Dr. Scott Steffensen, Department of Psychology

Completion of Academic Objectives

Research in my lab is dedicated to the elucidation of brain substrates underlying drug addiction. Elder Boyd K. Packer has stated, “It is my conviction, and my constant prayer, that there will come through research, through inspiration to scientists if need be, the power to conquer narcotic addiction through the same means which cause it.”(Packer 1989). This plea from Elder Packer is emblazoned on a poster at the entrance to my laboratory to remind us of the seriousness of addiction research and the stranglehold that addiction has on the lives of many of God’s children. We study critical brain circuits involved in natural rewarding behaviors and drug addiction. I proposed a mentored project in my laboratory in 2009 to characterize the neurophysiological substrates of alcohol addiction. We have made significant progress on this project thanks to this funding and the students under my purview. Indeed, we published three original, peer-reviewed articles directly related to this project. Here are the citations:

• Vargas-Perez, H., Kee, R.T., Walton, C.H., Hansen, D.M., Razavi, R., Clarke L., Bufalino M.R., Allison, D.W., Steffensen, S.C. and van der Kooy, D. Ventral tegmental area BDNF induces an opiate-dependent-like reward state in naive Rats. Science (2009) 324(5935): 1732-4
• Ludlow, K., Bradley, K., Allison, D.W., Taylor, S.R., Yorgason, J.T., Hansen, D.M., Walton, C.H., Sudweeks, S.N., and Steffensen, S.C. Acute and chronic ethanol modulate dopamine D2-subtype receptor responses in ventral tegmental area GABA neurons. Alcoholism: Clinical and Experimental Research (2009) 33(5): 804-11
• Steffensen, S.C., Walton, C.H., Hansen, D.M., Yorgason, J.T., Gallegos, R.A. and Criado, J.R. Contingent and non-contingent effects of low-dose ethanol on GABA neuron activity in the ventral tegmental area. Pharmacol Biochem Behav (2009) 92(1): 68-75

One of the 2009 articles was a Science paper that received a lot of media attention given its impact. There were two BYU undergraduate students and one BYU graduate student on that paper. The other 2009 papers included four BYU undergraduate students and 3 graduate students. All three journals that BYU students published in are Tier 1 high impact journals. I am very proud of this work on many levels, both from a scientific and mentoring standpoint. We learned a lot from this experience, which I believe led to the decision by two of my undergraduate students to attend graduate school rather than medical school. This is consistent with last year and the year before that.
In association with this mentoring grant, I requested travel funds for 6 psychology/neuroscience students to attend the Society for Neuroscience meeting in Chicago, Ill in November 2008 and research stipends for 3 senior-level student research assistants to work directly on this project. These funds were used directly for that purpose. Four undergraduate students, including JD Wilcox, Caitlin Askew, Kyle Ellefsen, James Millward, four graduate students, including Dave Allison, JoAnn Petrie, Devin Taylor and JungJae Park and one Faculty Research Associate, Micah Hansen accompanied me to this meeting. I have taken students to the Neuroscience meeting the past 5 years with much-appreciated internal BYU MEG funds. I am consistently struck by how they are influenced by attendance at these meetings. Many have made contacts at these meetings that have resulted in their admittance into graduate programs, professional programs, etc… Indeed, some have changed their career track as a result of attending them, and now plan on pursuing academic rather than professional careers. For example, this year James Millward, Kyle Ellefsen, and Caitlin Askew, three senior Neuroscience students have applied for graduate schools. James Millward will pursue a combined MD/PhD program. Kyle and Caitlin both scored 1300 and 1500, respectively, on the GRE. They will likely be able to choose from a number of prestigious schools. Thus, in my opinion, this is the single-most important event in their undergraduate career, and as their mentor I would like to support as many promising students as possible in this enterprise. I am so grateful for the support I have been given in this regard.

