Transcriptional regulation of Homer1a during Pavlovian Fear Conditioning Open Access
Mahan, Amy Louise (2011)
Abstract
The consolidation of fear conditioning involves upregulation of
genes necessary for long-
term memory formation. We examined whether homer1a, which is
required for memory
formation, is downstream of BDNF - TrkB activation. In chapter 3 we
demonstrate that homer1a
mRNA 1) increases after fear conditioning in vivo within
both amygdala and hippocampus, 2)
increases after BDNF application to primary hippocampal and
amygdala cultures in vitro, 3) these
increases are dependent on transcription and MAPK signaling, and 4)
we demonstrate that a trkB
agonist, 7,8-DHF enhances long-term memory for Pavlovian fear
conditioning in vivo as well as
increasing expression level of homer1a in vitro, and that
inhibiting trkB signaling impairs
homer1a expression during Pavlovian conditioning in the
amygdala and hippocampus. In chapter 4
we demonstrate that 1) Pavlovian fear conditioning induces distinct
modifications of histones
bound to the Homer1 promoter; 2) BDNF induced plasticity produced
similar modifications of
histones bound to the Homer1a promoter in primary amygdala and
hippocampal cell culture; and
3) Sodium Butyrate, a histone deacetylase inhibitor, enhanced
contextual fear memories,
hippocampal mRNA expression and hippocampal H3 acetylation around
the Homer1 promoter. In
Chapter 5 we demonstrate that homer1a gene transcription and
changes in histone modifications
during fear conditioning are mediated through CREB binding around
the Homer1 promoter by: 1)
demonstrating that CREB and CBP are increasingly bound to the
Homer1 promoter after fear
conditioning and 2) that inhibiting CREB inhibits homer1a
expression, CBP binding and histone
modifications after fear conditioning. Together these data suggest
that CREB and CBP are critical
for regulation of homer1a expression, in part via modulation
of histone acetylation regulating
chromatin containing the homer1 gene. This body of work
provides evidence for dynamic
regulation of homer1a following BDNF-induced plasticity or
during a BDNF-dependent learning
process.
Transcriptional Regulation of Homer1a During Pavlovian Fear
Conditioning
B.S., Trinity University
Advisor: Kerry J. Ressler, M.D., Ph.D.
A dissertation submitted to the Faculty of the
James T. Laney School of Graduate Studies of Emory University
in partial fulfillment of the requirements for the degree of Doctor
of Philosophy in the Graduate
Division of Biological and Biomedical Sciences
Neuroscience
2011
Table of Contents
Table of Contents
Chapter 1: Introduction Fear Conditioning, Synaptic Plasticity, and the Amygdala:
Implications for Posttraumatic Stress Disorder 1
1.1 Abstract 2
1.2 Introduction 2
1.3 Pavlovian fear conditioning as a model for understanding the underlying
mechanisms of pathological fear responses 4
1.4 Neurotrophic mechanisms of synaptic plasticity in fear conditioning 7
1.5 GABAergic Inhibitory Regulation of Neuronal Circuits in Fear Conditioning 13
1.6 Glutamatergic Signaling in Fear conditioning 17
1.7 Conclusions 20
1.8 Figures 22
1.9 References 38
Chapter 2 The Role of Homer1 in Posttraumatic Stress Disorder and Psychiatric Disease 56
2.1 Homer1 genetic association studies in Psychiatric Disease 57
2.2 The Homer1 gene family: Structure and Function 59
2.3 Role of Homer1a in animal models of psychiatry 62
2.4 Homer1a and Pavlovian Fear conditioning 64
2.5 Conclusions 66
2.6 Figures 67
2.7 References 71
Chapter 3 Homer 1a transcription is upregulated by Pavlovian Fear conditioning
and BDNF-TrkB signaling in the amygdala and Hippocampus 81
3.1 Abstract 82
3.2 Introduction 82
3.3 Methods 84
3.4 Results 88
3.6 Discussion 91
3.7 Figures 95
3.8 References 108
Chapter 4 Epigentetic Regulation of Homer1a during Pavlovian fear conditioning and BDNF induced plasticity 111
4.1 Introduction 112
4.2 Methods 113
4.3 Results 118
4.4 Discussion 119
4.5 Figures 123
4.6 References 127
Chapter 5 CREB and CBP Regulation of Homer1a during Pavlovian
fear conditioning and BDNF 129
5.1 Abstract 130
5.2 Introduction 130
5.3 Methods 133
5.4 Results 138
5.5 Discussion 141
5.6 Figures 144
5.7 References 160
Chapter 6 General Discussion/Conclusion: Summary of Findings, Future Directions, and Clinical Implications 163
6.1 Summary of Findings 164
6.2 Limitations of Findings 164
6.3 Epigenetics and Pavlovian Fear Conditioning 167
6.4 Homer1a and Pavlovian Fear conditioning 169
6.6 Homer1a in PTSD 171
6.7 Future Directions 171
6.7 Figures 173
6.8 References 175
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