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«Distribution Agreement In presenting this thesis or dissertation as a partial fulfillment of the requirements for an advanced degree from Emory ...»

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Distribution Agreement

In presenting this thesis or dissertation as a partial fulfillment of the requirements for an advanced

degree from Emory University, I hereby grant to Emory University and its agents the nonexclusive license to archive, make accessible, and display my thesis or dissertation in whole or in

part in all forms of media, now or hereafter known, including display on the world wide web. I

understand that I may select some access restrictions as part of the online submission of this thesis or dissertation. I retain all ownership rights to the copyright of the thesis or dissertation. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation.

Signature:

__________________________________ __________________

David Ehrlich Date Critical Periods in the Development of Amygdala Inhibition: The Effects of Prenatal Stress By David Ehrlich Doctor of Philosophy Graduate Division of Biological and Biomedical Science Neuroscience _________________________

Donald Rainnie, Ph.D.

Advisor _________________________

Kerry Ressler, Ph.D.

Committee Member _________________________

Peter Wenner, Ph.D.

Committee Member _________________________

Gretchen Neigh, Ph.D.

Committee Member _________________________

Andrew Jenkins, Ph.D.

Committee Member

Accepted:

_________________________

Lisa A. Tedesco, Ph.D.

Dean of the James T. Laney School of Graduate Studies _________________________

Date Critical Periods in the Development of Amygdala Inhibition: The Effects of Prenatal Stress By David Ehrlich B.S. Neuroscience, Brown University, 2007 Advisor: Donald Rainnie, Ph.D.

An

Abstract

of A dissertation submitted to the Faculty of the James T. Laney School of Graduate Studies of

–  –  –

The amygdala plays a key role in emotional processing, and dysfunction of the amygdala is implicated in a variety of psychiatric disorders. Growing evidence suggests many disorders, including anxiety, depression, autism, and schizophrenia, are neurodevelopmental in origin.

During development, brain circuits undergo “sensitive periods” when environmental factors have potent effects that include long-term consequences for emotional processing. We hypothesized that a risk factor for psychiatric disorders, prenatal stress, alters the trajectory of amygdala maturation and thereby influences emotional outcomes. In order to test this hypothesis, however, it was necessary to first understand how the amygdala typically develops. While a number of gross structural and functional changes have been identified in the normally developing amygdala, no studies have characterized amygdala development in terms of the function of neurons. Here, we report the first findings of changes to electrophysiology of the developing amygdala. We used patch clamp in ex vivo rat brain slices to describe the electrophysiology of amygdala neurons, discovering a number of changes. Amygdala neurons exhibited profound maturation of their intrinsic properties from birth through infancy, including reduced excitability, faster action potentials produced at higher rates, and altered expression of membrane currents and the ion channels that mediate them. Developing amygdala neurons also showed corresponding morphological changes, including expansion of dendritic arbors and the emergence of dendritic spines. In addition, synapses for the neurotransmitter gamma-aminobutyric acid (GABA) exhibited changes to kinetics, excitability, and synaptic plasticity. GABA regulates a variety of neurodevelopmental processes, including cell proliferation, migration, and differentiation, as well as synapse maturation, suggesting perturbation of the GABA system could alter amygdala development. We found that GABAergic function in the amygdala was altered by exposure to prenatal stress, with deficits emerging during infancy that preceded long-term changes to neuron excitability. Furthermore, these changes to amygdala maturation correspond with deficits in amygdala-dependent, emotional behavior. In sum, we have provided the first account of physiological development of amygdala neurons, and identified ways in which this process is perturbed by a risk factor for psychiatric illness.

Critical Periods in the Development of Amygdala Inhibition: The Effects of Prenatal Stress

–  –  –

I would like to thank my thesis committee for their patient and generous guidance and their commitment to my development as a scientist. This work would not have been possible without funding from the National Institutes of Mental Health, the Yerkes National Primate Research Center animal care and veterinary staff, or the support, training, and motivation of the entire Rainnie Lab, including Dr. Chen-Chen Li, Teresa Madsen, Sarah Dewitt, Tom Hennessey, Dr. Stefanie Ritter, Dr. Andrea Crowell, and Wei Liu. Special thanks are owed to Drs. Ji-Dong Guo, Rimi Hazra, and Joanna Dabrowska for sharing an abundance of technical expertise. Drs.

