Inhibiting Rho-kinase promotes goal-directed decision-making and blocks habitual responding for cocaine Öffentlichkeit

Abstract

The ability to select actions based upon a desired outcome is critical for survival. While a number of brain regions are involved in these processes, the prelimbic prefrontal cortex is necessary for associating actions with their consequences, enabling goal-directed decision-making. However, the relationship between deep-layer dendritic spines and outcome-based decision-making remains opaque. We provide evidence, using a Rho-kinase inhibitor, that glucocorticoid receptor-mediated dendritic spine remodeling is causally related to outcome-based decision-making. To better understand how dendritic spines remodel in response to postnatal stressor exposure, we also enumerated dendritic spines during and after chronic stress hormone exposure in hippocampal CA1, deep-layer prefrontal cortex, and the basal amygdala. Corticosteroid exposure modified dendritic spine density in these regions, but with the exception of the orbitofrontal cortex, densities normalized with a recovery period. Using mice with reduced gene dosage of p190rhogap, a cytoskeletal regulatory protein localized to dendritic spines, we isolated structural correlates of both behavioral vulnerability (spine elimination) and resilience (spine proliferation) to stress hormone exposure within the orbitofrontal cortex. We also find that the strength of action-outcome conditioning correlates with prelimbic cortical dendritic spine densities, suggesting that new action-outcome learning involves dendritic spine plasticity. We inhibited Rho-kinase, which enhanced action-outcome memory, resulting in goal-directed behavior in mice that would otherwise express stimulus-response habits. Rho-kinase inhibition transiently reduced prelimbic cortical dendritic spine density during a period of memory consolidation, but only when paired with new learning. It also blocked habitual responding for cocaine, an effect that persisted over time, across multiple contexts, and depended upon actin polymerization, suggesting that Rho-kinase inhibition promotes goal-oriented action selection by augmenting the plasticity of prelimbic cortical dendritic spines during the consolidation of new action-outcome memories, and that it has therapeutic potential for cocaine use disorders. Finally, we developed an approach to investigate the structural effects of cocaine on prelimbic cortical dendritic spines in vivo. We found that while low-dose cocaine did not alter dendritic spine density, it increased the rate of dendritic spine turnover. Together, these findings provide strong evidence for the importance of deep-layer prelimbic cortical dendritic spine plasticity in outcome-based decision-making.

Table of Contents

Table of Contents

Introduction. 1

Actions and habits. 2

Neuroanatomical basis actions and habits. 4

General neuroanatomy. 4

Cortical organization. 4

Cortico-striatal circuits. 5

Rodent and human homology. 6

Modulation of the prelimbic cortex. 7

Prelimbic cortex. 9

Dendritic spines. 11

Structure and function. 11

Morphology. 12

Classification. 13

Dendritic arbors and dendritic spine density. 15

Dendritic spines, learning, and memory. 16

Molecular regulation of dendritic spine structure. 17

Actin cytoskeleton. 17

RhoA signaling. 18

Approaches to identify structural correlates of decision-making strategies. 20

Instrumental conditioning. 20

Action-outcome contingency degradation. 21

Outcome devaluation. 21

Dendritic spine imaging. 22

In vivo methodologies. 22

Dendritic spine analysis. 23

Major points of the dissertation. 24

References. 26

Figures. 42

Figure 1. Goal-directed vs. habitual decision-making. 42

Figure 2. The prelimbic cortex is part of the prefrontal cortex. 43

Figure 3. 3-D reconstruction of dendritic spines. 44

Figure 4. Rho-ROCK signaling. 45

Figure 5. Instrumental conditioning and action-outcome contingency degradation can be used to determine action-outcome sensitivity in mice. 46

Chapter 1: Glucocorticoid receptor regulation of action selection and prefrontal cortical dendritic spines 47

Abstract. 48

Body text. 49

GR occupation regulates dendritic spine density in deep-layer prelimbic cortex. 50

Regulation of complex decision-making by the GR antagonist RU38486 and Rho-kinase inhibition 52

Discussion. 54

Works Cited. 57

Figures. 62

Figure 1. Corticosterone exposure and GR blockade modify prelimbic cortical dendritic spines. 62

