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 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)

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 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 Weiss et. al, Pharmacol Biochem Behav 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

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)

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

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

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

Can SwLo Rats (“Sad Rats”) Serve as a Model of Depression & Epilepsy Co-Morbidity? SwLo rats show decreased latency to limbic motor seizure following acute pilocarpine administration (380 mg/kg). *p<0.001, n=11 Hippocampal pilocarpine levels were not significantly different between SwLo and SwHi lines. p>0.05, n=3

Increased Seizure Susceptibility in SwLo (“Sad Rats”) is Selective for Temporal Lobe Seizures There is no significant difference between SwLo and SwHi rats in susceptibility to generalized flurothyl-induced seizure. P>0.05, n=8 Adapted from Tabb et al, 2008

SwLo Rats Are More Susceptible to Electrically Induced Seizures There is no significant difference between SwLo and SwHi rats in susceptibility to generalized flurothyl-induced seizure. P>0.05, n=8 *

SwLo Rats Are More Susceptible to Pilocarpine- Induced Epileptogenesis SwLo rats show heightened occurrence of spontaneous limbic motor seizures 5 weeks following pilocarpine-induced status epilepticus (p>0.05, n=6-9 rats per line). 4 / 9 0/6

SwLo and SwHi Rats Do Not Differ In Amygdala Kindling Rates SwLo and SwHi rats show no difference in number of amygdala stimulations required to reach a kindled state, p>0.5, n=6-8 rats per line.

Differential Genetic Expression Between SwHi and SwLo Rat Lines Microarray analysis of hippocampal tissue revealed 210 genes with significantly different expression between SwHi and SwLo (in red). Differential expression was determined by fold difference >2, p< Genes with > 2 Fold Increase in SwHi Comt Gabbr1 Gabrb2 Nrcam 89 Genes with > 2 Fold Increase in SwLo Hcn1 Kcnj10 C3 C5r1

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??

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:

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:

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 Lesch- Nyhan Disease Heather A. Mitchell April 30, 2010

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

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

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

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 +/-

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

Locomotor behavior

Amphetamine-induced stereotypy

Resident-intruder aggression

Deficits in striatal dopamine

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

Animats

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.

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.

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):

Animats ?slide=1&slideView=4

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

Animats and Learning

Animats and Art

Are Animal Models Valid?

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

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