Transcript Current Research in Epilepsy & Depression

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
180
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
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