Transcript In Urban Architectural Design: Long Evans Rats and

Nina Kajijia
Gordon H Dashb
S. Tiffany Donaldsonc
a Computer
Science and Statistics, University of Rhode Island
b
b
c Development
College of Business Administration, University of Rhode Island
Interdisciplinary Neuroscience Program, University of Rhode Island
and Brain Sciences, Department of Psychology, University of Massachusetts Boston
EMAILS: [email protected] , [email protected], [email protected]
For Presentation at the:
Euro Working Group on Operational Research for Development Workshop (July 9-10, 2015)
Research was funded by a grant from:
National Institute of Minority Health and Health Disparities (NIMHD) P20MD002290
Additional support provided by:
•The NKD Group, Inc., USA
•University of Rhode Island
Research Objective
Major Findings
Economic Development and Social Housing
Addiction and Stress
Animal Model and Analysis
Conclusion & Future Work
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Conduct research to investigate how housing environments
and biological sex interact to modulate neural markers of
anxiety-like behavior in subjects exposed to low dose
exposure to a drug.
We conduct an in vivo experiment on Long-Evans rats and provide
the scientific and statistical evaluation of the results.
Drug exposure was to amphetamine (AMPH)
Cognitive behavior changes (or neural activation) are studied in the brain
regions that are implicated in fear/anxiety, fear/reward, and cognitive
control of emotion.
Suggest a framework for implementing the findings from the
animal model to urban economic development (social housing)
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Findings from Parametric Models
SEX, TRAIT, and ENVIRONMENT are significant explanatory
factors for the increase in protein (Fos) levels due to
exposure to fear in AMPH-exposed rats.
In the region of the brain that controls emotional response
to fear (Cg1), we find that:
Males exhibiting High anxiety or Low anxiety show significant increase in the
protein (Fos) levels
Isolation v/s social grouping show a significant increase in the protein (Fos)
levels
In the region of the brain modified by frequent exposure to
fear (VMH) only the Female group shows a positive change
in the protein (Fos) levels
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Findings from Non-Parametric Models
Although affecting different regions of the brain; overall SEX
and ENVIRONMENT are relatively more important in
explaining Fos variation in AMPH-exposed subjects. TRAIT is
an important factor especially in the reward and fear
pathways (NAc and VMH).
Overall - TRAIT and ENVIRONMENT have different impact by
SEX.
Specifically, males were more adversely affected by housing conditions,
showing greater evidence of stress living in crowded social housing.
By contrast, differences in Fos protein varied in female rats due to trait;
high anxious females showed greater Fos activity.
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Economic Development & Social Housing
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Definition of “Economic Development”
A focus on policy intervention by public sector officials who
seek to promote a defined standard of living and economic
well-being
Most theories for Economic Development up until recently
were based on the Expected Utility Theory (EU) model.
Ignores psychological realms of real-world decision making.
Advances in Cognitive Neuroscience & Computational
Neuroscience has redefined economic decision-making to
one that seeks to illuminate the mappings between brain
systems and cognitive behavior.
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The design of high-rise urban public housing projects and
the projected impact of such housing on human conditions
has been studied for years:
“Rat Cities” studies of Calhoun (1952)
“Fight or Flight” studies of Christian (1950; 1961)
“Welfare State” rat studies of Richter (1959)
Jackson (2013) summarizes how these studies applied to regional
economic development
Akan (2012) provides an interesting international examination
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“We came from the shelter system,” says Bronx-born
Arzuga, who did prison time for small-time drug
peddling as a young man. “This changed our lives.
When you’ve been in a shelter, you realize how
important a home is. When I first saw it, I couldn’t
believe how nice it was. The wood floors are beautiful
things. I am so grateful for this house and to be able to
live here.”
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A Closer Look at Addiction and Stress….