Yoland Smith, Ronald Calabrese, Larry Young, and Shawn Hochman, along with Gary Longstreet and Sonia Hayden, constituted a support system much appreciated and often necessitated. The students of the Emory Neuroscience program, including Dr. Damon Lamb, Christopher Makinson, and Mallory Bowers, were an endless source of scientific inspiration, motivation, and perspective. Distinct gratitude is reserved for Steve Ryan, for a productive partnership with a rare mix of heated debate, mutual respect, and true compromise. Finally, to the mentor who inspired these strangers to a common cause and served as a constant advocate and selfless patron: thank you for everything.





In dedication to my mother, who taught me to formulate hypotheses,

–  –  –

Abbreviations

Chapter 1: The Basolateral Amygdala and Early-Life Stress in Anxiety Disorder Etiology. 2

1.1 Neurodevelopmental Basis of Anxiety Disorders

1.1.1 Emergence of Anxiety Disorders in Children and Adolescents

1.1.2 Early Life Sensitivity to Stress

1.1.3 ‘Critical Periods’ in Development as Windows of Vulnerability

1.2 Juvenile and Adult Anxiety Disorders Involve Dysfunction of the Amygdala................. 11 1.2.1 Implicating Amygdala Dysfunction in Anxiety Disorders

1.2.2 The BLA in the Responses to Acute and Chronic Stress

1.2.3 GABA, a Key Regulator of BLA Function

1.3 Maturation of Amygdala Physiology and Function

1.3.1 A Critical Period for Amygdala Influence on Emotional Development

1.3.2 Development of the Human Amygdala

1.3.3 Development of the Rodent Amygdala

1.4 Impact of Early Life Experience on Amygdala Development

1.4.1 Early Life Stress and the Trajectory of Amygdala Development

1.4.2 Experiential Factors Promoting Resiliency

1.5 Conceptual Summary

Chapter 2: Postnatal development of electrophysiological properties of principal neurons in the rat basolateral amygdala

2.1 Abstract

2.2 Introduction

2.3 Methods

2.3.1 Ethical approval

2.3.2 Animals

2.3.3 Slice preparation

2.3.4 Patch clamp recording

2.3.5 Data Analysis

2.3.6 Membrane Properties and Intrinsic Currents

2.3.7 Action Potentials and Spike Trains

2.3.8 Resonance and Oscillations

2.3.9 Statistics

2.4 Results

2.4.1 Postnatal Maturation of Passive Membrane Properties

2.4.2 Postnatal Maturation of Intrinsic Currents

2.4.3 Postnatal Maturation of Spiking

2.4.4 No Effect of Sex on Postnatal Changes in Physiological Properties

2.5 Discussion

2.5.1 Maturation of passive membrane properties

2.5.2 Maturation of membrane potential oscillations and resonance

2.5.3 Maturation of Ih and its contribution to resonance

2.5.4 Maturation of trains of action potentials

2.5.5 Maturation of action potentials and AHPs

2.5.6 Maturation of amygdala connectivity and neuronal morphology

Chapter 3: Morphology and Ion Channel Expression of Developing Principal Neurons in the Rat Basolateral Amygdala

3.1 Abstract

3.2 Introduction

3.3 Methods

3.3.1 Ethical approval

3.3.2 Animals

3.3.3 Slice Physiology

3.3.4 Patch clamp recording

3.3.5 Histochemical Processing

3.3.6 Neuronal reconstruction and Data Analysis

3.3.7 Single Cell RT-PCR

3.3.8 Statistics

3.4 Results

3.4.1 Soma size

3.4.2 Growth and Retraction of Dendritic Arbor

3.4.3 Maturation of Dendritic Branching

3.4.4 Developmental Emergence of Dendritic Spines

3.4.5 Expression of Ion Channel Transcripts

3.5 Discussion

3.5.1 Somatic Development

3.5.2 Dendritic Morphology

3.5.3 Dendritic Spine Emergence

3.5.4 Voltage-gated Ion Channel Expression

Chapter 4: Postnatal maturation of GABAergic transmission in the rat basolateral amygdala

