Answers to Interview Questions for the ISBRA Newsletter

November 2020

    1 How did you become interested in alcohol research?

    I think it's important for me to tell you how my interest in the field of behavioral genetics grew in the first place. I started studying music in college, but I soon found that my desire outweighed my talent, and I was smart enough to know when to take another direction. By then, I had already been introduced to psychology - but not yet genetics - and my circumstances led me to move to the eastern United States. With that move came the opportunity to take a unique course in behavioral genetics, a course not offered by many programs at the time, and I was given the opportunity to do research in a behavioral genetics laboratory. I fell in love with the idea that behavior has a genetic component and that this could be demonstrated by the ability to selectively breed for different levels of a particular behavior.

    My first contact with this genome manipulation method, which would become one of the pillars of my research, was with mice bred to obtain differences in brain weight (how that was done is a story for another time). My move into alcohol research came when my then mentor, Dr. Martin ("Marty") Hahn, introduced me to Dr. Bruce Dudek, who would become my Ph.D. mentor. Dr. Dudek investigated the Long Sleep and Short Sleep lines of mice, bred for their differences in sensitivity to the sedative effects of alcohol, and the second set of selected lines that I would work with. My interest in alcohol research was fueled by my desire to understand and identify the genetic factors underlying the traits relevant to addiction. At the meetings of ISBRA, the Society for Research on Alcoholism, and the Society for Neuroscience, I met the small group of addiction scientists in the field of behavioral genetics and began to expand my network. As the cadre of researchers with knowledge of quantitative genetics grew, so did our ability to map genes for complex traits, and the dream of identifying specific genes and genetic variants relevant to addiction came true. My interest in research on alcohol and addiction was consolidated.

    1. What were the challenges you encountered during the early stage of your career as a scientist and how did you overcome them?

    Like so many women in the historically male-dominated STEM (Science, Technology, Engineering, and Math) disciplines, I suffered from imposter syndrome early in my career, without having a name for it. I did a postdoctoral fellowship with Dr. John Crabbe, and as the critical juncture in which a career decision had to be made approached, I casually commented to Dr. Crabbe that perhaps he would consider hiring me as his director. laboratory. Without hesitation, and in no uncertain terms, he kindly said no to me and then explained to me why he thought it would be a waste of my talent and what imposter syndrome is. His trust in me was the push I needed to first jump into the abyss and then get out of it, supporting myself, my research, my technicians, my students, and my fellows solely on grants. Of course, the climb was steep and required the insight and help of close colleagues and mentors (I could name so many names here), to whom I attribute the provision of resources and opportunities that benefited my success. These include resources for collecting preliminary research data, speaking opportunities at national and international meetings (including ISBRA), inclusion of my research projects in consortium grants, and nominations for committee membership and prestigious professional awards.

    1. What are the areas of research on alcohol that you are currently focusing on?

    My current research on alcohol is focused on the discovery of genetic and transcriptomic elements that underlie differences in chronic alcohol use in mouse models. One of the models takes me back to my roots, which is a select line model bred for high versus low levels of voluntary alcohol intake. In collaboration with Dr. Robert Hitzemann, we are studying the risk of alcohol intake by comparing the transcriptome between the high and low lines in the brain's reward circuitry. A second model we are using is a highly heterogeneous population of mice that allows us to take advantage of the genetic diversity found when standard and wild inbred mouse strains are crossed. In this model, the transcriptome is examined after a 3-month period of chronic alcohol consumption, with the aim of defining the transcriptomic effects of different levels of consumption in specific brain regions. So far, our data have focused on the extracellular matrix and the primary cilium, a thin stretch of the cell membrane that protrudes from the surface of most cells. I run the Portland Alcohol Research Center (PARC) and the renewal of PARC's competence is currently under consideration. The consistency of the results in the rodent and non-human primate models of chronic alcohol consumption has led to the focus on the tetrapartite synapse, with components including the pre and postsynaptic neuron, astroglial processes, and the extracellular matrix. PARC intends to conduct genetic, epigenetic, transcriptomic, functional and pharmacological investigations to study the tetrapartite synapse.

    1. What were the landmark studies (from bank to bedside and vice versa) that caught your attention during your career in alcohol research?

    I had just started my involvement in the field of alcohol research when fundamental data was being generated on the importance of dopamine in multiple addictive drugs, including alcohol. I was especially drawn to addiction theories that crossed drug classes, and at that time little research had been done in the area of ​​alcohol-induced sensitization. Research on sensitization dominated the early years of my career, from the perspectives of genetic susceptibility, mechanism, and relevance to addiction. As research on stressors and the stress axis grew and supported their role in addiction and addiction relapse, my attention turned to questions about cross-sensitization between alcohol and stressors in when it comes to craving. Promising preclinical studies led to clinical trials to test the effect of corticotropin releasing factor receptor 1 antagonists on stress-induced alcohol craving. Overall, the results were disappointing, calling into question whether this receptor remains a valid target for treatment, and the literature offers different opinions. In my opinion, the heterogeneity of the response (that is, individual differences) will be a factor to be carefully considered as research on the treatment of these and other possible therapies progresses.

    1. How do you envision the direction of alcohol research in the coming decades?

    In my opinion, heterogeneity of response (ie individual differences) will be an important consideration in research on response to alcohol and its treatment. This is not especially insightful, but rather a reminder that risk factors and treatment efficacy are not universally common. An end point can be reached in several ways, and knowledge of the different pathways, which represent specific mechanisms, is key to developing personalized treatments. We miss out on important findings if we only consider mean responses, something the research community has realized, and I suspect that genetic information will continue to feature prominently in future research on both risk and response. Furthermore, attention to gender differences and, in particular, the inclusion of women in research, including that of alcohol, has only just begun and is extremely important. Finally, throughout my career there have been remarkable discoveries in the field of epigenetics, and there is a need to focus more on interaction effects; identifying combinations of genetic and environmental factors that reduce and increase risk or response, and how they do so. We are living a current example created by the pandemic. Even among those who do not contract the virus, there is almost certainly a differential situational impact on alcohol consumption that may have long-term consequences for some.

    1. What is the message you want to convey to young researchers?

    Future generations still have a lot to research and technological advances are enormously helpful. When I entered this field, we were in the phase of demonstrating that there was a genetic component in the effects of alcohol and its consumption. We are now in the phase of not only identifying risk genes, but risk variants, of being able to interrogate brain circuits with genetically modified receptors and light, of studying neurocircuits in an increasingly sophisticated way with advanced imaging technology and to rapidly make permanent alterations to the genome. I encourage those new to this field to maintain their lifeline with their good mentors and to grow their collaborative networks to enable integrative approaches. There are strengths and weaknesses in each research tool and methodology, and in animal and human research. I encourage preclinical and clinical researchers to share their ideas, to add creativity to discussions about animal models of addiction and consilience with the human condition, to contribute to the creation of new models and new methods, and to be honored to have the opportunity to contribute to this research effort.