IMPACT_Final_Presentation2

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


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


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



III. Our Hypothesis

IV. Our Rationale


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


AnxietyIs Bipolar Disorder abnormally prevalent in patients exposed to situations with chronic stress? Q.

Childhood Trauma

Sexual & Physical Abuse

Combat Veterans

YES


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



Disorder

Behavioral Analysis

x Familial History

Misdiagnosis

Chronic Stress History Behavioral Analysis




III. Our Hypothesis

IV. Our Rationale


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



III. Our Hypothesis

IV. Our Rationale


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



III. Our Hypothesis

IV. Our Rationale


SignificanceCurrent Inclusion/Exclusion Criteria



Disorder

x Familial History Behavioral

Analysis

Misdiagnosis


SignificanceImpacting Inclusion/Exclusion Criteria



Disorder

Behavioral Analysis

x Familial History

Misdiagnosis

Chronic Stress History Behavioral Analysis


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

Documents

IMPACT_Final_Presentation2