1) The presentation hypothesizes that chronic stress can cause bipolar disorder by upregulating the endocrine stress response and releasing high levels of glucocorticoids.
2) These glucocorticoids are absorbed by astrocytes in the prefrontal cortex and can lead to their degeneration over time.
3) Experiments in mice and cell cultures provide evidence that glucocorticoid exposure reduces astrocyte number and function in the prefrontal cortex and hippocampus.
Resuscitation Science tips: The NYC Project Hypothermia rationale for phase IIEmergency Live
Resuscitation Science tips: The NYC Project Hypothermia
Intra-arrest induction of Therapeuitic Hypothermia via large-volume ice-cold saline infusion improves immediate outcomes for out-of-hospital cardiac arrest
The original source of this article is the AHA Journlas
http://circ.ahajournals.org/cgi/content/meeting_abstract/124/21_MeetingAbstracts/A2
Background: New York City Project Hypothermia is a collaborative effort involving the Fire Department of New York (FDNY), Greater New York Hospital Association, Health and Hospitals Corporation, the Regional Emergency Medical Advisory Committee, and the New York State Department of Health. As part of this effort, the FDNY implemented a pilot protocol in the New York City 9-1-1 System on August 1, 2010 that introduced the induction of therapeutic hypothermia during initial resuscitation efforts via large-volume ice-cold saline infusion.
Purpose: We sought to assess the effects of this protocol on immediate survival end-points following out-of-hospital cardiac arrest (OOHCA).
Methods: OOHCA data was analyzed for the following periods: August 1, 2009 - May 31, 2010 (historicalcontrol group) and August 1, 2010 - May 31, 2011 (study group). Except for the intra-arrest induction of hypothermia, no other aspect of the regional resuscitation protocols differed between the two periods. Standard Utstein definitions were utilized. Due to the large sample sizes, Chi-square analyses without Yates' correction were utilized, and a p <0.05 was considered significant.
Results: 5,582 resuscitations for nontraumatic adult cardiac arrests during the control period were compared to 4,727 resuscitations in the study period that included the intra-arrest induction of hypothermia. The groups did not differ with respect to age, response time, bystander witnessed status, or frequency of bystander CPR. Patients in the study period were less likely to be male (52.3% vs 54.6%, p = 0.019), less likely to be white (32.8% vs 35.1%, p = 0.013), and less likely to have an EMS-witnessed arrest (8.3% vs 9.5%, p=0.026). Return of spontaneous circulation (ROSC) and sustained ROSC were improved in the study group as compared to the control group: 31.7% vs 29.0% (p=0.003) and 24.1% vs 21.9% (p=0.0014), respectively.
The administration of large-volume, ice-cold saline for the intra-arrest initiation of therapeutic hypothermia improves immediate survival for out-of-hospital cardiac arrest.
Further work is required to assess the impact of this effect on long-term, neurologically intact survival and specific patient population for which this therapy may be of greatest benefit.
Special Thanks from the AHA to All of the Certified First Responder, Emergency Medical Technicians, and Paramedics of the FDNY and the New York City 9-1-1 System.
Presentation made by Tony Wyss-Coray on the 20th of April, 2017, at the live webinar hosted by Alzforum: http://www.alzforum.org/webinars/webinar-cortex-aging-too-fast-blame-tmem106b-and-progranulin
Resuscitation Science tips: The NYC Project Hypothermia rationale for phase IIEmergency Live
Resuscitation Science tips: The NYC Project Hypothermia
Intra-arrest induction of Therapeuitic Hypothermia via large-volume ice-cold saline infusion improves immediate outcomes for out-of-hospital cardiac arrest
The original source of this article is the AHA Journlas
http://circ.ahajournals.org/cgi/content/meeting_abstract/124/21_MeetingAbstracts/A2
Background: New York City Project Hypothermia is a collaborative effort involving the Fire Department of New York (FDNY), Greater New York Hospital Association, Health and Hospitals Corporation, the Regional Emergency Medical Advisory Committee, and the New York State Department of Health. As part of this effort, the FDNY implemented a pilot protocol in the New York City 9-1-1 System on August 1, 2010 that introduced the induction of therapeutic hypothermia during initial resuscitation efforts via large-volume ice-cold saline infusion.
Purpose: We sought to assess the effects of this protocol on immediate survival end-points following out-of-hospital cardiac arrest (OOHCA).
Methods: OOHCA data was analyzed for the following periods: August 1, 2009 - May 31, 2010 (historicalcontrol group) and August 1, 2010 - May 31, 2011 (study group). Except for the intra-arrest induction of hypothermia, no other aspect of the regional resuscitation protocols differed between the two periods. Standard Utstein definitions were utilized. Due to the large sample sizes, Chi-square analyses without Yates' correction were utilized, and a p <0.05 was considered significant.
