Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Current Topics in Neuropsych Research June 28, 2011 Current Research in Epilepsy & Depression Seizure Susceptibility in a Rodent Model of Depression & Epilepsy Co-Morbidity S. Alisha Epps Emory University Dept of Human Genetics Neuroscience Program Weinshenker Lab Co-morbidity: Epilepsy & Depression o Bidirectional Co-morbidity o Epileptics are ~5 times more likely to develop depression Likewise, patients with depression also have a heightened risk of developing epilepsy Particularly strong correlation with Temporal Lobe Epilepsy (TLE) Creating an Animal Model of Depression o o o o Plexiglas cylinder 65 cm tall and 30 cm in diameter filled with water (25°C) Animal initially displays escape-oriented behavior, but eventually will display only movements sufficient to keep their head above water or “floating” Antidepressants reduce “floating” behavior Problems?? “Struggle” “Float” Weiss et. al, Pharmacol Biochem Behav. 1998 From Defense by Kroshona Tabb, Emory University, 2008 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 Model of Depressive-like Behavior Struggle LESS Float MORE Struggle MORE Float LESS 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) From Defense by Kroshona Tabb, Emory University, 2008 Swim Low-Active & High-Active o SwLo Selectively bred for low activity in swim test (increased floating) Respond to many antidepressants after chronic treatment Anhedonic-like behavior o SwHi Rats: “Depression-susceptible” Rats: “Depression-resistant” Selectively bred for high activity in swim test (decreased floating) Swim Test: SwLo Drug Administration: Time (seconds) 125 Struggling 1 Day 12 Days 26 Days * 100 75 * * 50 * * 25 * * 0 VEH Time (seconds) 900 AMI IMI DMI VEN FLU BUP PHE CAF AMP HAL Floating * 600 * * * * * * o * * 300 0 VEH AMI IMI DMI VEN FLU BUP PHE Drugs From Lecture by Jay Weiss, Emory University, 2006 CAF AMP HAL West H. K., & Weiss J. M. (1998) Pharmacol. Biochem. & Behav. 61, 67-79. What might underlie these differences in depression-like behaviors? Hippocampus-NE SwHi vs. SwLo ng/mg of protein 6.0 50% 200 70 4.0 140 60 3.0 120 50 0 Hi Lo NS ng/mg of protein 6.0 4.0 3.0 From Lecture by Jay Weiss, Emory University, 2006 Lo NS Hi 90 39% Lo NS Nac-DA Striatum-DA 200 20% 5.0 0 Hi Hippocampus-NE 10% 80 2% 160 0.0 Resistants vs. Susceptibles 90 180 5.0 Nac-DA Striatum-DA 180 80 160 70 140 60 120 50 47% What might underlie these differences in depression-like behaviors? CORTICOSTERONE ACTH 300 400 CD & NS (n=35) SwHi (n=17) SwLo (n=22) 250 350 300 250 Cort ng/ml ACTH pg/ml 200 150 100 200 150 100 50 50 0 0 -30 5 15 30 45 60 Sampling time in minutes relative to stressor STRESSOR From Lecture by Jay Weiss, Emory University, 2006 90 -30 5 15 30 45 60 Sampling time in minutes relative to stressor STRESSOR 90 So Where Do We Go From Here? o o o AKA…what will Alisha do when Duke TIP is over Now Introducing: Exercise! Wait….what?? http://www.christopherchua.com/me/out-of-the-rat-race Exercise, Epilepsy, & Depression o o Exercise is known to be anticonvulsant. It’s also known to be antidepressant. 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. How Might This Work? o o o Chronic exercise increases levels of galanin in the brain. Galanin is a neuropeptide that is co-released with norepinephrine. 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. 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? Reading Circles Generalized Anxiety Disorder Post-Traumatic Stress Disorder PTSD, Cont’d Specific Phobia Specific Phobia, Cont’d Behavioral Characterization of a Mouse Model for LeschNyhan Disease Heather A. Mitchell April 30, 2010 Lesch-Nyhan Disease (LND) o X-linked genetic disorder caused by dysfunction in HPRT gene (Hypoxanthineguanine phosphoribosyltransferase) o HPRT Severity of disease correlated with amount of HPRT Required for purine metabolism Loss leads to increased uric acid blood levels 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 HPRT KO mice o o o No obvious abnormal phenotype Normal locomotor behavior Enhanced responses to amphetamine Locomotor activity over 15 hours Jinnah, et al., 1992 HPRT and PRTFDC1 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 o Creation of transgenic mice PRTFDC1 Tg/ HPRT WT WT/WT x WT/WT PRTFDC1 Tg/ HPRT +/- x 6 generations WT/ HPRT KO PRTFDC1/ HPRT +/- x WT/WT WT/ HPRT KO PRTFDC1 Tg/ HPRT WT PRTFDC1 Tg/ HPRT KO Behavioral characterization o Locomotor behavior Exploratory Circadian Amphetamine-induced stereotypy o Resident-intruder aggression o Locomotor behavior Amphetamine-induced stereotypy Resident-intruder aggression Deficits in striatal dopamine Are these mice a good model for LND? Human LND patients o o o o o Impaired motor control Mental retardation Aggressive behavior Self-injurious behavior Losses in striatal DA Mice o o o o o No visible Ioss of motor control Mental retardation - not tested Aggressive behavior Amphetamine-induced stereotypy similar to fingerbiting Losses in striatal DA Animats Animats & Computer Technology o What is an Animat? “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. How to Create an Animat 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. o 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 Animats http://www.wired.com/medtech/health/multimedia/2006/08/714 57?slide=1&slideView=4 http://discovermagazine.com/2006/nov/minibrains-dishes http://en.wikipedia.org/wiki/Hybrot Why Would We Make an Animat? We can use the animat to study learning and neural plasticity. o How? o Animats and Learning Animats and Art http://www.neuro.gatech.edu/groups/potter/MEART.html http://news.bbc.co.uk/2/hi/science/nature/3096973.stm Are Animal Models Valid? Animal Model Validity Etiology (Etiological): the extent to which the model represents the true nature of the disease o Genetic predisposition Symptomatology (Face): Human manifestations occurring in the model resemble those occurring in the disease o Anhedonia Biochemistry (Construct): Underlying pathophysiology basis is similar to the human disorder o Neurotransmitter deficiencies Response to Treatment (Predictive): the extent to which effective clinical therapies are also effective in the model o Antidepressant drugs reverse depression-like behaviors From Defense by Kroshona Tabb, Emory University, 2008 Validating SwLo rat as a model of depression and epilepsy co-morbidity Validation Criteria Etiology Symptomatology Biochemistry Response to Treatment Epilepsy Depression Genetic Predisposition Genetic Predisposition Spontaneous generalized seizures Decrease NE in hippocampus Low-motor activity in the FST Decrease NE in hippocampus ? Antidepressants From Defense by Kroshona Tabb, Emory University, 2008