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Stress as a Non-Genetic Cause for Bipolar Disorder
Presenters:Anant Naik, Department of Biomedical EngineeringBhavani Murakonda, Department of Biomedical EngineeringAdvised by:Dr. Atsushi Asakura, Department of NeurologyUniversity of Minnesota, Twin Cities
The Fundamentals of Bipolar Disorder
Grande et al., 2015, The Lancet
Life Progression of Bipolar DisorderMania
Hypomania
Euthymia
Subthreshold Depression
Major Depression
Mixed State
Seve
rity
of
Man
iaSe
veri
ty o
f D
epre
ssio
nMacro-level Background
The Fundamentals of Bipolar Disorder
Micro-level Background
Cell Density Deficits in the Prefrontal Cortex
Sagittal View
Coronal View
Ongur et al., 1998, PNAS
The Fundamentals of Bipolar DisorderCellular-level Background
Cell Density Deficits in the Prefrontal Cortex
Ongur et al., 1998, PNAS
Glial Number in PFC for Mood Disorders15
10
5
x106
Glia
l N
umbe
rfBD - Familial Bipolar DisorderoBD - Other Bipolar Disorder
The Relation BetweenStress and
Anxiety
Is Bipolar Disorder abnormally prevalent in patients exposed to situations with chronic stress? Q.
Posing the Question
Iraq and Afghanistan war veterans are more likely to have Anxiety and Mood disorders, particularly Bipolar Disorder.
Bagalman, 2013, Congressional Research Service
The Relation BetweenStress and
AnxietyIs Bipolar Disorder abnormally prevalent in patients exposed to situations with chronic stress? Q.
Childhood Trauma
Sexual & Physical Abuse
Combat Veterans
YES
The Relation BetweenStress and
AnxietyIs Bipolar Disorder abnormally prevalent in patients exposed to situations with chronic stress? Q.
Sample Characteristics Sample Size Rate of PTSD%Bipolar patients admitted for mania or mixed 71 17National general population survey: respondents with bipolar I characterized by euphoria, grandiosity, and excessive energy
29 39
Inpatient and outpatient bipolar patients 50 40Bipolar patients, manic or mixed: first admission for psychosis 77 21
Bipolar I and II outpatients recruited from community 288 7Bipolar patients: first admission for psychosis 102 11Bipolar I and II, treatment-seeking outpatients in the Systematic Treatment Enhancement Program for bipolar disorder 475 17
Bipolar I and II, treatment-seeking outpatients 122 19
Otto et al., 2004, Bipolar Disorder
Our HypothesisMacro-level Hypothesis
Endocrine GC Feedback to
stress
Endocrine response to
stress
GC release due to stress
PFCStress
Hypothalamus
Adrenal Gland
Cerebrum and Cerebellum1. Chronic Stress induces
an upregulation in the endocrine response
2. High concentrations of glucocorticoids (GC) are released
3. Cells in the Prefrontal Cortex are degenerated in the long run
Prefrontal Cortex
Our HypothesisCellular-level Hypothesis
Blood Vessel
Neuron
Astrocyte
GC
Astrocytes in the Prefrontal Cortex absorb glucocorticoids (GC), resulting in their degeneration, and thus Bipolar Disorder.
Time
Blood Vessel
Neuron
Degeneration of Astrocyte
GC Bipolar Disorder
Astrocytes Degeneratewith GC exposure in vitro
Cortisone Impact on Astrocyte Number
Cortisone Impact on GR RNA Prevalence
Cortisone Impact on Astrocyte
Functionality
MTT
redu
ctio
n of
act
ivity
% o
f con
trol
Control 0.01 0.1 1Corticosterone
(µM)
% o
f Brd
U+/ G
FAP+
cel
ls
% o
f Brd
U+/ G
FAP+
cel
ls
Unemura et al., 2012, J Phar Sci.
Astrocytes Degeneratewith GC exposure in vivo
Unemura et al., 2012, J Phar Sci.
Saline ACTH
GFA
P
Num
ber o
f GFA
P+ c
ells P < 0.05
Saline ACTH
ACTH – Adrenocorticotropic Hormone
ACTH vs. Saline Injections in Mice
Prefrontal CortexAggregate Astrocytes
for mPFC and Hippocampus
Astrocytes Degeneratewith GC exposure in vivo
Cerqueira et al., 2007, J Neurosci
Volume of Neurons in mPFC: Pre/post-stress
* (P < 0.05), ** (P < 0.01)
SignificanceCurrent Inclusion/Exclusion Criteria
Familial History Behavioral Analysis
Appropriate Diagnosis of Bipolar
Disorder
x Familial History Behavioral
Analysis
Misdiagnosis
Total Patients withBipolar Disorder
SignificanceImpacting Inclusion/Exclusion Criteria
Familial History Behavioral Analysis
Appropriate Diagnosis of Bipolar
Disorder
Behavioral Analysis
x Familial History
Misdiagnosis
Chronic Stress History Behavioral Analysis
Total Patients withBipolar Disorder
Proposed Experiments
Behavioral Tests
Immuno-staining
Stem Cell and Gene Therapy
Measure decline in glial densities
by exposure to chronic stress in
naive mice
Correlate Decline in glial density to
behavioral progression in mice
Promote astrocyte growth in PFC using stem
cell therapy in naïve and Bipolar
mouse models
Thank YouQuestions? Concerns? Comments?
Acknowledgements:For their guidance for the project, we would like to thank
Dr. Atsushi Asakura, Ph.D., Department of NeurologyDr. Russell Carter, Ph.D., Department of Neuroscience