Figure 2. GR blockade regulates outcome-based decision-making. 63

Chapter 2: Corticosteroid-induced neural remodeling predicts behavioral vulnerability and resilience 64

Abstract. 65

Introduction. 66

Results. 68

A history of corticosteroid exposure modifies dendritic spines and behavior. 68

Discussion. 70

Hippocampal networks and stress-related structural reorganization. 70

Prefrontal cortical dendritic spines reorganize in response to corticosteroid exposure. 71

Methods. 74

References. 77

Figures. 82

Figure 1. Chronic corticosteroid exposure has regionally-selective effects on dendritic spine density. 82

Figure 2. p190RhoGAP determines the cellular response to CORT exposure. 83

Chapter 3: Inhibiting Rho-kinase promotes goal-directed decision-making and blocks habitual responding for cocaine 85

Abstract. 86

Introduction. 87

Results. 89

Inducible inactivation of the prelimbic prefrontal cortex impairs the ability of mice to select actions based on their consequences. 89

Prelimbic cortical dendritic spine density predicts reward-related decision-making strategies in mice 89

ROCK blockade transiently remodels dendritic spines in a conditioning-dependent manner. 93

ROCK inhibition blocks habitual responding for cocaine. 94

Inhibiting F-actin polymerization blocks fasudil's effects on action selection. 97

Discussion. 99

Cortico-striatal-limbic circuits balance actions and habits. 99

ROCK blockade inhibits habit-based cocaine seeking. 101

The effects of ROCK inhibition are dependent upon F-actin turnover. 103

Conclusions. 103

Methods. 105

References. 111

Figures. 120

Figure 1. Chemogenetic silencing of the prelimbic prefrontal cortex impairs the ability of mice to select actions based on their consequences. 120

Figure 2. ROCK inhibition enhances goal-directed action selection. 121

Figure 3. ROCK inhibition remodels prelimbic cortical dendritic spines. 123

Figure 4. ROCK inhibition blocks habitual responding for cocaine. 124

Figure 5. Blocking F-actin polymerization in the prelimbic cortex prevents ROCK inhibition from promoting goal-directed action selection. 126

Figure S1. Delayed fasudil injection has no effects, and ROCK inhibition also does not influence response extinction. 127

Figure S2. Ablating Arg kinase, an endogenous ROCK inhibitor, induces habit-based behavior. 128

Figure S3. Fasudil selectively enhances sensitivity to action-outcome contingency. 129

Supplemental Table 1: Morphological measurements of prelimbic cortical dendritic spines. 130

Chapter 4: In vivo imaging of prelimbic cortical dendritic spines. 131

Abstract. 132

Introduction. 133

Results. 136

Cocaine blocks the consolidation of action-outcome conditioning, occluding goal-directed responding 136

Structural effects of acute cocaine in the prelimbic prefrontal cortex. 137

Turnover rates of cortical dendritic spines in female mice. 138

Discussion. 140

Methods. 145

References. 152

Figures. 157

Figure 1: Cocaine interferes with consolidation of action-outcome learning and memory. 157

Figure 2: Cocaine decreases the rate of dendritic spine formation and increases the rate of elimination in the prelimbic cortex. 158

Figure 3: Densities and turnover rates of dendritic spines in the prelimbic prefrontal cortex of female mice. 159

Table 1: Morphological parameters of vehicle- and cocaine-treated prelimbic cortical dendritic spines 160

Table 2: Morphological parameters of prefrontal cortical dendritic spines in female mice. 162

Concluding discussion. 163

Summary. 164

Fasudil's mechanism of action. 165

The balance between actions and habits. 166

Action-outcome learning and prelimbic cortical dendritic spine elimination. 168

Correlative vs. causative mechanisms of decision-making strategies. 170

In vivo imaging of prelimbic cortical dendritic spines. 172

Conclusion. 173

References. 175

Figures. 179

Figure 1. ROCK inhibition facilitates remodeling of prelimbic cortical dendritic spines, promoting goal-directed decision-making. 179

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
Stichwort	decision-making
Committee Chair / Thesis Advisor	Gourley, Shannon L, Emory University
Committee Members	Zheng, James, Emory University Bassell, Gary, Emory University Rainnie, Donald, Emory University Faundez, Victor, Emory University

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