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Prevalence (9.2% US population)
Enduring, relapsing disorder
Long-term vulnerability
No FDA-approved treatment
Personalized approach
NIDA Report
3.1 Million
Illicit Drug
Users
Stimulant
Users
Amphetamine – Study Drug
AMPH Short Term Effects
AMPH Long Term Effects
Increased heart rate & BP
Insomnia, restlessness
Reduced appetite
Paranoid psychosis
Dilation of pupils
Hallucinations
Feelings of happiness and power
Violent and aggressive behavior
Reduced fatigue
Weight loss; Tremors
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Definition of “Stress”
a state of mental or emotional strain or tension resulting
from adverse or very demanding circumstances
Good vs. Bad stress
Adaptive vs. Maladaptive
Early Life Stress / Chronic Stress
Change underlying physiological & brain
Anxiety disorders
Mood and Anxiety Disorders – Co-morbid with Addiction
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First use
“Self-medication”
Curiosity
Escalation
Repeated use
Impulsive behavior
Compulsive use
Relapse / precipitating withdrawal
Stress-induced relapse
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Face Validity
Definition: A simple form of validity in which researchers
determine if the test seems to measure what is intended to
measure. Essentially, researchers are simply taking the
validity of the test at face value by looking at whether a
test appears to measure the target variable.
Our Expt: Can the animal model mirror its presentation in
clinical populations? Yes, “anxiety disorder” rats are hypervigilant and show more anxiety-like behavior in mild,
anxiogenic tests
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Construct Validity
Definition: Exists if a test demonstrates an association between the test
scores and the prediction of a theoretical trait.
Our Expt: Do the same underlying mechanisms contribute to human
anxiety disorders? Yes, for the HAn rats, they have elevated blood
pressure, heart rate, core body temperature, & increased stress
hormone --- as do humans with anxiety.
Predictive Validity
Definition: Occurs when the criterion measures are obtained at a time
after the test
Our Expt: Can the animal model be used to screen for new therapeutic
targets for treating clinical anxiety? Do drugs that reduce anxiety in
humans do so in the animal model as well? Yes, to both.
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The Animal Model…
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The Long-Evans rat is an outbred rat developed by Drs. Long
and Evans in 1915 by crossing several Wistar females with a
wild gray male. The Wistar rat is an outbred albino rat. These
rats were developed at the Wistar Institute in 1906 for use in
biological and medical research. They are notably the first rat
developed to serve as a model organism at a time when
laboratories primarily used the common house mouse. LongEvans rats are white with a black hood, or occasionally white
with a brown hood. They are utilized as a multipurpose model
organism, frequently in behavioral and obesity research (see
Wikipedia: http://en.wikipedia.org/wiki/Laboratory_rat; and,
Charles River, Inc http://www.criver.com/productsservices/basic-research/find-a-model/long-evans-rat )
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Take adult third generation (filial 3) Long-Evans rats
exhibiting extreme anxiety
The parental lines were subjected to the elevated plus
maze after sexual maturation for phenotyping as having
high (HAn) or low (LAn) anxiety
Less fearful
More fearful
Elevated Plus Maze (EPM)
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Afterwards, HAn males from the lower quartile
(<40% time on OA) were crossed with unrelated HAn
females. Similarly, LAn males from the upper quartile
(>45% time on OA) were crossed with unrelated LAn
females. This breeding procedure served to establish
future generational lines with trait anxiety
differences
On postnatal day (PND) 23, the filial 3 (F3) generation
pups were weaned and subjected to the elevated
plus maze (EPM) to establish baseline measurements
in trait anxiety.
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After EPM, the rats were given AMPH.
The rats were then separated into different housing
environments based on a combination of trait
anxiety and gender. The two housing environments
were: isolated (IE); or social (SE). SE generally had 4
to 5 rats per cage.
Isolated Environment (IE)
Social Environment (SE)
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Thus we have a total of 8 distinct groups as follows:
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4 rats from each group were subjected to an open
field apparatus (inducing fear) for 60 min and then
anesthetized.
c-Fos or Fos readings were taken from the left- and
right- side of the brain for each of the following
regions:
periaqueductal gray (PAG);
ventral medial hypothalamus (VMH),
the amygdala (Amy),
the nucleus accumbens core and shell (NAc(c) and
NAc(sh)); and,
the cingulate cortex (Cg1 and Cg2).
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The brain regions are:
Amy, PAG, NAc
Blue=Reward; Red=Aversion
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PAG is implicated by stimulant drugs and
social stress
VMH & Amy are both implicated by fear
Both forms of NAc are implicated in the
cognitive and reward pathways
Both Cg1 and Cg2 are implicated in the
cognitive control of emotions
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Expression of c-Fos is an indirect marker of neuronal activity
because c-fos is often expressed when neurons fire action
potentials.
Upregulation of c-Fos in a neuron indicates recent activity.