Results: 5,582 resuscitations for nontraumatic adult cardiac arrests during the control period were compared to 4,727 resuscitations in the study period that included the intra-arrest induction of hypothermia. The groups did not differ with respect to age, response time, bystander witnessed status, or frequency of bystander CPR. Patients in the study period were less likely to be male (52.3% vs 54.6%, p = 0.019), less likely to be white (32.8% vs 35.1%, p = 0.013), and less likely to have an EMS-witnessed arrest (8.3% vs 9.5%, p=0.026). Return of spontaneous circulation (ROSC) and sustained ROSC were improved in the study group as compared to the control group: 31.7% vs 29.0% (p=0.003) and 24.1% vs 21.9% (p=0.0014), respectively.
The administration of large-volume, ice-cold saline for the intra-arrest initiation of therapeutic hypothermia improves immediate survival for out-of-hospital cardiac arrest.
Further work is required to assess the impact of this effect on long-term, neurologically intact survival and specific patient population for which this therapy may be of greatest benefit.
Special Thanks from the AHA to All of the Certified First Responder, Emergency Medical Technicians, and Paramedics of the FDNY and the New York City 9-1-1 System.
Presentation made by Tony Wyss-Coray on the 20th of April, 2017, at the live webinar hosted by Alzforum: http://www.alzforum.org/webinars/webinar-cortex-aging-too-fast-blame-tmem106b-and-progranulin
Next-generation small molecule neuro regeneration therapy
Dual actions of increasing endogenous stem cells and
suppressing glial differentiation of neural stem cells to
regenerate neurons by peripheral administration of low
molecular weight compounds.
Next-generation small molecule neuro regeneration therapy
Dual actions of increasing endogenous stem cells and suppressing glial differentiation of neural stem cells to regenerate neurons by peripheral administration of low molecular weight compounds.
Next-generation hair regenerative medicine
Hair regrowth by a low molecular weight compound that stimulates the proliferation of hair follicle stem cells.
"Bioluminescent Imaging of Histidyl-Transfer RNA Synthetase-Induced Myositis ...Nicholas Young
My talk from the American College of Rheumatology Meeting in Boston, MA, November 14-19, 2014: • "Bioluminescent Imaging of Histidyl-Transfer RNA Synthetase-Induced Myositis Reveals Early-Phase Involvement of NF-kB-Mediated Inflammation".
Cardiac Inflammation and Repair Following Myocardial InfarctionInsideScientific
Join Dr. Merry Lindsey as she discusses her research involving the physiology of recovery from cardiac events.
Age plays a pivotal role in the deterioration of cardiovascular functionality, resulting in an increased risk of cardiovascular disease in older adults. The prevalence of cardiovascular disease has also been shown to increase with age, in both men and women, including the prevalence of atherosclerosis, stroke and, myocardial infarction.
Following myocardial infarction (MI), the left ventricle (LV) undergoes a series of cardiac wound healing responses that involve both the stimulation of robust inflammation to clear necrotic myocytes and tissue debris and the induction of extracellular matrix (ECM) protein synthesis to generate an infarct scar. Collectively, this process in known as LV remodeling. Matrix metalloproteinase-9 (MMP-9) is a key regulator of LV remodeling post-MI, through direct effects on ECM turnover as well as indirect effects on the regulation of the major cell types that coordinate cardiac wound healing- namely the infiltrating leukocytes and the cardiac fibroblasts. We will discuss recent research that has expanded our understanding of MI LV remodeling, including recent proteomic advances focused on the ECM compartment to provide novel functional and translational insights. In summary, this webinar will provide an overview of how cardiac ECM research has evolved over the last decade and will provide insight into future directions that will drive further understanding of MMP directed cardiac ECM turnover after MI.
The slide shows the cellular stress response leading to growth arrest as explained by the induction of the universal cell cycle inhibitor p21(WAF1) by the tumor suppressor p53.
Next-generation small molecule neuro regeneration therapy
Dual actions of increasing endogenous stem cells and
suppressing glial differentiation of neural stem cells to
regenerate neurons by peripheral administration of low
molecular weight compounds.
Next-generation small molecule neuro regeneration therapy
Dual actions of increasing endogenous stem cells and suppressing glial differentiation of neural stem cells to regenerate neurons by peripheral administration of low molecular weight compounds.
Next-generation hair regenerative medicine
Hair regrowth by a low molecular weight compound that stimulates the proliferation of hair follicle stem cells.
"Bioluminescent Imaging of Histidyl-Transfer RNA Synthetase-Induced Myositis ...Nicholas Young
My talk from the American College of Rheumatology Meeting in Boston, MA, November 14-19, 2014: • "Bioluminescent Imaging of Histidyl-Transfer RNA Synthetase-Induced Myositis Reveals Early-Phase Involvement of NF-kB-Mediated Inflammation".