The primary objective of this MEG project was to evaluate the role of GABA electrical networks in mediating alcohol intoxication. Our central hypothesis was that ventral tegmental area (VTA) GABA neurons, linked by electrical synapses via connexin-36 (Cx36) gap junctions (GJs) to a broader GABA network in the brain, are the primary neural substrates involved in natural rewarding behaviors and in the rewarding effects of ethanol, and that changes in the electrical connectivity between these neurons mediated by GJs might play a role in the progressive increase in the motivation to seek and take ethanol. Given this evidence suggesting a role for Cx36 GJs in mediating ethanol effects on VTA GABA neurons, for this proposal I hypothesized that: 1) Mice lacking Cx36 (knock-outs) will be less sensitive to the intoxicating effects of ethanol on behavior (i.e., measures of ataxia) and VTA GABA neuron activity; and 2) That they will not self-administer ethanol. This was the thesis project of Katie Bradley in Neuroscience. I was her faculty mentor. We have recently submitted a manuscript on this work to the Journal of Pharmacology and Experimental Therapeutics. To accomplish these studies we evaluated the effects of ethanol on neuronal and behavioral responses in Cx36 knock-out (KO) mice. Nearly every Specific Aim that was proposed in the MEG application was achieved thanks to solid efforts of Katie Bradley, the first author on this paper, and the many undergraduate students that worked with her on this project. The abstract of this paper is pasted below. It represents work directly associated with the Specific Aims of this MEG.

Ventral tegmental area (VTA) GABA neurons appear to be critical substrates underlying the acute and chronic effects of ethanol (EtOH ) on dopamine (DA) neurotransmission in the mesocorticolimbic system implicated in alcohol reward. VTA GABA neurons appear to form part of a larger syncytium of GABA neurons in the reticular formation that are linked by electrical synapses via connexin-36 (Cx36) gap junctions (GJs; (Lassen et al., 2007)). Acute intoxicating doses of EtOH and GJ antagonists, including the (Cx36) selective antagonist mefloquine (MFQ), suppress electrical coupling between VTA GABA neurons (Stobbs et al., 2004; Allison et al., 2006). The aim of this study was to examine the role of Cx36 GJs in producing EtOH’s intoxicating and rewarding effects. Using behavioral, pharmacological, molecular and neurochemical methods we compared the effects of contingent and non-contingent EtOH in Cx36 knockout (KO) mice to their wild-type (WT) controls. Cx36 KO mice exhibited significantly more EtOH-induced ataxia in the open field test, but more disruption in motor coordination than their WT controls in the rotarod paradigm. There were no differences between WT and KO mice for ataxia or deficits in motor coordination produced by the GABA modulating sedative/hypnotic pentobarbital or the NMDA antagonist MK-801; however, while Cx36 KO mice did not differ from WT mice in motor activation produced by the DAT inhibitor methylphenidate (MPH), they were insensitive to deficits in motor coordination produced by MPH. Accordingly, Cx36 KO mice showed a marked down-regulation in DAT activity, as assessed by DA voltammetry and quantitative RTPCR. Most importantly, Cx36 KO mice consumed significantly less EtOH than their WT controls in the drink-in-the-dark procedure. These findings provide further support that Cx36 GJs between VTA GABA neurons are important neural substrates for EtOH effects and that loss of Cx36 GJ-mediated coupling results in deficits in DA neurotransmission and the hedonic valence of EtOH reward.

Thus, the deliverables to BYU, the scientific community, and to the community in general in association with this MEG include: 1) Basic discoveries regarding the neurophysiological substrates involved in alcohol addiction; 2) Elucidation of pharmacological and behavioral strategies for treatment of addiction; 3) Meaningful mentoring environment for students pursuing professional and academic careers; and 4) An understanding of the addiction process will help improve the emotional, spiritual, and physical well-being of our brothers and sisters whose lives are altered due to addiction’s stranglehold on their lives.

