Mesocorticolimbic Generation of Desire and Dread along a Rostrocaudal Gradient in Medial Shell ...

206 Pages·2012·4.98 MB·English

Mesocorticolimbic Generation of Desire and Dread along a Rostrocaudal Gradient
in Medial Shell of Nucleus Accumbens

by

Jocelyn Marget Richard

A dissertation submitted in partial fulfillment
of the requirements for the degree of
Doctor of Philosophy
(Psychology)
in the University of Michigan
2012

Doctoral Committee:

Professor Kent C. Berridge, Chair
Professor J. Wayne Aldridge
Assistant Professor Brandon J. Aragona
Professor Israel Liberzon
© Jocelyn Marget Richard
All Rights Reserved
2012
In loving memory of Elizabeth Richard
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Acknowledgements

Firstly, I would like to thank my graduate advisor, Kent Berridge, who has provided
superb guidance and encouragement, and has taught me more than I could have predicted about
affective neuroscience, writing, and science in general. I would also like to thank the other
members of my committee - Brandon Aragona, Wayne Aldridge and Israel Liberzon – for their
support, and for taking the time to discuss all these projects with me. Brandon Aragona in
particular has been a great source of experimental, career and life advice.
Many of my colleagues in the Berridge lab have provided important training, technical
support, critical discussion and, importantly, friendship during my time in the lab. In particular I
would like to thank Steve Mahler for all of his training, advice and friendship, and Eric Jackson,
Chao-Yi Ho and Mike Robinson for being great sources of advice and discussion. Alex
DiFeliceantonio and Daniel Castro have been both very willing sources of proofreading and
discussion, as well as great friends. Numerous undergraduate research assistants helped in the
completion of the described experiments, by handling animals, prepping testing chambers and
equipment, and watching many hours of videorecordings to quantify behavioral data. I would
especially like to acknowledge those students who stuck around to conduct thesis projects related
to this line of research: Aaron Garcia, Andrea Plawecki, Adam Wilensky and Gabriel Stellman.
Andrea conducted the experiment investigating the dopamine dependence of GABAergic eating
and fear described in Chapter 2. I also received critical immunohistochemical and other
technical support from Michelle Dimondo, Victor Baron, Stephen Burwell, and Ryan Selleck, as
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well as from Aaron Garcia, who was also instrumental in setting up our lab’s optogenetics
program.
I have been fortunate to have a great set of Ann Arbor friends beyond the lab as well,
including my fabulous cohort - Jeremiah Bertz, Eila Roberts, Caitlin Orsini and Benjamin
Saunders - as well as Lindsay Yager, Matt Howe, Kirsten Porter-Stransky, Josie Urban, Shanna
Harkey, Liz Cogan, Anne Berry, Jeff Pettibone, Alaina Neary Case, Morgan Gustison, and Katy
Goldey. You all helped me stay sane. A special thanks to Ben, for the many things you are to me.
And finally, to my parents, Jeff and Kit, for always believing I could do whatever I wanted with
my life, and to Alice, for being the coolest sister a girl could have.
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Table of Contents

Dedication ii
Acknowledgements iii
List of Figures vii
Abstract ix

Chapter

1. Introduction 1
Figures 23

2. Eating and Fear Generated by GABAergic Inhibition in Nucleus
Accumbens Shell Needs No Dopamine and Resists Environmental
Retuning 26
Introduction 26
Methods 28
Results 36
Discussion 41
Figures 48

3. Nucleus Accumbens Dopamine/Glutamate Interaction Switches Mode to
Generate Desire versus Dread: D1 Alone for Appetitive Eating but D1 and
D2 Together for Fear 57
Introduction 57
Methods 59
Results 66
Discussion 77
Figures 83

4. Prefrontal Cortex Modulates Desire and Dread Generated by Nucleus
Accumbens Glutamate Disruption 92
Introduction 92
Methods 94
Results 101
Discussion 105
Figures 111

5. New and Future Directions 119
Introduction 119
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DREADD-Mediated Inhibition of Medial Shell 121
Methods 121
Results and Discussion 125
Optogenetic Inhibition of Medial Shell 126
Methods 127
Results and Discussion 129
Future Directions 130
Figures 141

