1. Current Topics in Neuropsych Research June 28, 2011

2. Current Research in Epilepsy & Depression

3. Seizure Susceptibility in a Rodent Model of Depression & Epilepsy Co-Morbidity S. Alisha Epps Emory University Dept of Human Genetics Neuroscience Program Weinshenker Lab

4. Co-morbidity: Epilepsy & Depression o Bidirectional Co-morbidity Epileptics are ~5 times more likely to develop depression Epileptics are ~5 times more likely to develop depression Likewise, patients with depression also have a heightened risk of developing epilepsy Likewise, patients with depression also have a heightened risk of developing epilepsy o Particularly strong correlation with Temporal Lobe Epilepsy (TLE)

5. Creating an Animal Model of Depression o o Plexiglas cylinder 65 cm tall and 30 cm in diameter filled with water (25°C) o o Animal initially displays escape-oriented behavior, but eventually will display only movements sufficient to keep their head above water or “floating” o o Antidepressants reduce “floating” behavior o o Problems?? “Struggle”“Float” Weiss et. al, Pharmacol Biochem Behav. 1998 From Defense by Kroshona Tabb, Emory University, 2008

6. Caveats of FST model 1.False positives (e.g. amphetamine) 2.False negatives (e.g. Selective Serotonin Reuptake Inhibitors (SSRIs)) 3.Time course of antidepressant drug efficacy Develop (or select) a rat that is vulnerable or “ sensitive ”, and can therefore display a more severe and long-lasting depression-like symptoms when exposed to the FST From Defense by Kroshona Tabb, Emory University, 2008

7. Model of Depressive-like Behavior Weiss et. al, Pharmacol Biochem Behav. 1998 For more than a decade, the Weiss lab has selectively-bred rats exhibiting depression-like phenotypes (i.e. high and low motor activity in the FST) Struggle LESS Float MORE Struggle MORE Float LESS From Defense by Kroshona Tabb, Emory University, 2008

8. Swim Low-Active & High-Active o SwLo Rats: “Depression-susceptible” Selectively bred for low activity in swim test (increased floating) Selectively bred for low activity in swim test (increased floating) Respond to many antidepressants after chronic treatment Respond to many antidepressants after chronic treatment Anhedonic-like behavior Anhedonic-like behavior o SwHi Rats: “Depression-resistant” Selectively bred for high activity in swim test (decreased floating) Selectively bred for high activity in swim test (decreased floating)

9. West H. K., & Weiss J. M. (1998) Pharmacol. Biochem. & Behav. 61, 67-79. From Lecture by Jay Weiss, Emory University, 2006

10. What might underlie these differences in depression-like behaviors? From Lecture by Jay Weiss, Emory University, 2006

11. What might underlie these differences in depression-like behaviors? From Lecture by Jay Weiss, Emory University, 2006

12. So Where Do We Go From Here? o AKA…what will Alisha do when Duke TIP is over  o Now Introducing: Exercise! o Wait….what?? http://www.christopherchua.com/me/out-of-the-rat-race

13. Exercise, Epilepsy, & Depression o Exercise is known to be anticonvulsant. It’s also known to be antidepressant. o Might voluntary exercise be a safe and effective treatment for co-morbid epilepsy and depression? Reiss, J. I., R. K. Dishman, et al. (2009). "Chronic activity wheel running reduces the severity of kainic acid-induced seizures in the rat: possible role of galanin." Brain research 1266: 54-63.

14. How Might This Work? o Chronic exercise increases levels of galanin in the brain. o Galanin is a neuropeptide that is co-released with norepinephrine. o Galanin is primarily inhibitory, and may regulate neuronal excitation within the hippocampus. Reiss, J. I., R. K. Dishman, et al. (2009). "Chronic activity wheel running reduces the severity of kainic acid-induced seizures in the rat: possible role of galanin." Brain research 1266: 54-63.

15. Experiments in Exercise o What might the results of these experiments mean for our understanding of epilepsy and depression, and for treatment of patients with this co-morbidity?

