Cortical mechanisms and developmental contributions to habit formation Open Access

DePoy, Lauren Marie (2016)

Permanent URL: https://etd.library.emory.edu/concern/etds/sj139242w?locale=en
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Abstract

Adolescence is characterized by high rates of experimental drug use and heightened vulnerability to the development of neuropsychiatric disorders, including substance dependence. Adolescence is also a time of activity-dependent neocortical refinement, consisting of synaptic reorganization and dendritic spine proliferation and then pruning. This reorganization might open a window of vulnerability to insults, such as cocaine exposure. Addiction is characterized by maladaptive decision making, a loss of control over drug consumption, and habit-like drug seeking despite adverse consequences. These cognitive changes likely reflect the effects of repeated drug exposure on prefrontal cortical neurobiology that then further promote drug use. Broadly, this dissertation will focus on the role of the orbitofrontal prefrontal cortex (oPFC) in action-outcome conditioning, which is critical for intact, goal-directed decision making. On the other hand, oPFC damage causes reward-seeking habits, which are increasingly recognized as an etiological factor in the development and maintenance of addiction. I will first show that adolescent cocaine exposure simplifies the dendritic structure of excitatory neurons in the oPFC. Cocaine also eliminates dendritic spines on the same neurons, and I will provide evidence that this structural remodeling is causally associated with adolescent vulnerabilities to developing drug-induced habit-based behavior. I will next shift my focus to receptor subunits that are implicated in addiction-related behavior across multiple species. I will show that silencing β1-integrin, which stimulates downstream signaling partners to coordinate actin dynamics, in the oPFC causes stimulus-response habits and a hyper-sensitivity to conditioned stimuli in a sex- and developmentally-selective fashion. Lastly, I will provide a ‘snapshot' of another important prefrontal cortical structure, the medial prefrontal cortex (mPFC), which is known to regulate the acquisition of action-outcome conditioning; however, developmental contributions are unclear. I will show that developmental silencing of GABAAα1 impairs action-outcome conditioning, which is associated with delayed acquisition of a cocaine-reinforced response in cocaine self-administering mice. Together, these results suggest that the normative development of multiple sub-regions of the prefrontal cortex is critical for goal-directed decision making in adulthood. Aberrant structural remodeling or deficiencies in key cytoskeletal regulatory proteins during adolescence, either due to drug exposure or other factors, such as stressor exposure, might contribute to or trigger problematic drug use.

Table of Contents

Table of Contents

Chapter 1: An introduction to the orbitofrontal prefrontal cortex (oPFC)…………………....1

1.1 Introduction………………………………………………………………………….............................................2

1.2 Functions of the oPFC……………………………………………………………….........................................2

1.2.1 Regulation of reversal learning…………………………………………….........................................2

1.2.2 Regulation of stimulus-outcome devaluation………………………………..................................3

1.2.3 Regulation of actions and habits…………………………………………..........................................4

1.3 The oPFC and addiction etiology……………………………………………………....................................6

1.4 Dissertation overview………………………………………………………………….......................................7

Chapter 2: Adolescent cocaine exposure simplifies orbitofrontal prefrontal cortical

dendritic arbors…………………………….................................................................................9

2.1 Context, Author's Contribution, and Acknowledgement of Reproduction…………................10

2.2 Abstract…..………………………………………………………………………….............................................10

2.3 Introduction…………………………………………………………………………............................................11

2.4 Methods……………………………………………………………………………...............................................12

2.4.1 Subjects……………………………………………………………………...................................................13

2.4.2 Adolescent cocaine exposure……………………………………………...........................................13

2.4.3 Instrumental reversal learning…………………………………………….........................................13

2.4.4 Locomotor monitoring……………………………………………………..............................................14

2.4.5 Dendritic arbor reconstruction and measurement……………………….................................15

2.4.6 Statistical analyses………………………………………………………...............................................16

2.5 Results………………………………………………………………………………..............................................16

2.6 Discussion…………………………………………………………………………..............................................19

2.6.1 Prefrontal cortical dendrites reorganize in response in cocaine…………..........................19

2.6.2 oPFC dendrite morphology in drug-naïve cocaine-vulnerable mice is intact..………………...22

