+ TEAM RITALIN Mentor: Matthew Roesch Librarian: Francy

+ TEAM RITALIN Mentor: Matthew Roesch Librarian: Francy

+ TEAM RITALIN Mentor: Matthew Roesch Librarian: Francy Stilwell Team Members: Research in Testing ADHD's Link to Impulsivity in

Brian Barnett Valerie Cohen Taylor Hearn Emily Jones Reshma Kariyil Alice Kunin Sen Kwak Jessica Lee Brooke Lubinski Gautam Rao Ashley Zhan Introduction Attention Deficit Hyperactivity Disorder (ADHD)

Affects 5-10% of all school age children Twentyfold increase in prescription of ADHD drugs in past 30 years Limited research on the neurobiology of the disorder Diagnoses based on qualitative observations Frequent misdiagnoses and rising medical costs Prenatal Nicotine Exposure (PNE) PNE is linked to many psychiatric disorders Women who smoke during pregnancy are three times as likely to have children diagnosed with ADHD

1 in 5 women still smoke during pregnancy Several studies show behavioral, neuroanatomical, & neurochemical disturbances after PNE that are similar to ADHD Benefits of methylphenidate point to PNE as a valuable animal model of impulsivity PNE rats and humans with ADHD had similar deficits on behavioral tasks that measure impulsivity

Introducti on Attention Deficit Hyperactivity Disorder (ADHD) & PNE PNE rats and humans with ADHD exhibit similar behavioral symptoms: inattention, hyperactivity, and impulsivity Inattention: difficulty concentrating, distractibility, and problems completing tasks Hyperactivity: high or excessive levels of motion Impulsivity: tendency toward rapid, unplanned actions

without considering the negative consequences of these actions Human Stop-signal tasks measure impulsivity Mirabella G, Iaconelli S, Modugno N, Giannini G, Lena F, et al. (2013) Stimulation of subthalamic nuclei restores a near normal planning strategy in parkinsons patients. PLoS ONE 8(5): e62793. doi:10.1371/journal.pone.0062793 Introducti on Medial Prefrontal Cortex (mPFC)

Gass, J.T., & Chandler, L.J. (2013). The plasticity of extinction: contribution of the prefrontal cortex in treating addiction through inhibitory learning. Frontiers in psychiatry, 4(46): 1-13. Our Approach Understanding of mPFC neural signaling is essential to treatment Experimental system will elucidate foundation of behavior

Correlation between behavior and neural firing will allow us to pinpoint the signals involved in impulsive behavior Our Goal Hypothesis: PNE rat model is a valid model for the study of ADHD-like symptoms 1. Show that PNE rats are more impulsive during performance on a stop-signal task that measures the ability you inhibit unwanted responses

2. Demonstrate that activity in mPFC is correlated with performance on the stop-signal task 3. Evaluate neural signals in mPFC in PNE rats during performance of the stop-signal task Rat Breeding & Selection Acclimate dams to nicotine in

water Breed rats 10 mothers total Acclimation to nicotine 0.2 0.4 0.6 mg/mL

17 PNE and 23 control male pups Cross-fostered to control mother Select pups Rat Breeding & Selection Acclimate dams to nicotine in water Breed rats Select pups

No significant differences in pregnancy duration, pups per litter, pup birth weight, or hyperactivity (t-test; p > 0.05) Randomly selected 8 males each from 17 PNE pups (from 3 dams) and 23 control pups (from 3 dams) Stop-signal Task Training & Surgery Task Training

Implant electrodes Rat Stop-signal task measures impulsivity 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 Rats performed significantly worse on STOP trials compared to GO trials

* Percent Correct 75 Control 50 GO STOP *(t-test; p < 0.05)

PNE Rats performed significantly worse on STOP trials compared to controls Control Nicotine Percent Correct 75 * PNE

50 GO STOP * (t-test; p < 0.05) Rats were slower on correct STOP trials Movement Time (ms)

750 Control 300 GO STOP STOP error PNE rats were significantly faster

on all trial-types Movement Time (ms) 750 Control PNE Nicotine * *

* 300 GO STOP STOP error * (t-test; p < 0.05)

Speed-Accuracy Tradeoff: When rats were slower, they performed better PNE r2 = 0.1289 r2 = 0.1735 p < 0.0001 Summary Behavior

PNE rats were more impulsive (reduced stop accuracy) PNE rats were faster on STOP and GO trials When rats were slower they were better at inhibiting behavior (speed-accuracy tradeoff) Neural Recording & Analysis

