An Animal Model of a Behavioral
Intervention for Depression
Daniela D. Pollak, Francisco J. Monje,1 Lee Zuckerman,
Christine A. Denny, Michael R. Drew,1 and Eric R. Kandel
Neuron,2008
Speaker: Kuo Chung-Hsun(郭忠訓)
Advisor: Dr. Hong Chen-Jee (洪成志)

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Introduction
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Materials
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Methods & Results
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Conclusion
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Comment

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Instinctive and learned fear are essential for survival.
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In humans, pathological forms of learned fear are hallmarks of severe psychopathologies such as anxiety disorders, posttraumatic stress disorders, and depression

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Learned fear - a positive correlation (pairing).
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Learned safety - a negatively correlated (unpaired).
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Learned safety as the learning and memory resulting from a conditioned inhibition of fear training procedure
(Rogan et al.,2005)
.
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The ability to identify events that afford relief from ongoing strain is thought to be crucial for the prevention of chronic stress, a precipitating factor for the development of anxiety disorders and depression
(Chan et al., 2001; Davis and Shi, 1999; LeDoux,1993; Rogan et al., 2001)
.

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Learned safety, as a predictor of a break from continuously imminent, stress-producing danger, may have antidepressant effects

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Antidepressant effects in animal model.
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The molecular mechanisms of learned safety.

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Male C57BL6/N mice (10 – 12 weeks old)
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Charles River Laboratories,
Willington,MA
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Mice were kept in clear plastic cages with ad libitum food and water.

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Freezing, defined as complete immobility except for breathing, is a common response to sudden fearful situations in many species
CS (cue) – Tone, 350Hz, 72dB, 20s
US (shock) – 0.6mA, 2S

preCS

Learned Safety Retards Subsequent Fear
Conditioning to the Same Stimulus
Learned safety +
Learned fear 1 day naive +
Learned fear 1 day
Learned safety +
Learned fear 2 day naive +
Learned fear 2 day

Learned Safety Exerts Anxiolytic Effects

No training Learned safety Learned safety No training

Unpredictable Chronic Mild Stress (UCMS)
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Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol. Psychiatry, 2007
The following stimuli were administered each week in a random order for four weeks
3hrs of 45°cage tilt, two times a week
Shocked cage for 12hrs, once a week
Water deprivation for 14hrs, once a week
Lights on for 9hrs during the dark phase, once a week
Noise in the room for 3hrs, three times a week
Flashing light for 30mins, three times a week

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Twelve hours after exposure to the last stressor of the UCMS regime
Animals were deprived of food and water and tested for sucrose preference 23 hr later.
Testing was carried out in the home cage in the form of a two bottle choice paradigm (2% sucrose versus water) in the presence of the CS for 1 hr.
Sucrose preference rate was calculated according to the formula: % preference = [(sucrose intake/total intake) × 100%]

@ @
UCMS

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Brain-derived neurotrophic factor – BDNF
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BDNF is known to be induced by antidepressant treatment in the hippocampus, particularly in the dentate gyrus
.(Nibuya et al.,
1995; Russo-Neustadt et al., 2004)
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BDNF could be responsible for the increase in and survival of hippocampal neurons following antidepressant drug treatment
(Duman, 2004a, 2004b)

Learned Safety Leads to Increased
Expression of BDNF in the Dentate Gyrus of the Hippocampus
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Dentate gyrus BDNF immunohistochemistry in mice sacrificed 4 hr after the last day of behavioral training

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Bromodeoxyuridine (5-bromo-
2-deoxyuridine, BrdU)
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BrdU is commonly used in the detection of proliferating cells in living tissues
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BrdU can be incorporated into the newly synthesized
DNA of replicating cells.

Learned Safety And Newborn Cells in the Hippocampal Dentate Gyrus
Survival
BrdU labeled
Learned Fear
Learned Safety
Tone Control
Proliferation Learned Fear
Learned Safety
Tone Control
How many cells remain after different behavior protocol?
BrdU labeled
How many cells born after different behavior protocol?

Learned Safety Promotes the Survival of Newborn
Cells in the Hippocampal Dentate Gyrus
No data

Ablation of Hippocampal Neurogenesis
Retards Safety Learning

Genes Differentially Expressed in the Basolateral
Amygdala of Learned-Safety and Learned-Fear Mice
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Dopamine 2 receptor
Substance P
Prodynorphin
Preproenkephalin 1

mRNA Expressed in the Basolateral Amygdala
Dopamine 2 receptor Substance P

Dopamine 2 Receptor Is Critically
Involved in Learned Safety
Blockade before the memory recall test
Agonist before the memory recall test
Blockade
Prior to the FST

Blockade
During training on the response to the CS in the memory recall test
Agonist
During training on the response to the CS in the memory recall test

5-HT1A Receptors Are Not Critically
Involved in Learned Safety
Blockade
During training on the response to the CS in the memory recall test
Blockade before the memory recall test

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Behavioral outcomes similar to pharmacological interventions.
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Induce cell-biological changes known to result from antidepressant pharmacotherapy but is mediated through different molecular pathways.

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Learned safety is like the protection in clinical
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In author ’ s data, the learned fear is hard to be changed.
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Learned fear is like the depression

Ablation of Hippocampal Neurogenesis Inactivates the Antidepressant Effect of the Safety Signal

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Siemens Stabilopan X-ray
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A cumulative 15Gy dose was the minimum necessary to produce a reduction of cell proliferation greater than 85% in the dentate gyrus, which lasted for at leasted two month.
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Used x-irradiation of the dentate gyrus to ablate hippocampal neurogenesis in mice.
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Verified the absence of newly generated cells by doublecortin immunohistochemistry (a marker for neurons younger than 1 month of age) 6 weeks later.