How value informs decision making: A molecular and circuit-level approach Restricted; Files Only

Abstract

In day-to-day life, we often select our actions based on envisioned outcomes, mentally representing

the possible consequences of our behaviors and integrating their current values into existing

knowledge. The combination of these processes ultimately informs our decisions, yet the molecular

and neural mechanisms underlying flexible behavior are still being fully delineated. With a readily

accessible genetic toolbox, rodents provide copious and potentially innovative opportunities to better

understand the mechanisms underlying decision-making processes. This dissertation begins by

describing the neurobiological mechanisms underlying reward-related decision making in humans and

how components of this process are recapitulated in rodents. I focus on the medial orbitofrontal

cortex (MO) and its role in decision-making processes. Next, I report that the neurotrophin receptor

tropomyosin receptor kinase B (TrkB) in the MO is necessary for mice to integrate updated outcome

value information into future choice. This function appears attributable to outcome value memory

updating and, potentially, the stabilization of dendritic spines on excitatory MO neurons. I show that

projections from the ventral hippocampus (vHC) to the MO are essential for updated outcome value

information to be integrated into future choice – the vHC likely transferring emotive information

about the potential outcomes of one’s behavior – and that this process is TrkB-dependent. Next, I

investigate how flexible response strategies may be coordinated into motor action. I detail the role of

proline-rich tyrosine kinase 2 (Pyk2), a protein that controls the neuronal actin cytoskeleton, and the

neurocircuits involved. I demonstrate that Pyk2 in the dorsomedial striatum, a striatal compartment

that is indispensable for flexible behavior, is necessary to flexibly arbitrate between rewarded and nonrewarded

behaviors. I further show that Pyk2-dependent action relies upon stable connections with

the medial prefrontal cortex, which includes the MO. Together, these findings provide insight into the

molecular and circuit-level mechanisms coordinating value-based decision making, with molecular

factors likely acting, at least in part, to stabilize critical neural connections. This dissertation thus

illuminates mechanistic factors underlying decision-making strategies in healthy individuals, providing

potential avenues for treatment for individuals diagnosed with neuropsychiatric illnesses in which

aberrant decision making can be symptomatic, and even reinforcing, of illness.

Table of Contents

CHAPTER 1: HOW VALUE INFORMS ACTION SELECTION: ROLE OF THE

MEDIAL ORBITOFRONTAL CORTEX 1

1.1 CONTEXT, AUTHOR’S CONTRIBUTION, AND ACKNOWLEDGEMENT OF

REPRODUCTION 2

1.2 ABSTRACT 2

1.3 INTRODUCTION 3

1.3.1 Anatomical and functional subdivision of the ventromedial prefrontal cortex in

humans 3

1.4 HOW DOES VALUE INFORM OUR CHOICES? 4

1.4.1 Defining “value” 5

1.5 HOW CAN WE USE RODENTS TO STUDY VALUE-BASED DECISION

MAKING? 8

1.5.1 Retrieval of value memories 9

1.5.2 Brain-Derived Neurotrophic Factor: A molecular contributor to value-based action

12

1.6 NEURAL CIRCUITRY UNDERYLING VALUE-BASED ACTION 12

1.7 FRAMEWORK AND OVERVIEW OF THE DISSERTATION 13

CHAPTER 2: MEDIAL ORBITOFRONTAL NEUROTROPHIN SYSTEMS

INTEGRATE HIPPOCAMPAL INPUT INTO VALUE UPDATING 18

2.1 CONTEXT AND AUTHOR’S CONTRIBUTION 19

2.2 ABSTRACT 19

2.3 INTRODUCTION 20

2.4 RESULTS 21

2.4.1 TrkB is necessary for value memory updating, but not retrieval 21

2.4.2 TrkB in the MO is necessary for value memory updating 23

2.4.3 TrkB-mediated signaling controls dendritic spine density and structure on excitatory

MO neurons 26

2.4.4 vHC-to-MO projections are necessary for mice to use value information to guide

future choice 27

2.4.5 vHC-MO coordination of value-based action requires TrkB 29

2.5 DISCUSSION 32

2.5.1 TrkB is necessary for value-based action 33

2.5.2 Identifying substrates and connections for prospective action selection 34

2.5.3 Conclusions 37

2.6 MATERIALS AND METHODS 38

2.6.1 Subjects 38

2.6.2 Intracranial surgery 38

2.6.3 Behavioral testing 40

2.6.4 Drugs (preparation and administration) 43

2.6.5 Histological procedures and immunostaining 43

2.6.6 Dendritic spine imaging and characterization 46

2.6.7 Statistical analyses 47

2.7 FUNDING 48

2.8 ACKNOWLEDGEMENTS 48

CHAPTER 3: PYK2 STABILIZES STRIATAL MEDIUM SPINY NEURON

STRUCTURE AND STRIATAL-DEPENDENT ACTION 69

3.1 CONTEXT, AUTHOR’S CONTRIBUTION, AND ACKNOWLEDGEMENT OF

REPRODUCTION 70

3.2 ABSTRACT 70

3.3 INTRODUCTION 71

3.4 RESULTS 72

3.4.1 Pyk2 supports behavioral flexibility 72

3.4.2 Enrichment of striatal Pyk2 or FAK improves action flexibility 74

3.4.3 mPFC stimulation reinstates flexible behavior following striatal Pyk2 loss 74

3.5 DISCUSSION 77

3.5.1 Pyk2 in the DMS is necessary for flexible behavior 77

3.5.2 Identifying substrates and connections for flexible behavior 79

3.5.3 Conclusions 82

3.6 MATERIALS AND METHODS 82

3.6.1 Subjects 82

3.6.2 Viral vector delivery 82

3.6.3 Behavioral testing 83

3.6.4 CNO administration and experimental design 84

3.6.5 Locomotor activity 85

3.6.6 Histological verification of viral vector placement 86

3.6.7 Statistical analyses 86

3.7 FUNDING 87

3.8 ACKNOWLEDGEMENTS 87

CHAPTER 4: CONCLUSIONS AND FUTURE DIRECTIONS 92

4.1 ABSTRACT 93

4.2 DYSFUNCTION OF THE MEDIAL ORBITOFRONTAL CORTEX IN

OBSESSIVE COMPULSIVE DISORDER 93

4.3 MOLECULAR AND CIRCUIT-LEVEL MECHANISMS CONTRIBUTING

TO MO FUNCTION 95

4.3.1 How does TrkB contribute to value-based decision making? 96

4.3.2 How does the MO orchestrate decision-making strategies? 99

4.3.3 Novel evidence for TrkB control of reward-related action within the

basolateral amygdala 101

4.4 FROM DECISION-MAKING STRATEGIES TO ACTION SELECTION 105

4.4.1 Translating decision-making strategies into action 105

4.4.2 How does Pyk2 stabilize synaptic connections? 108

4.5 CONCLUSIONS 109

APPENDIX A: MATERIALS AND METHODS, FUNDING, AND

ACKNOWLEDGEMENTS FOR SECTION 4.3.3: TRKB CONTROL OF REWARDRELATED

ACTION WITHIN THE BASOLATERAL AMYGDALA 119

APPENDIX B: PUBLICTIONS TO WHICH THE AUTHOR HAS CONTRIBUTED 125

REFERENCES 126

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Mot-clé	orbitofrontal decision making neurotrophin reward ventral hippocampus
Committee Chair / Thesis Advisor	Shannon Gourley, Emory University Arthur English, Emory University Robert Liu, Emory University Katharine McCann, Emory University
Committee Members	Kate Wassum, University of California, Los Angeles

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