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