,
Thank you for appreciating my poster. I think the next step would be to characterize how does 5-HT2A receptor hyperactivity lead to antisocial behaviors because that is the only step in my diagram that does not have a direct explanation. As of now, I have not done enough literature research in that domain to give conjectures on experimental designs to do so.
Great poster. Looks like alot of research went into your findings.
Sure excited you’ll be finishing soon. Congratulations.
Alex, very interesting. I was not aware of the relationship between ASB and specific pharmacodynamic mechanisms.
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