Effects of stress and psychoactive drugs on adult hippocampal neurogenesis in the rat Público

Abstract

The subgranular zone of the dentate gyrus is one of only two sites of adult
neurogenesis in mammalian species. It is widely hypothesized to be downregulated by
psychological stress and upregulated by antidepressant drugs and to play a role in the
psychopathology of major depression. However, increasing evidence of inconsistencies
and complications surrounding this hypothesis has led to the questioning of its accuracy
and support for a more nuanced understanding of the relation of hippocampal
neurogenesis to other stress-regulated systems of the brain. The experiments presented
here show that the processes involved in hippocampal neurogenesis, primarily
proliferation of neural progenitor cells (NPC), are not susceptible to alteration by either
psychological stress or antidepressant drugs under all circumstances. Robust and
prolonged stress experiences, including restraint, tail shock, and social defeat, failed to
affect the proliferation rate of NPCs and short or long term survival of resulting newborn
cells. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and escitalopram,
the CRF1 antagonist R121919, and the atypical antipsychotics paliperidone and
ziprasidone also failed to affect neurogenesis in any measure examined. Chronic
treatment with the mood stabilizer lithium caused a significant increase in NPC
proliferation but no alteration in survival rate of newborn cells. Additionally, NPC
proliferation in adolescent animals showed no greater responsivity to either stress or
drug treatment than was seen in young adults. These results, seemingly in conflict with
the accepted model of the association of adult hippocampal neurogenesis with stress
and antidepressant drug response, are part of an emerging, more complex grasp of the
role neuroplasticity plays in stress response.

Table of Contents

1: Background 1
A. Timeline and markers of hippocampal neurogenesis 1
B. Effects of neurogenesis on hippocampal function 5
C. Role of neurotrophic factors 9
D. Stress and neurogenesis 11
E. Antidepressants and neurogenesis 14
F. The neurogenesis hypothesis of depression 16
G. Project rationale 18
H. References 19

2: Effects of stress 26
A. Introduction 26
B. Materials and methods 27
a. Animals
b. Monitor hyper rating
c. Stress procedures
i. Restraint stress
ii. Tail shock stress
iii. Social defeat stress
d. Serum corticosterone analysis
e. BrdU administration and sacrifice
f. Immunocytochemistry
g. In situ hybridization
C. Results 35
a. Restraint stress
b. Tail shock stress
c. Tail shock stress in HYPER line
d. Social defeat stress
D. Discussion 37
E. References 44
F. Figures 46
Figure 2-1. BrdU cell counts indicating cell proliferation rate in the dentate gyrus after acute restraint stress.
Figure 2-2. Serum corticosterone levels during the on-site tail shock experiment.
Figure 2.3. BrdU cell counts indicating cell proliferation rate in the dentate gyrus after on-site tail shock.
Figure 2.4. BrdU cell counts indicating cell proliferation rate in the dentate gyrus after off-site tail shock.
Figure 2.5. In situ hybridization of BDNF mRNA after on-site tail shock.
Figure 2.6. In situ hybridization of BDNF mRNA after off-site tail shock.
Figure 2.7. BrdU cell counts indicating cell proliferation rate in the dentate gyrus according to monitor hyper ratings.
Figure 2.8. In situ hybridization of BDNF mRNA according to monitor hyper ratings.
Figure 2.9. BrdU cell counts indicating cell proliferation rate in the dentate gyrus after social defeat stress.
Figure 2-10. BrdU cell counts indicating short term cell survival in the dentate gyrus after social defeat stress.
Figure 2-11. BrdU cell counts indicating long term cell survival rate in the dentate gyrus after social defeat stress.
Figure 2-12. In situ hybridization of BDNF mRNA after social defeat stress.
Figure 2-13. In situ hybridization of GR mRNA after social defeat stress.

3: Effects of psychoactive drugs 59
A. Introduction 59
B. Materials and methods 61
a. Animals
b. Drug administration
c. BrdU administration and sacrifice
d. Immunocytochemistry
e. In situ hybridization
C. Results 66
a. Fluoxetine and R121919
b. Lithium and paliperidone
c. Escitalopram and ziprasidone
D. Discussion 68
E. References 73
F. Figures 76
Figure 3-1. BrdU cell counts indicating cell proliferation rate in the dentate gyrus after chronic treatment with fluoxetine or R121919.
Figure 3-2. In situ hybridization of BDNF mRNA after chronic treatment with fluoxetine or R121919.
Figure 3-3. BrdU cell counts indicating cell proliferation rate in the dentate gyrus after chronic treatment with lithium and/or paliperidone.
Figure 3-4. BrdU cell counts indicating 14-day cell survival rate in the dentate gyrus after chronic treatment with lithium and/or paliperidone.
Figure 3-5. In situ hybridization of BDNF mRNA after chronic treatment with lithium and/or paliperidone.
Figure 3-6. BrdU cell counts indicating cell proliferation rate in the dentate gyrus after chronic treatment with escitalopram and/or ziprasidone.

4: Variations in adolescence 82
A. Introduction 82
B. Materials and methods 85
a. Animals
b. Social defeat stress
c. Drug administration
d. BrdU administration and sacrifice
e. Immunocytochemistry
f. In situ hybridization
C. Results 91
a. Social defeat stress
b. Fluoxetine and R121919
D. Discussion 92
E. References 94
F. Figures 96
Figure 4-1. BrdU cell counts indicating cell proliferation rate in the dentate gyrus after chronic social defeat stress.
Figure 4-2. In situ hybridization of BDNF mRNA after chronic social defeat stress.
Figure 4-3. In situ hybridization of GR mRNA after chronic social defeat stress.
Figure 4-4. BrdU cell counts indicating cell proliferation rate in the dentate gyrus after chronic treatment with fluoxetine or R121919.
Figure 4-5. Ki-67 cell counts indicating cell proliferation rate in the dentate gyrus after chronic treatment with fluoxetine or R121919.
Figure 4-6. Correlation of individual BrdU+ and Ki-67+ cell counts from adolescent fluoxetine/R121919 experiments.

5: General discussion 102
A. Stress and neurogenesis 102
B. Antidepressants and neurogenesis 105
C. References 107

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Palabra Clave	stress dentate gyrus neurogenesis antidepressant
Committee Chair / Thesis Advisor	Nemeroff, Charles B, University of Miami
Committee Members	Davis, Michael, Emory University Owens, Michael J, Emory University Weiss, Jay M, Emory University Duman, Ronald S., Yale University

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