4.1 Abstract

4.2 Introduction

4.3 Methods

4.3.1 Ethical approval.

4.3.2 Animals.

4.3.3 Slice preparation.

4.3.4 Whole-cell patch clamp.

4.3.5 Spontaneous inhibitory postsynaptic currents

4.3.6 Stimulation-evoked postsynaptic potentials and currents.

4.3.7 Picospritzer response.

4.3.8 Single-cell and whole tissue RT-PCR

4.3.9 Statistics.

4.4 Results

4.4.1 Compound synaptic response to local electrical stimulation.

4.4.2 Kinetics of fast synaptic inhibition of BLA principal neurons.

4.4.3 Depolarized reversal potential of GABAA receptors in immature BLA principal neurons.

4.4.4 Short-term plasticity of GABAA IPSCs.

4.4.5 Spontaneous GABA activity is rhythmically organized throughout the first postnatal month.

4.5 Discussion

4.5.1 Shift from depolarizing to hyperpolarizing GABAA transmission.

4.5.2 Development of a GABAergic shunt of the network response.

4.5.3 Faster IPSCs with age.

4.5.4 Short-term synaptic depression of GABAA IPSCs in immature BLA.

Chapter 5: The Developmental Trajectory of Amygdala Neuron Excitability and GABAergic Transmission are Altered by Prenatal Stress

5.1 Abstract

5.2 Introduction

5.3 Methods

5.3.1 Ethical Approval

5.3.2 Animals

5.3.3 Prenatal Stress

5.3.4 Electrophysiology

5.3.5 Quantitative RT-PCR

5.3.6 Behavioral Testing

5.3.7 Statistics

5.4 Results

5.4.1 Reduced emotionality in adult and juvenile PS rats

5.4.2 PS altered intrinsic properties of BLA principal neurons during development.......... 200 5.4.3 PS reduced excitability of BLA principal neurons in adulthood

5.4.4 PS altered the developmental trajectory of GABAergic transmission in the BLA..... 202 5.4.5 PS reduced BLA expression of the GABAA receptor α1 subunit during a development critical period

5.5 Discussion

5.5.1 PS Reduces Anxiety-Like Behavior and May Reduce Sociability

5.5.2 PS Alters Electrophysiological Properties of Developing BLA Neurons

5.5.3 PS Alters GABAergic Transmission and Receptor Expression in the BLA............... 209 Chapter 6: Spike-Timing Precision and Neuronal Synchrony are Enhanced by an Interaction between Synaptic Inhibition and Membrane Oscillations in the Amygdala.... 239

6.1 Abstract

6.2 Introduction

6.3 Methods

6.3.1 Animals and housing conditions

6.3.2 Electrophysiological procedures

6.3.3 Data and statistical analysis

6.4 Results

6.4.1 Primate BLA principal neurons receive spontaneous, synchronized, rhythmic IPSPs that coordinate action potential timing.

6.4.2 Compound IPSPs enhance spike-timing precision in rat BLA principal neurons...... 251 6.4.3 Compound IPSPs synchronize the firing activity of multiple BLA principal neurons.

6.4.4 Compound IPSPs facilitate an intrinsic membrane potential oscillation in BLA principal neurons

6.4.5 The membrane potential oscillation is sensitive to modulation of its component currents.

6.5 Discussion

6.5.1 Synchronized inhibition drives coordinated activity of BLA principal neurons........ 258 6.5.2 Resonance frequency and intrinsic membrane oscillations in BLA principal neurons

6.5.3 Implications for learning and memory

Chapter 7: Discussion

7.1 Summary of Results

7.2 Integration of Findings

7.2.1 Importance of Studying Developmental Trajectories

7.2.2 Potential Impact of Prenatal Stress on Emotion Via Amygdala Network Oscillations

7.2.3 Applying Critical Period Concepts to BLA Development

References

List of Tables and Figures

Chapter 1 Chapter 5

Figure 1.1……………………………...45 Figure 5.1…………………………….215 Figure 5.2…………………………….217 Figure 5.3…………………………….219 Chapter 2 Figure 2.1……………………………...77 Figure 5.4…………………………….221 Figure 2.2……………………………...78 Figure 5.5…………………………….223 Figure 2.3……………………………...81 Figure 5.6…………………………….225 Figure 2.4……………………………...83 Figure 5.7…………………………….227 Figure 2.5……………………………...85 Figure 5.8…………………………….229 Figure 2.6……………………………...87 Figure 5.9…………………………….231 Figure 2.7……………………………...89 Figure 5.10…………………………...233 Figure 2.8……………………………...91 Figure 5.11…………………………...235 Figure 2.9……………………………...93 Figure 5.12…………………………...237

Chapter 3 Chapter 6



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