16. Reading Circles

17. Generalized Anxiety Disorder

18. Post-Traumatic Stress Disorder

19. PTSD, Cont’d

20. Specific Phobia

21. Specific Phobia, Cont’d

22. Behavioral Characterization of a Mouse Model for Lesch- Nyhan Disease Heather A. Mitchell April 30, 2010

23. Lesch-Nyhan Disease (LND) o X-linked genetic disorder caused by dysfunction in HPRT gene (Hypoxanthine- guanine phosphoribosyltransferase) o HPRT Severity of disease correlated with amount of HPRT Severity of disease correlated with amount of HPRT Required for purine metabolism Required for purine metabolism Loss leads to increased uric acid blood levels Loss leads to increased uric acid blood levels

24. Neurological symptoms Mental retardation Very variable, but average IQ is 60 Motor disabilities Losses in striatal dopamine Aggressive and self-injurious behavior Finger-biting Eye-poking Sticking fingers in wheelchair spokes

25. HPRT KO mice o No obvious abnormal phenotype o Normal locomotor behavior o Enhanced responses to amphetamine Jinnah, et al., 1992 Locomotor activity over 15 hours

26. HPRT and PRTFDC1 o Removing HPRT alone in a mouse model does not cause a behavioral phenotype o PRTFDC1 is in the HPRT gene family, function unknown o Humans have PRTFDC1 and mice do not o Hypothesis: Both lack of HPRT and expression of PRTFDC1 are necessary for behavioral phenotype of LND

27. Creation of transgenic mice WT/WT x x x WT/ HPRT KO PRTFDC1 Tg/ HPRT KO PRTFDC1 Tg/ HPRT WT WT/ HPRT KO PRTFDC1 Tg/ HPRT WT PRTFDC1 Tg/ HPRT +/- 6 generations PRTFDC1/ HPRT +/-

28. Behavioral characterization o Locomotor behavior Exploratory Exploratory Circadian Circadian o Amphetamine-induced stereotypy o Resident-intruder aggression

29. Locomotor behavior

30. Amphetamine-induced stereotypy

31. Resident-intruder aggression

32. Deficits in striatal dopamine

33. Are these mice a good model for LND? Human LND patients o Impaired motor control o Mental retardation o Aggressive behavior o Self-injurious behavior o Losses in striatal DA Mice o No visible Ioss of motor control o Mental retardation - not tested o Aggressive behavior o Amphetamine-induced stereotypy similar to finger- biting o Losses in striatal DA

34. Animats

35. Animats & Computer Technology o What is an Animat? “A computer simulated or robotic animal behaving in an environment” --Steve Potter, PhD “A computer simulated or robotic animal behaving in an environment” --Steve Potter, PhD Put another way: Neurons can be used to control robots and make them behave in a particular way. Put another way: Neurons can be used to control robots and make them behave in a particular way.

36. How to Create an Animat o Neurons from the cortex of a rat are removed and grown on a surface covered in electrodes. o These electrodes can both provide electrical stimulation to the neurons and record electrical signals from the neurons. o The electrical signals from the neurons are then connected to a computer and used to influence the behavior of the animat. o The computer can then also provide a feedback response to the neurons about the behavior of the animats by applying an electrical stimulation through the electrode.

37. Animat Setup Demarse, T. B., D. A. Wagenaar, et al. (2001). "The Neurally Controlled Animat: Biological Brains Acting with Simulated Bodies." Autonomous robots 11(3): 305-310

38. Animats http://en.wikipedia.org/wiki/Hybrot http://www.wired.com/medtech/health/multimedia/2006/08/714 57?slide=1&slideView=4 http://discovermagazine.com/2006/nov/minibrains-dishes

39. Why Would We Make an Animat? o We can use the animat to study learning and neural plasticity. o How?

40. Animats and Learning

41. Animats and Art http://www.neuro.gatech.edu/groups/potter/MEART.html http://news.bbc.co.uk/2/hi/science/nature/3096973.stm

42. Are Animal Models Valid?

43. o o Etiology (Etiological): the extent to which the model represents the true nature of the disease Genetic predisposition o o Symptomatology (Face): Human manifestations occurring in the model resemble those occurring in the disease Anhedonia o o Biochemistry (Construct): Underlying pathophysiology basis is similar to the human disorder Neurotransmitter deficiencies o o Response to Treatment (Predictive): the extent to which effective clinical therapies are also effective in the model Antidepressant drugs reverse depression-like behaviors Animal Model Validity From Defense by Kroshona Tabb, Emory University, 2008

44. Validating SwLo rat as a model of depression and epilepsy co-morbidity Validation Criteria EpilepsyDepression Etiology Genetic Predisposition SymptomatologySpontaneous generalized seizures Low-motor activity in the FST Biochemistry Decrease NE in hippocampus Response to Treatment ?Antidepressants From Defense by Kroshona Tabb, Emory University, 2008