Neural Recording Histology Data Analysis 16 rats in total from the control and PNE groups performed 349 sessions, over which we collected neural firing data from 631 and 552 cells, respectively Plexon

Single cell example of a neuron that increased firing during the task Left Activity was stronger on STOP trials when behavior had to be inhibited Left Right Average neural firing over all increasing-type neurons

(Control: n = 121; PNE: n = 131) Control PNE Average neural firing was modulated by response (solid versus dashed) on GO trials Control PNE Average neural firing was stronger on STOP trials in both control and PNE

rats Control PNE (Wilcoxon; p < 0.001) However, overall firing was significantly reduced in PNE rats relative to controls Control PNE

(Wilcoxon; p < 0.001) mPFC firing was positively correlated with percent correct (higher firing = better behavior) Summary Increasing-type cells Neural activity was modulated by response direction

Neural activity was stronger during STOP trials Neural activity was correlated with behavioral performance Neural activity was significantly reduced in PNE rats compared to controls

Other neurons decreased firing during performance of the task Average neural firing over all decreasing-type neurons (Control: n = 182; PNE: n = 174) Control PNE Decreasing-type neurons also fired more strongly on STOP versus GO trials Control

PNE (Wilcoxon; p < 0.05) However, the activity of decreasingtype was not correlated with percent correct Instead, neural activity was positively correlated with movement time (high firing = slower) Summary

Decreasing-type cells Neural activity was modulated by response direction Neural activity was stronger during STOP trials Neural activity was correlated with motor output in controls only

Neural activity was significantly reduced in PNE rats as compared to controls Conclusions Behavior PNE rats were more impulsive (reduced stop accuracy)

PNE rats were faster than controls on both STOP and GO trials Neural recordings Neural activity in mPFC was stronger during STOP trials during which rats had to inhibit behavior Neural activity in mPFC was correlated with performance and speed

Neural activity of mPFC neurons was significantly attenuated in PNE rats as compared to controls PNE rat model is a useful model to study the neural underpinnings of impulsive-like behavior observed in ADHD Future Directions Studies should target mPFC. Specifically, artificially increasing neural activity in mPFC should alleviate impulsivity in PNE rats. Creative Commons Wired

Courtesy of Deisseroth lab Acknowledgements Mentor - Dr. Matthew Roesch Librarians - Ms. Francy Stilwell Mr. Jim Miller Gemstone Staff Dr. Frank Coale Dr. Kristan Skendall Mrs. Vickie Hill Mrs. Leah Kreimer Tobin Ms. Faith Rusk Mr. James Trainor Roesch Lab Members Mr. Daniel Bryden

Ms. Amanda Burton Ms. Ronny Gentry Mr. Vadim Kashtelyan Ms. Nina Lichtenberg Discussants Dr. Ricardo Araneda Dr. Gregory Bissonette Dr. Erica Glasper Dr. Elizabeth Redcay Dr. Thomas Stalnaker Funding: Howard Hughes Medical Institute, University of Maryland Gemstone Honors Program, and National Institute on Drug Abuse . References

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 Gass, J.T., & Chandler, L.J. (2013). The plasticity of extinction: contribution of the prefrontal cortex in treating addiction through inhibitory learning. Frontiers in psychiatry, 4(46): 1-13. Heath, C. J., & Picciotto, M. R. (2009). Nicotine-induced plasticity during development: modulation of the cholinergic system and long-term consequences for circuits involved in attention and sensory processing. Neuropharmacology, 56

Suppl 1, 254-262. doi: 10.1016/j.neuropharm.2008.07.020 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. Mirabella G, Iaconelli S, Modugno N, Giannini G, Lena F, et al. (2013) Stimulation of subthalamic nuclei restores a near normal planning strategy in parkinsons patients. PLoS ONE 8(5): e62793. doi:10.1371/journal.pone.0062793 van Gaalen,

M. M., van Koten, R., Schoffelmeer, A. N., & Vanderschuren, L. J. (2006). Critical involvement of dopaminergic neurotransmission in impulsive decision making. Biol Psychiatry, 60(1), 66-73. doi: 10.1016/j.biopsych.2005.06.005 Wasserman, G. A., Liu, X., Pine, D. S., & Graziano, J. H. (2001). Contribution of maternal smoking during pregnancy and lead exposure to early child behavior problems. Neurotoxicol Teratol, 23(1), 13-21. doi: S0892-0362(00)00116-1 [pii] 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

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