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Stress as a Non-Genetic Cause for Bipolar Disorder
Presenters:Anant Naik, Department of Biomedical Engineering
Advised by:Dr. Atsushi Asakura, Department of NeurologyUniversity of Minnesota, Twin Cities
Table of ContentsI. Fundamentals of Bipolar Disorder
II. The Relationship Between Stress and Anxiety
III. Our Hypothesis
IV. Our Rationale
V. Significance/Impact
The Fundamentals of Bipolar Disorder
Adults* in the United States have been diagnosed with Bipolar
Disorder
2.6%
=5.7million
*adults defined as persons 18+ years of age
Kessler et al., Archives of General Psychiatry, 2005
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
Table of ContentsI. Fundamentals of Bipolar Disorder
II. The Relationship Between Stress and Anxiety
III. Our Hypothesis
IV. Our Rationale
V. Significance/Impact
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
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
Table of ContentsI. Fundamentals of Bipolar Disorder
II. The Relationship Between Stress and Anxiety
III. Our Hypothesis
IV. Our Rationale
V. Significance/Impact
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
Table of ContentsI. Fundamentals of Bipolar Disorder
II. The Relationship Between Stress and Anxiety
III. Our Hypothesis
IV. Our Rationale
V. Significance/Impact
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
Unemura et al., 2012, J Phar Sci.
% o
f Brd
U+/ G
FAP+
cel
ls
(Adapted)
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
Neurons 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)
Pre-stressPost-stress
Table of ContentsI. Fundamentals of Bipolar Disorder
II. The Relationship Between Stress and Anxiety
III. Our Hypothesis
IV. Our Rationale
V. Significance/Impact
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
Blocking receptors
Block GC Receptors on the astrocytes in naïve and Bipolar mouse
modelsExpected Results:
Decline in glial cells.
Expected Results:
Decline in glial cells is
correlated with increased
depression/mania.
Expected Results:
Blocking GC Receptors
prevents the onset of Bipolar
Disorder.
Expected Results:
Promoting stem cell growth
mitigates affects of stress-induced Bipolar Disorder.
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