1. + Team Members: Brian Barnett Valerie Cohen Taylor Hearn Emily Jones Reshma Kariyil Alice Kunin Sen Kwak Jessica Lee Brooke Lubinski Gautam Rao Ashley Zhan Research in Testing ADHD's Link to Impulsivity in Neuroscience Mentor: Matthew Roesch Librarian: Jim Miller TEAMRITALIN TEAM RITALIN

2. + Introduction Attention Deficit Hyperactivity Disorder (ADHD) Twentyfold increase in prescription of ADHD drugs in past 30 years [1] Limited research on the neurobiology of the disorder Diagnoses based on qualitative observations Frequent misdiagnoses and rising medical costs Research valuable to professionals and patients

3. + Importance of Our Project Animal models could present a solution No valid animal model of ADHD developed yet Women who smoke during pregnancy are three times as likely to have children diagnosed with ADHD [2] 1 in 5 women still smoke during pregnancy [3] Nicotine causes changes in the development that alters dopaminergic pathways in the brain Fetal nicotine rats and humans with ADHD had similar deficits on behavioral tasks Goal Validate fetal nicotine rat model to further study ADHD

4. + Our Approach Rats perform the stop-signal task (a measure of impulsivity) Record from dorsal prelimbic cortex (dPL), a brain area responsible for controlling impulsive behavior Administer Adderall ® to experimental groups Measure performance differences (Bryden et al,. 2012)

5. + Our Approach Rats perform the stop-signal task (a measure of impulsivity) Record from dorsal prelimbic cortex (dPL), a brain area responsible for controlling impulsive behavior Administer Adderall ® to experimental groups Measure performance differences (Bryden et al., 2012)

15. + Our Approach Rats perform the stop-signal task (a measure of impulsivity) Record from dorsal prelimbic cortex (dPL), a brain area responsible for controlling impulsive behavior Administer Adderall ® to experimental groups Measure performance differences (Bryden et al,. 2012)

16. + Our Approach Rats perform the stop-signal task (a measure of impulsivity) Record from dorsal prelimbic cortex (dPL), a brain area responsible for controlling impulsive behavior Administer Adderall ® to experimental groups Measure performance differences (Bryden et al,. 2012)

17. + Our Approach Rats perform the stop-signal task (a measure of impulsivity) Record from dorsal prelimbic cortex (dPL), a brain area responsible for controlling impulsive behavior Administer Adderall ® to experimental groups Measure performance differences (Bryden et al,. 2012)

18. + Research Questions & Hypotheses Research Questions I.Is there a correlation between neural firing in the dPL cortex and impulsivity in control rats? II.Is neural firing in the dPL cortex disrupted and impulsivity increased in fetal nicotine rats? III.Will administration of Adderall ® increase dPL firing and improve stop-signal task performance in fetal nicotine rats? Hypotheses I.dPL will exhibit increased firing during correct stop-signal trials II.Fetal nicotine rats will exhibit reduced neural firing in the dPL cortex and increased impulsivity III.Adderall ® administration will increase dPL activity and improve task performance in fetal nicotine rats

19. + Research Questions & Hypotheses Research Questions I.Is there a correlation between neural firing in the dPL cortex and impulsivity in control rats? II.Is neural firing in the dPL cortex disrupted and impulsivity increased in fetal nicotine rats? III.Will administration of Adderall ® increase dPL firing and improve stop-signal task performance in fetal nicotine rats? Hypotheses I.dPL will exhibit increased firing during correct stop-signal trials II.Fetal nicotine rats will exhibit reduced neural firing in the dPL cortex and increased impulsivity III.Adderall ® administration will increase dPL activity and improve task performance in fetal nicotine rats

20. + Research Questions & Hypotheses Research Questions I.Is there a correlation between neural firing in the dPL cortex and impulsivity in control rats? II.Is neural firing in the dPL cortex disrupted and impulsivity increased in fetal nicotine rats? III.Will administration of Adderall ® increase dPL firing and improve stop-signal task performance in fetal nicotine rats? Hypotheses I.dPL will exhibit increased firing during correct stop-signal trials II.Fetal nicotine rats will exhibit reduced neural firing in the dPL cortex and increased impulsivity III.Adderall ® administration will increase dPL activity and improve task performance in fetal nicotine rats

21. + Research Questions & Hypotheses Research Questions I.Is there a correlation between neural firing in the dPL cortex and impulsivity in control rats? II.Is neural firing in the dPL cortex disrupted and impulsivity increased in fetal nicotine rats? III.Will administration of Adderall ® increase dPL firing and improve stop-signal task performance in fetal nicotine rats? Hypotheses I.dPL will exhibit increased firing during correct stop-signal trials II.Fetal nicotine rats will exhibit reduced neural firing in the dPL cortex and increased impulsivity III.Adderall ® administration will increase dPL activity and improve task performance in fetal nicotine rats