2.7 Summary…………………………………………………………………………...24

Chapter 3: Induction and reversal of adolescent cocaine-induced habits...................29

3.1 Context, Author's Contribution, and Acknowledgement of Reproduction………...................30

3.2 Abstract…..………………………………………………………………………...............................................30

3.3 Introduction………………………………………………………………………..............................................31

3.4 Methods……………………………………………………………………………...............................................33

3.4.1 Subjects………………………………………………………………….....................................................33

3.4.2 Experimenter-administered cocaine, amphetamine…………...…………..............................33

3.4.3 Instrumental response training…………………………………………..........................................33

3.4.4 Action-outcome contingency degradation……………………………….....................................34

3.4.5 Fasudil, ifenprodil, CP-101,606……………………............................................................35

3.4.6 Intracranial infusion, histology…………………………………………...........................................35

3.4.7 Dendritic spine imaging, quantification………………………...............................................36

3.4.8 Cardiovascular function…………………………………………………..............................................37

3.4.9 Intravenous cocaine self-administration………………………..............................................37

3.4.10 Statistical analyses………………………………………….........................................................38

3.5 Results……………………………………………………………………………................................................39

3.5.1 Dendritic spines remodel following adolescent cocaine exposure……............................40

3.5.2 Recapitulation and reversal of cocaine-induced habits………..………….............................41

3.5.3 The effects of ifenprodil are Abl-family kinase-dependent…...…………............................42

3.5.4 Blockade of cocaine-induced habits with the NMDAR NR2B antagonist CP-101,606….....44

3.5.5 Ifenprodil reduces cue-induced reinstatement of cocaine seeking…….….......................44

3.6 Discussion…………………………………………………………………………..............................................45

3.6.1 Blockade of cocaine-induced habits………………………..……………......................................47

3.6.2 Ifenprodil reduces cue-induced reinstatement of cocaine seeking………........................48

3.6.3 Regulation of learning and memory systems in combatting cocaine-induced

behavioral vulnerabilities……………………………………………....……….............................................50

Chapter 4: Adolescent-onset Itgb1 knockdown regulates reward-related decision making………………………………………………………………………………………….........................................60

4.1 Context, Author's Contribution, and Acknowledgement of Reproduction…………................61

4.2 Abstract…..………………………………………………………………………….............................................61

4.3 Introduction……………………………………………………………………….............................................62

4.4 Methods……………………………………………………………………………..............................................63

4.4.1 Subjects…………………………………………………………………....................................................63

4.4.2 Intracranial infusion…………………………………………...…………............................................63

4.4.3 Instrumental response training………………………………………….........................................64

4.4.4 Action-outcome contingency degradation…………………………….......................................64

4.4.5 Stimulus-outcome conditioning……………………….........................................................65

4.4.6 Intravenous cocaine self-administration…………………………………....................................66

4.4.7 Sucrose consumption………………………………………………..................................................67

4.4.8 Histology……………...………………………………………….........................................................68

4.4.9 Immunoblotting……………………….………………………........................................................68

4.4.10 Statistical analyses…………………………………………........................................................69

4.5 Results……………………………………………………………………………….............................................69

4.5.1 Itgb1 knockdown impairs action-outcome conditioning and increases the salience of

conditioned stimuli……………………………………………….............................................................70

4.5.2 Implications for illicit drug use………………………………..…………........................................71

4.5.3 Resiliencies to the effects of oPFC-selective Itgb1 knockdown…………..........................74

4.6 Discussion………………………………………………………………………….............................................75

4.6.1 Impaired action-outcome decision making and increased salience of conditioned

stimuli……………………..…………………………..………….................................................................76