Cardiac Inflammation and Repair Following Myocardial InfarctionInsideScientific
Join Dr. Merry Lindsey as she discusses her research involving the physiology of recovery from cardiac events.
Age plays a pivotal role in the deterioration of cardiovascular functionality, resulting in an increased risk of cardiovascular disease in older adults. The prevalence of cardiovascular disease has also been shown to increase with age, in both men and women, including the prevalence of atherosclerosis, stroke and, myocardial infarction.
Following myocardial infarction (MI), the left ventricle (LV) undergoes a series of cardiac wound healing responses that involve both the stimulation of robust inflammation to clear necrotic myocytes and tissue debris and the induction of extracellular matrix (ECM) protein synthesis to generate an infarct scar. Collectively, this process in known as LV remodeling. Matrix metalloproteinase-9 (MMP-9) is a key regulator of LV remodeling post-MI, through direct effects on ECM turnover as well as indirect effects on the regulation of the major cell types that coordinate cardiac wound healing- namely the infiltrating leukocytes and the cardiac fibroblasts. We will discuss recent research that has expanded our understanding of MI LV remodeling, including recent proteomic advances focused on the ECM compartment to provide novel functional and translational insights. In summary, this webinar will provide an overview of how cardiac ECM research has evolved over the last decade and will provide insight into future directions that will drive further understanding of MMP directed cardiac ECM turnover after MI.
The slide shows the cellular stress response leading to growth arrest as explained by the induction of the universal cell cycle inhibitor p21(WAF1) by the tumor suppressor p53.
Schizophrenia Research Forum Live Webinar - June 28, 2017 - Rusty Gage wef
Fred Gage's live presentation at the Schizophrenia Research Forum's live webinar of June 28, 2017 - http://www.schizophreniaforum.org/forums/webinar-modeling-neuropsychiatric-disorders-using-vitro-models
Electrophysiology of Human Native Receptors in Neurological and Mental DisordersInsideScientific
Dr. Agenor Limon presents research integrating functional metrics with large anatomical, transcriptomic, and proteomic datasets to evaluate the relationship between synaptic E/I ratio and behavioral abnormalities across postmortem intervals and brain banks.
Alterations in synaptic function have been found in transcriptomic, genetic, and proteomic studies of neurological and mental disorders. Clinical and preclinical studies suggest that synaptic dysfunction and behavioral abnormalities in disorders like Alzheimer’s disease and schizophrenia may be mechanistically linked to the emergence of imbalances between excitatory (E) and inhibitory (I) receptors. However, until recently, the electrophysiological E/I synaptic ratio had only been measured in animal models.
Using pioneering methods developed in the lab including reactivation and microtransplantation of synaptic receptors from frozen human brains, Dr. Agenor Limon’s research team has obtained electrophysiological metrics of global synaptic E/I ratios in cortical brain regions of subjects that were affected by Alzheimer’s Disease and synaptic measurements in schizophrenia.
In this webinar, Dr. Agenor Limon will present recent research integrating functional metrics with large anatomical, transcriptomic, and proteomic datasets to evaluate the relationship between synaptic E/I ratio and behavioral abnormalities across postmortem intervals and brain banks.
Key Topics Include:
- Understand the global synaptic excitation to inhibition ratio between excitatory and inhibitory synaptic receptors determined from reactivated frozen human brain tissue
- Understand the relationship between electrophysiological metrics of receptor function and multi-omic data in neurodegenerative disorders
- Understand the role of deviations of the excitation to inhibition ratio with clinical presentation in Alzheimer’s disease
1. Stress as a Non-Genetic Cause
for Bipolar Disorder
Presenters:
Anant Naik, Department of Biomedical Engineering
Bhavani Murakonda, Department of Biomedical Engineering
Advised by:
Dr. Atsushi Asakura, Department of Neurology
University of Minnesota, Twin Cities
2. The Fundamentals
of Bipolar Disorder
Grande et al., 2015, The Lancet
Life Progression of Bipolar Disorder
Mania
Hypomania
Euthymia
Subthreshold Depression
Major Depression
Mixed State
Severityof
Mania
Severityof
Depression Macro-level Background
3. The Fundamentals
of Bipolar Disorder
Micro-level Background
Cell Density Deficits in the
Prefrontal Cortex
Sagittal View Coronal View
Ongur et al., 1998, PNAS
4. The Fundamentals
of Bipolar Disorder
Cellular-level Background
Cell Density Deficits in the Prefrontal
Cortex
Ongur et al., 1998, PNAS
Glial Number in PFC for Mood Disorders
15
10
5
x106
GlialNumber
fBD - Familial Bipolar Disorder
oBD - Other Bipolar Disorder
5. The Relation Between
Stress 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
6. The Relation Between
Stress and Anxiety
Is Bipolar Disorder abnormally prevalent in patients exposed to
situations with chronic stress?Q.