22. + Research Design Independent variables Nicotine Adderall ® Dependent variables Movement time Percent correct Neural recording Phase 1: Phase 1: control rats vs nicotine rats Variables Phase 1 Phase 2 Phase 2: Phase 2: fetal nicotine w/saline injections vs fetal nicotine w/Adderall ® injections (Bryden et al., 2012)

23. + Methodology: Phase 1 Breed ratsSelect pupsTask training Between-group difference observed Implant electrodes Match on task performance Neural Recording HistologyData Analysis

24. + Methodology: Phase 2 Breed ratsSelect pupsTask training Between-group difference observed Implant electrodes Match on task performance Drug Administration (Adderall ®) Neural Recording HistologyData Analysis

25. + Preliminary Results: Percent Correct (Go) (Bryden et al,. 2012)

26. + Preliminary Results

27. + Preliminary Results: Movement Times (Go) (Bryden et al,. 2012)

28. + Preliminary Results

29. + Preliminary Results: Percent Correct (Go) (Bryden et al,. 2012)

30. + Preliminary Results

31. + Preliminary Results: Percent Correct (Go and Stop) (Bryden et al,. 2012)

32. + Preliminary Results

33. + Preliminary Results: Movement Times (Go and Stop) (Bryden et al,. 2012)

34. + Preliminary Results

35. + Results Summary & Expectations Nicotine rats learned task significantly faster than control rats No significant differences on movement times during go trials between groups Nicotine rats performed significantly better during stop trials than control rats Nicotine rats are significantly slower during stop trials than control rats Expectations Significant differences in neural firing of dorsal prelimbic cortex Correlations with behavioral data above

36. + Future Directions Trained fetal nicotine & control group on the SST Performed surgeries Recording neural data Complete Phase 1 Analyze behavior results Fall 2012 Complete Phase 2 Analyze behavior results Present at Undergraduate Research Day Begin drafting thesis Winter 2012/Spring 2013 Complete data analysis Continue writing thesis Attend & present at SfN conference Contact discussants Summer/ Fall 2013 Complete writing thesis paper Present at Senior Thesis Conference Submit for publication Spring 2014

37. + Anticipated Conclusions Neurophysiological pathway disruption in inhibiting impulsivity Repaired with Adderall ® Nicotine exposure correlation of ADHD Fetal nicotine rats as valid models of ADHD, applicable to humans

38. + Team Composition Everyone contributes to writing & working in lab Lab: each person 4 hrs/wk Literature review: 3 subgroups Data analysis: 1 subgroup Assignments/Internal Deadlines Split up based on skill sets Always have team deadlines at least 2 weeks before the assignment is due! Good relationship with mentor

39. + Team Challenges Scheduling for meetings/lab work  Utilize Google calendar! Rat fatalities during/after surgeries Improperly implanted electrodes Explaining our current results

40. + Advice to Freshmen Start early! Don’t procrastinate Grant applications & ethics approval (IACUC) take longer than you think Keep your Gemstone project a priority Helps with scheduling meetings Take good meeting minutes Keep up with literature review Constant communication Use your resources! (mentor, Gemstone staff, librarian, etc)

41. + Acknowledgements Our mentor, Dr. Matthew Roesch Graduate Students/Lab Assistants Greg, Dan, Amanda, Ronnie, Vadim, Nina, Mindy Our Experts Dr. Ricardo Araneda & Dr. Elizabeth Redcay Howard Hughes Medical Institute Gemstone Staff Librarian: Jim Miller

42. + References [1]: Sroufe, A. L. (2012, January 28). Ritalin Gone Wrong. The New York Times. Retrieved from http://www.nytimes.com/2012/01/29/opinion/sunday/childrens-add-drugs-dont-work-long- term.html?_r=1&pagewanted=all http://www.nytimes.com/2012/01/29/opinion/sunday/childrens-add-drugs-dont-work-long- term.html?_r=1&pagewanted=all [2]: Linnet, K., Wisborg, K., Obel, C., Secher, N.J., Thomsen, P.H., Agerbo, E., & Henriksen, T.B. (2005) Smoking during pregnancy and the risk for hyperkinetic disorder in offspring. Pediatrics, 116(2), 462-467. [3]: Zhu, J., Zhang, X., Xu, Y., Spencer, T. J., Biederman, J., & Bhide, P. G. (2012). Prenatal nicotine exposure mouse model showing hyperactivity, reduced cingulate cortex volume, reduced dopamine turnover, and responsiveness to oral methylphenidate treatment. J Neurosci, 32(27), 9410-9418. doi: 32/27/9410 [pii] 10.1523/JNEUROSCI.1041-12.2012 [4]: Bryden, D. W., Burton, A. C., Kashtelyan, V., Barnett, B. R., & Roesch, M. R. (2012). Response inhibition signals and miscoding of direction in dorsomedial striatum. Front Integr Neurosci, 6, 69. doi: 10.3389/fnint.2012.00069

43. + Questions?