Identifying Orbitofrontal Cortical Neuron Populations Involved in Goal Seeking and Compulsive like Behaviors Restricted; Files Only
Yount, Sophie (Fall 2024)
Abstract
The orbitofrontal cortex (OFC) is thought to catalog information necessary to develop strategies to obtain desired outcomes. As such, OFC activity is essential for flexible decision making, i.e., making a choice based on changes in outcome expectation. This behavioral flexibility is antithetical to habitual behavior, which is instead reflexively triggered by cues and not outcome predictability. Habitual behavior is adaptive under many circumstances, but it can also be antecedent to compulsions – intrusive thoughts that drive persistent and potentially maladaptive behavior. Activation of neurons within the OFC can cause habitual and compulsive-like behavior in otherwise healthy rodents and is associated with obsessive-compulsive behavior in humans. How can the OFC support such antithetical behaviors? This dissertation begins by describing molecular mediators within the OFC that influence reward-related behaviors. I then identify a molecularly defined OFC neuron population that controls compulsive- but not habit-like behavior. Using mice bred to display habit-based action strategies and compulsive-like grooming behavior as a tool, I discovered that they also suffered dendritic spine attrition on excitatory neurons in the OFC. Nevertheless, synaptic melanocortin 4 receptor (MC4R) content was preserved, leading to the hypothesis that MC4R-mediated signaling or Mc4r+ neurons may drive habit-like and/or compulsive-like behavior in these mice. Intriguingly, repeated chemogenetic stimulation of Mc4r+ OFC neurons triggered compulsive- and not habit-like behavior. Thus, I identify an OFC neuron population that has dissociable control of compulsive-like and habit-based behaviors. Next, I investigate a neuron population within the OFC that instead contributes to behavioral flexibility. I find that memory traces (MTs) of flexible action strategies are stored within OFC neuron ensembles. MT ensemble activity is both necessary and sufficient for behavioral flexibility. Moreover, MT neurons are distinguished by increased proportions of mature dendritic spines relative to neighboring non-MT neurons, and these patterns are associated with new learning. Activity of basolateral amygdala (BLA) neurons upon learning new information about response-outcome relationships is necessary for optimal memory encoding within the OFC and later expression of updated action strategies. I further find that BLA–MT neuron coordination supporting flexible behavior is tropomyosin receptor B (TrkB) dependent. Overall, this dissertation elucidates mechanisms driving compulsive-like and decision-making behavior, offering potential treatment targets for alleviating aberrant decision making and harmful compulsions.
Table of Contents
CHAPTER 1: CONTRIBUTIONS OF THE ORBITOFRONTAL CORTEX TO ACTION STRATEGIES AND MOLECULAR INFLUENCERS 1
1.1 CONTEXT, AUTHOR’S CONTRIBUTION 2
1.2 ABSTRACT 2
1.3 INTRODUCTION 2
1.3.1 Defining action strategy 3
1.3.2 Role of the frontal cortex (FC) in memory 4
1.3.3 Role of the Orbitofrontal cortex (OFC) in action strategy 5
1.4 HOW RODENTS CAN BE USED TO STUDY ACTION STRATEGY 5
1.4.1 Common assays for understanding OFC function 6
1.5 MOLECULAR MECHANISMS CONTROLLING OFC FUCTION 11
1.5.1 Endocannabinoid signaling 11
1.5.2 Neurotrophin signaling 14
1.5.3 Control of decision-making behavior by BDNF in the OFC 17
1.5.4 Cell adhesion molecules 18
1.5.5 Conclusions 21
1.6 FRAMEWORK AND OVERVIEW OF THE DISSERTATION 21