6. General Discussion 145

References 168

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List of Figures

Figure

1.1: Rostral Shift of Anatomical Markers in the Coronal View 23

1.2: Glutamatergic and GABAergic NAc Circuits 25

2.1: Summary Graphs of the Effect of Local Dopamine Blockade on
Muscimol-Generated Eating and Fearful Behaviors 48

2.2: Effects of Dopamine Antagonism on Muscimol-Induced Eating and
Defensive Behaviors 49

2.3: Summary Maps of Behavioral Valence in Three Environments 51

2.4: Changes in Motivational Valence Between the Home and Stressful
Environments 52

2.5: Effect of Changing Environmental Ambience on Defensive Treading
Produced by DNQX or Muscimol 53

2.6: Effect of Changing Environmental Ambience on Defensive Reactions
to the Experimenter Produced by DNQX or Muscimol 54

2.7: Effect of Changing Environmental Ambience on Eating Produced by
DNQX or Muscimol 55

2.8: Fos Plume Analysis 56

3.1: Summary Maps of Behavior and Fos Plume Analysis 83

3.2: Motivated Behavior Summary Graphs 85

3.3: Effects of D1 and D2 Antagonism on DNQX-induced Eating and
Defensive Behaviors 86
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3.4: Environmental Ambience Shifts Glutamate-Dopamine Interaction Mode 88

3.5: Appetitive and Defensive Behavior Elicited from Mixed Valence Sites
in the Stressful Environment 89

3.6: Mesocorticolimbic Circuits Impacted by Glutamate-Dopamine
Interactions 91

4.1: Microinjection Conditions and DNQX Effects 111

4.2: Maps of Prefrontal Activation Effects on NAc Shell DNQX Generated
Eating and Defensive Treading 112

4.3: Motivated Behavior Graphs 113

4.4: Maps of Prefrontal Inhibition Effects on NAc Shell DNQX Generated
Eating and Defensive Treading 114

4.5: Fos Plume Analysis and NAc-Prefrontal Interactions 115

4.6: Potential Mechanisms of Prefrontal Modulation of DNQX Generated
Motivated Behaviors 117

5.1: DREADD Expression and Maps of Eating Produced by DREADD-
Mediated Inhibition 141

5.2: Graphs of Effects of DREADD-Mediated Inhibition on Food Intake and
Eating Behavior 142

5.3: Graphs of Effects if DREADD-Mediated Inhibition on Other Behaviors 143

5.4: ArchT-GFP Expression 144

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Abstract
Behaviors related to desire versus dread are generated by localized inhibitions along a
rostrocaudal anatomical gradient within medial shell of nucleus accumbens of the rat. Either
GABA receptor-mediated inhibitions, via microinjections of the GABA agonist muscimol, or
A
corticolimbic glutamate disruption, via microinjections of the AMPA antagonist DNQX,
generate intense eating at rostral sites and fearful behaviors at more caudal sites. Importantly,
local endogenous dopamine is needed for eating and fear generation by glutamate blockade.
Additionally, environmental ambience can retune the valence of behavior produced by glutamate
disruption, promoting appetitive behavior in a familiar environment, and promoting fearful
behavior in a stressful environment. Here, I investigated what signals might contribute to desire
versus dread. In Chapter 2 I found that behaviors generated by GABAergic inhibition of
accumbens resist environmental retuning, and do not need endogenous dopamine. These results
suggest that subcortical GABAergic generation of motivation is more robust, autonomous and
anatomically biased than glutamatergic generation in accumbens. In Chapter 3 I found that only
endogenous local signaling at D1 dopamine receptors is needed for generation of excessive
eating by glutamate disruptions, whereas fear generation requires both D1 and D2 dopamine
signaling simultaneously. Furthermore, when motivation valence generated by glutamate
disruptions was flipped by manipulating environmental ambience, the roles of local D1 versus
D2 signaling also switched dynamically to match the motivation valence generated at the
moment. The experiments in Chapter 4 examined whether medial prefrontal cortex can modulate
intense motivations generated by accumbens shell glutamate disruptions. I found that activation
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