Childhood
Trauma
Sexual &
Physical
Abuse
Combat
Veterans
YES
7. The Relation Between
Stress and Anxiety
Is 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 17
National general population survey: respondents with bipolar I
characterized by euphoria, grandiosity, and excessive energy 29 39
Inpatient and outpatient bipolar patients 50 40
Bipolar patients, manic or mixed: first admission for psychosis 77 21
Bipolar I and II outpatients recruited from community 288 7
Bipolar patients: first admission for psychosis 102 11
Bipolar 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
8. Our Hypothesis
Macro-level Hypothesis
Endocrine GC
Feedback to
stress
Endocrine
response to
stress
GC release due
to stress
PFC
Stress
Hypothalamus
Adrenal Gland
Cerebrum and Cerebellum
1. 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
9. Prefrontal Cortex
Our Hypothesis
Cellular-level Hypothesis
Neuron
Astrocyte
Blood vessel
GC
Neuron
Blood vessel
GC
Degeneration
of Astrocyte
In Prefrontal Cortex
Blood Vessel
Neuron
Astrocyte
GC
Astrocytes in the Prefrontal Cortex absorb glucocorticoids (GC),
resulting in their degeneration, and thus Bipolar Disorder.
Time
Neuron
Astrocyte
Blood vessel
GC
Neuron
Blood vessel
GC
Degeneration
of Astrocyte
In Prefrontal Cortex
Blood Vessel
Neuron
Degeneration of
Astrocyte
GC
Blood ves
Neuron
Blood ves
GC
Degeneration
of Astrocyte
Bipolar Disorder
Bipolar Disorder
10. Astrocytes Degenerate
with GC exposure in vitro34 K Unemura et al
results suggest that glucocorticoids inhibited astrocyte GR knockdown led
Fig. 2. Corticosterone (CRT) and dexamethasone (DEX) reduced the number of astrocytes
not induce astrocytic damage. A, B: The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazol
formed 72 h after treatment with CRT (0.01 – 1 μM) and DEX (0.01 – 1 μM). C: The lacta
performed 72 h after treatment with CRT (1 μM) and DEX (1 μM) or 24 h after treatment w
assay was performed 72 h after treatment with CRT (1 μM); DEX (1 μM); RU486 (0.3 – 3 μ
(10 μM), a mineralcorticoid receptor antagonist. n = 4. ***P < 0.001 vs. control, ###
P < 0.0
significant.
These results suggest that secretion of high concentra-
tions of glucocorticoids induced by repeated ACTH ad-
tion (Figs. 2 and 3). T
those of a previous rep
F
k
t
e
s
t
C
a
p
B
t
0
Cortisone Impact on
Astrocyte Number
Cortisone Impact on
GR RNA Prevalence
Cortisone Impact on
Astrocyte Functionality
MTTreductionofactivity
%ofcontrol
Control 0.01 0.1 1
Corticosterone (µM)
%ofBrdU+/GFAP+cells
%ofBrdU+/GFAP+cells
Unemura et al., 2012, J Phar Sci.
11. Astrocytes Degenerate
with GC exposure in vivo
Unemura et al., 2012, J Phar Sci.
corticotropic hormone (ACTH) administration decreased glucocorticoid receptor (GR) expression and
in vivo. A, B: GR expression in the frontal cortex (A) and hippocampus (B) after 14 days of saline or
e bottom graphs show the quantified data of the GR/GAPDH ratio. n = 3. C: GFAP and GAPDH were
ng in the frontal cortex after 14 days of repeated ACTH administration. D: Neuronal nuclei (NeuN)- or
stained by immunohistochemistry and their numbers calculated from 30 slices. E: Representative pic-
Saline ACTH
GFAP
P
NumberofGFAP+cells
P < 0.05
Saline ACTH
ACTH – Adrenocorticotropic Hormone
ACTH vs. Saline Injections in Mice
Prefrontal Cortex
Aggregate Astrocytes for
mPFC and Hippocampus
12. Astrocytes Degenerate
with GC exposure in vivo
Cerqueira et al., 2007, J Neurosci
Volume of Neurons in mPFC: Pre/post-stress
* (P < 0.05), ** (P < 0.01)
13. Significance
Current Inclusion/Exclusion Criteria
Familial History
Behavioral Analysis
Appropriate Diagnosis
of Bipolar Disorder
x Familial History
Behavioral Analysis
Misdiagnosis
Total Patients with
Bipolar Disorder
14. Significance
Impacting 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 with
Bipolar Disorder
15. 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
16. Thank You
Questions? Concerns? Comments?
Acknowledgements:
For their guidance for the project, we would like to thank
Dr. Atsushi Asakura, Ph.D., Department of Neurology
Dr. Russell Carter, Ph.D., Department of Neuroscience