Budget Summary

In the original proposal, we requested $12,000 in funds to cover 3 senior-level student research assistants at $10/hr for 10 hrs/wk for 40 weeks of the year. As requested, $12,000 was spent on stipends. We requested $7600 in funds to cover travel expenses for six senior-level undergraduate students to attend the Society for Neuroscience meeting in Chicago, Ill. Only four undergraduate students were able to attend the conference. The remainder of the grant funds were used to cover expenses for two of the four graduate students that attended the conference. I have pasted at the bottom of this report the 5 posters that were presented by students at this conference.

Mentoring Environment

The research laboratory is where students experience first-hand how to put their learning into creative practice. They formulate hypotheses, design experiments to test their hypotheses, develop the technology to perform the experiments, interpret the results of those experiments, and get credit for the discovery and dissemination of their findings. The teaching, mentoring and possibly the inspiring of students within the laboratory setting has clearly become a source of joy to me, as that is where it is obvious that I can make a difference in the lives of these motivated young adults. The majority of students under my purview aspire to medical/dental professional and research careers. The following undergraduate research courses, NS449R, Psych 499R and Psychology 430R, are vehicles for mentoring relationships in my lab. I mentored a total of 68 students in 2009 who took these courses. Not all the students under my purview take these courses. In fact, new students only observe in my lab the first semester in order for them to evaluate our operations and if they are interested in being involved and committed. The students who take my research courses are predominantly junior and senior-level Neuroscience and Psychology majors. These courses provide opportunities in hands-on laboratory research. Students are required to learn fundamentals and a variety of research methodologies including molecular, neurochemical, electrophysiological, behavioral, and clinical techniques and paradigms. I have mentored hundreds of undergraduate students since coming to BYU. Most of the students are motivated and smart before they work with me. However, their ability to secure positions in professional and graduate schools is in part a result of their research experience. Because of the experience in my lab they can see that there is a future in academia and research, and that it looks bright, in fact so bright that they are choosing this direction instead of the more lucrative professional school direction. I hope that they have seen in me the hope I have for their future in research. I hope that they have seen in me the joy I have in discovery. More and more schools demand this mentoring experience, if not highly recommend it. It’s what makes them stand out from the fray. I’m relatively certain that BYU’s emphasis on mentoring, ORCA support, and my continuing NIH funding has played a positive role in the ability of these students to achieve their career goals, which are generally lofty, gainful, and of high quality.

But, I’m absolutely certain that the mentoring experience in my laboratory has encouraged students to pursue combined professional/academic careers. I seriously doubt that they would have gone this route without my influence.

The more senior students in my lab are made stewards over their experiments, wherein they are wholly responsible for the technical and analytical outcomes. They also supervise the training of new students. They are, and will continue to be, included as co-authors on papers, according to their degree of effort and participation in the studies. Thanks to the support of ORCA mentoring grants, thirty six of them have attended scientific conferences with me (Society for Neuroscience in San Diego, Atlanta, Washington DC, and Chicago) as well as the Research Society for Alcoholism in Vancouver, Chicago, Washington, DC and San Diego). They all presented our findings at these international meetings. I encourage all our senior-level undergraduate students to apply for ORCA scholarships, and 24 have obtained them with my help. Finally, I have vested interest in the future of our students. I recommend them for positions after graduation. Not a week goes by that I don’t write a letter of recommendation for them or students in other courses, either for professional schools, employment, or graduate schools. I even employ them. For example, I have employed eight former Neuroscience students as Faculty Research Associates on a full-time basis. Presently, Micah Hansen and Becky Wilcox are Faculty Research Associates and former Neuroscience majors. I wish I could employ more. For the most part, the students are highly motivated, brilliant young people, with a spiritual bent to boot. I feel honored and privileged to work beside them. My only concern I have regarding mentoring is to try to identify students early on in their undergraduate experience who might have an interest in research. I really need two years with them to get them to a position wherein they can make a meaningful contribution to the laboratory and perhaps to the world. I need that time to develop an effective relationship with them such that a reciprocal trust is developed. Then, I am in a better position to write well-developed and strong letters of recommendation for their post-graduate pursuits. I dismay at times that I meet promising students in their senior year, when it is a little late.