CHAPTER 2: A MOLECULARLY DEFINED ORBITOFRONTAL CORTICAL NEURON POPULATION CONTROLS COMPULSIVE- BUT NOT HABIT-LIKE BEHAVIOR 29
2.1 CONTEXT, AUTHOR’S CONTRIBUTION, AND ACKNOWLEDGEMENT OF
REPRODUCTION 30
2.2 ABSTRACT 30
2.3 INTRODUCTION 31
2.4 RESULTS 33
2.4.1 Breeding mice for inflexibility results in habitual and compulsive-like behavior 33
2.4.2 Experimental breeding alters OFC neurobiology 37
2.4.3 Preservation of MC4R systems in mice displaying compulsive-like behavior 38
2.4.4 Control of compulsive-like behavior by molecularly defined OFC neurons 39
2.5 DISCUSSION 42
2.5.1 Mice experimentally bred for action inflexibility exhibit compulsive-like behavior 42
2.5.2 OFC neurobiology associates with compulsive-like behavior 43
2.5.3 Conclusions 47
2.6 MATERIALS AND METHODS 48
2.6.1 Subjects 48
2.6.2 Intracranial surgery and viral vectors 48
2.6.3 Instrumental response training 49
2.6.4 Test of action strategies 50
2.6.5 Breeding strategy of experimentally bred mice 50
2.6.6 Validation of the experimentally bred phenotype 51
2.6.7 Random interval training and reinforcer devaluation 51
2.6.8 Instrumental omission 52
2.6.9 Extinction 53
2.6.10 Food intake 53
2.6.11 Behavioral testing battery 53
2.6.12 Stimulated grooming assay 54
2.6.13 Drug administration 55
2.6.14 Dendritic spine imaging and reconstruction 56
2.6.15 In situ RNA analysis 56
2.6.16 Viral vector validation, c-Fos immunostaining, and quantification 57
2.6.17 Synaptoneurosome preparation and immunoblotting 58
2.6.17 Statistical analysis 60
2.7 FUNDING 61
2.8 ACKNOWLEDGEMENTS 61
CHAPTER 3: PARALLEL NEURONAL STRUCTURAL PLASTICITY WITH MEMORY TRACE FORMATION IN THE ORBITOFRONTAL CORTEX 74
3.1 CONTEXT, AUTHOR’S CONTRIBUTION 75
3.2 ABSTRACT 75
3.3 INTRODUCTION 76
3.4 RESULTS 77
3.4.1 Bidirectional control of action strategies 80
3.4.2 New learning triggers dendritic spine plasticity on MT neurons 81
3.4.3 Amygdalo-cortical interactions coordinate action strategy 83
3.4.4 Neurotrophin-related signaling within amygdalo-cortical circuits supports new learning 85
3.5 DISCUSSION 86
3.5.1 Long term memory storage within the OFC 86
3.5.2 Amygdala-orbital interactions in action flexibility 89
3.5.3 Conclusions 91
3.6 MATERIALS AND METHODS 91
3.6.1 Subjects 91
3.6.2 Instrumental response training 92
3.6.3 Test of response flexibility 93
3.6.4 Drug administration 94
3.6.5 Surgery 95
3.6.6 Chemogenetic manipulation of MT neuron populations 95
3.6.7 vTRAP affinity purification 96
3.6.8 Quantitiative PCR 97
3.6.9 Strategy to visualize dendritic spines on MT neurons 98
3.6.10 Dendritic spine imaging, reconstruction, and quantification 98
3.6.11 Identifying active neurons projecting to the OFC during memory encoding 99
3.6.12 Asymmetric viral vector infusions 100
3.6.13 Histology 101
3.6.14 Experimental design and tissue collection for validation of chemogenetic constructs 102
3.6.15 Determining the reactivation properties of neuron ensembles 103
3.6.16 cfos immunostaining 103
3.6.17 Analysis of expected versus actual overlap between active neuron populations 103
3.6.18 Statistical analysis 104
3.7 FUNDING 105
3.8 ACKNOWLEDGEMENTS 105
CHAPTER 4: CONCLUSIONS AND FUTURE DIRECTIONS 127
4.1 ABSTRACT 128
4.2 MECHANISMS GOVERNING ORBITOFRONTAL CORTEX FUNCTION 128
4.3 Mc4r+ NEURONS IN THE OFC: UNRAVELING A MOLECULAR BASIS OF COMPULSIVE BEHAVIOR 128
4.3.1 Identifying molecularly defined neuron populations that control compulsive-like behavior in the OFC 129
4.4 ACTION STRATEGY MEMORY WITHIN THE OFC 132
4.4.1 Dendritic spine morphology of neurons comprising action strategy engrams within the OFC 133
4.5 CONCLUSIONS 139
REFERENCES 145
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