4.6.2 Females might be resilient to the loss of β1-integrin………………...….............................78

4.6.3 Early adolescence is a sensitive period………………….……....………..................................78

4.7 Conclusions……………………………………………………………………...............................................80

Chapter 5: A snapshot into the medial prefrontal cortex (mPFC): Adoles cent-onset

GABAAα1 silencing regulates reward-related decision making…………………………..........89

5.1 Context, Author's Contribution, and Acknowledgement of Reproduction…………...............90

5.2 Abstract….…………………………………………………………………………............................................90

5.3 Introduction…………………………………………………………………………..........................................91

5.4 Methods…………………………………………………………………………….............................................92

5.4.1 Subjects…………………………………………………………………...................................................92

5.4.2 Intracranial surgery.………………………………………...……………...........................................93

5.4.3 Instrumental response training………………………………...…………......................................93

5.4.4 Action-outcome contingency degradation………………………………....................................94

5.4.5 Intravenous cocaine self-administration……...…………………….......................................95

5.4.6 Histology……………...………………………………………….........................................................96

5.4.7 Immunoblotting……………………….………………………........................................................96

5.4.8 Statistical…………………………………………………….............................................................97

5.5 Results……………………………………………………………………………...............................................97

5.5.1 Adolescent-onset Gabra1 knockdown delays the acquisition of a cocaine-reinforced

response………….………………………………………….....................................................................97

5.5.2 Adolescent-onset Gabra1 knockdown impairs goal-directed action selection………………..98

5.5.3 The effects of mPFC Gabra1 knockdown in adolescence and adulthood are

dissociable...............................................................................................................100

5.6 Discussion…………………………………………………………………………...........................................101

5.6.1 mPFC GABAAα1 regulates cocaine self-administration and goal-directed action

selection…………………………...………………………..………….........................................................102

5.6.2 The effects of mPFC Gabra1 knockdown in adolescence and adulthood are

dissociable……………………………………………………………...……....................................................105

5.7 Conclusions……………………………………………………………………..............................................107

Chapter 6: Synaptic cytoskeletal plasticity in the prefrontal cortex following

psychostimulant exposure……………………………………………………………………...........................113

6.1 Context, Author's Contribution, and Acknowledgement of Reproduction………................114

6.2 Abstract………….……………………………………………………...…………..........................................114

6.3 Introduction……………………………………………………………...…………........................................115

6.4 Psychostimulants remodel dendrites and dendritic spines, with opposite effects in the

mPFC and oPFC………………………………………………………………………...........................................117

6.4.1 Drugs of abuse remodel mPFC neurons, causing dendritic spine proliferation…………...118

6.4.2 Psychostimulant exposure leads to impoverished neurons in the oPFC.....................121

6.5 Cytoskeletal regulatory factors in the cerebral cortex regulate behavioral sensitivity to

cocaine………………………………………………………………………………….............................................125

6.5.1 Rho regulatory factors………………………………………………..............................................125

6.5.2 Adolescent critical periods and metaplasticity in neural structure……........................128

6.6 Psychostimulant exposure impacts complex behavior…...……………………….....................132

6.6.1 Cocaine-related impulsivity and behavioral inflexibility can be modeled in rodents…..132

6.6.2 Goal-directed decision making and reward-seeking habits…...……….........................135

6.7 Conclusions…………………………………………………………………….............................................139

Chapter 7: Summary and Future Directions………………………………………………...................145

7.1 Context, Author's Contribution, and Acknowledgement of Reproduction………...............146

7.2 Introduction……………………………………………………………...……….........................................146

7.3 Summary of results and future directions…………………………………………...........................146

7.3.1 Chapters 2 and 3……………………………………………….....................................................146

7.3.2 Chapter 4…………………………………………...………….......................................................148

7.3.3 Chapter 5………………………………………………...............................................................149

7.4 Conclusion………………………………………………………………………............................................149

Appendix: Complete list of publications to which the author has contributed during

her graduate training………………..…………………………………………………………….........................151


References
………………………………………………………………………………….…...................................152

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