Current Topics in Neuropsych Research June 28, 2011 Slide 2
Current Research in Epilepsy & Depression Slide 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 Slide 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) Slide 5 Creating an Animal Model of Depression
o o Plexiglas cylinder 65 cm tall and 30 cm in diameter filled with
water (25C) 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?? StruggleFloat Weiss et. al, Pharmacol
Biochem Behav. 1998 From Defense by Kroshona Tabb, Emory
University, 2008 Slide 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 Slide 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 Slide 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) Slide 9 West H. K., & Weiss
J. M. (1998) Pharmacol. Biochem. & Behav. 61, 67-79. From
Lecture by Jay Weiss, Emory University, 2006 Slide 10 What might
underlie these differences in depression-like behaviors? From
Lecture by Jay Weiss, Emory University, 2006 Slide 11 What might
underlie these differences in depression-like behaviors? From
Lecture by Jay Weiss, Emory University, 2006 Slide 12 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).
*p0.05, n=3 Slide 13 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 Slide 14 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 * Slide 15 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 Slide 16 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. Slide 17 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
2 Fold Increase in SwHi Comt Gabbr1 Gabrb2 Nrcam 89 Genes with >
2 Fold Increase in SwLo Hcn1 Kcnj10 C3 C5r1 Slide 18 So Where Do We
Go From Here? o AKAwhat 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 Slide 19
Exercise, Epilepsy, & Depression o Exercise is known to be
anticonvulsant. Its 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. Slide 20 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. Slide 21 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? Slide 22 Reading Circles Slide 23 Generalized Anxiety
Disorder Slide 24 Post-Traumatic Stress Disorder Slide 25 PTSD,
Contd Slide 26 Specific Phobia Slide 27 Specific Phobia, Contd
Slide 28 Behavioral Characterization of a Mouse Model for Lesch-
Nyhan Disease Heather A. Mitchell April 30, 2010 Slide 29
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 Slide 30 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 Slide 31 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
Slide 32 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 Slide 33 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 +/- Slide 34 Behavioral characterization
o Locomotor behavior Exploratory Exploratory Circadian Circadian o
Amphetamine-induced stereotypy o Resident-intruder aggression Slide
35 Locomotor behavior Slide 36 Amphetamine-induced stereotypy Slide
37 Resident-intruder aggression Slide 38 Deficits in striatal
dopamine Slide 39 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 Slide 40 Animats Slide 41
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. Slide 42 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. Slide 43
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 Slide 44 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 Slide 45 Why
Would We Make an Animat? o We can use the animat to study learning
and neural plasticity. o How? Slide 46 Animats and Learning Slide
47 Animats and Art
http://www.neuro.gatech.edu/groups/potter/MEART.html
http://news.bbc.co.uk/2/hi/science/nature/3096973.stm Slide 48 Are
Animal Models Valid? Slide 49 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 Slide 50 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