A highly stable (phosphorylated) form of ΔFosB, one that
persists in neurons for one or two months, slowly accumulates
following repeated exposure to stimulants.
ΔFosB functions as "one of the master control proteins" that
produces addiction-related structural changes in the brain,
and upon sufficient accumulation it induces an addictive state.
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After completion of the above experiment we have a
total of 32 observations (8 groups x 4 rats) of average
Fos cell counts for each side of the brain across all
seven brain regions.
We have two dependent (target) variables: Average
Fos counts for left- and right-side of the brain region.
Our three independent (fixed effects) variables are:
SEX, TRAIT, and ENVIRONMENT.
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Given gender, environment, and trait anxiety,
which regions of the brain show the most impact of
drug exposure?
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Which brain regions show a correlated effect
amongst ALL AMPH-exposed rats?
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Taken together the 7
regions of the brain
explain 76% of the
variation in the Fos
cells.
F1: Cognitive Factor
F2: Fear / Emotional Circuit
F3: Fear / Anxiety due to
Stimulant Drugs and Stress
F4: Fear / Anxiety Escape Circuit
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What is the effect of SEX, TRAIT, and ENVIRONMENT on
the variation in the Fos cell counts?
Y(Nxp) = W(Nxm) β
Where:
Y
W
Β
E
N
p
m
mxp
+ E(Nxp)
is the observed matrix (fos counts for left- and right- region)
is the design matrix (full factorial design)
is the matrix of parameters
is the matrix of random errors
is the total number of observations
is the number of dependent variables
is the number of parameters
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• Main effect of SEX in Amy &Cg1 –
regions controlling decision-making
and emotional reaction
•• Marginal
Main effect
Main
of TRAIT
effect in
of VMH – region
ENVIRONMENT
associated with in
fear/anxiety
NAc – region
and
associated
escape behavior
with both fear and reward
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SEX * TRAIT
Fos effect in Cg1 (related to emotional control of fear) is
statistically evident only in HAn and LAn male group.
Fos effect in VMH (related to fear) is statistically evident for the
female group as a whole – NOT by TRAIT.
SEX * ENVIRONMENT
Fos effect exists in the Cg1 brain region of the isolated rats.
Lastly, because we are using an acute anxiety-provoking
experience (time in the open field apparatus), it makes sense
we would see more significant interaction effects for changes
in Fos in Cg1 but not to the same degree in Cg2
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Provides a non-linear non-parametric view of
the MANOVA model
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Although affecting different regions of the brain;
overall SEX and ENVIRONMENT are relatively more
important in explaining Fos variation of AMPH –
treated rats. TRAIT is an important factor especially
in the reward and fear pathways (NAc and VMH).
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Animal studies indicate that Males and Females react differently
to anxiety, and drugs of abuse such as AMPH. Their reaction is
also tempered by the way they process fear and reward
situations. Additionally, their cognitive behavior is modified by
their exposure to the environment (isolation v/s social
grouping).
Additional studies both in animals and humans are
recommended so as to be able to better understand the
psychology of humans especially those that are addicted to
drugs and crime and living in social housing projects.
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Are there different underlying mechanisms that contribute to
sex differences? Sex hormones? Epigenetic variations in
response to postnatal rearing?
Would housing conditions impact the sexes differently across
development?
Do males and females react differently to other types of drugs of
abuse?
Can targeted treatments be made available depending on type
of stress, sex of individual, environmental conditions?
INFORMS 2014: 41 / 42
Akan, E. 2012. Architecture in Translation: Germany, Turkey, and
the Modern House, Duke University Press, Durham, NC.
Calhoun, J. B. 1952. The Social Aspects of Population Dynamics.
Journal of Mammaology 33: (2), 139-159.
Christian, J. J. 1961. Phenomena Associated with Population
Density. In: Proceedings of the National Academy of Sciences of
the United States of America, 1961. 47.4, 428-449.
Glimcher, P. W. & Fehr, E. 2014. Neuroeconomics: Decision
Making and the Brain, Elsevier, London, UK.
Richter, C. P. 1959. Rats, man and the Welfare State. American
Psychology, 14, 18-28.
INFORMS 2014: 42 / 42
QUESTIONS???
Contact Info:
Nina Kajiji
[email protected]
www.ninakajiji.net
Gordon Dash
[email protected] www.ghdash.net
Tiffany Donaldson [email protected]