How social information impacts decision making: Functions and development of the prefrontal cortex Restricted; Files Only

Abstract

      Social information carries tremendous weight in our choices, but the mechanisms by which social experiences influence our decision making remain unclear. In humans, the complex information processing demands of decision making in social contexts, or “social decision making,” are often dissected into component parts in the laboratory setting, which can be more easily examined and tested. To investigate underlying neural circuits and molecular mechanisms of social decision making, researchers have turned to reliable animal models. Most studies in this vein utilize non-human primates to investigate social decision making, due to their translational potential and robust set of complex social behaviors. However, rodents offer a much more readily accessible genetic toolbox, with recently developed tasks revealing the capacity to reliably test social decision making in mice and rats. This dissertation begins by describing how social decision making is dissected in humans in the laboratory setting, and how components of this process are mirrored in rodent models. We discuss the critical involvement of amygdalo-cortical connections in social decision making in both humans and rodents. Next, we identify a cellular adhesion factor, β1-integrin, that confers stability to amygdalo-cortical connections. β1-integrins are further necessary in the prelimbic subregion of the medial prefrontal cortex (PL) for the ability of mice to link actions with their consequences. Expression of β1-integrins is specifically necessary during adolescence, a time when one’s social world is increasing in magnitude and complexity. Next we develop a new task to investigate social decision making in rodents, social influence of future choice (SIFC). In SIFC, social experiences confer value to an external food reward, biasing mouse responding for one food pellet (the one paired with a social experience) over another. SIFC persists even following aversive social experiences, and relies on amygdalo-cortical projections, as well as projections from the PL to the nucleus accumbens. Neuronal ensembles active during a social experience are later required for SIFC to occur. These “social-sensitive” ensembles are similarly necessary for decision making in non-social contexts, supporting the notion that shared cortical ensembles in the PL can exert control over decision making with or without social content. Lastly, we show that cortico-amygdalar projections are required for SIFC, and that the formation of social associations in SIFC recruits neural activity in the basolateral amygdala (BLA). Further, SIFC modulates the structure of so-called “fear-inhibiting” neurons in the BLA. Together, these findings establish a new task, SIFC, that relies on interconnected communication between amygdalo-cortico-striatal structures. SIFC will serve as a valuable complementary tool to the emerging array of tasks assaying complex social decision-making processes in rodents. Given that deficits in social interactions and social decision making emerge in almost every neuropsychiatric disorder, new ways to examine and understand underlying circuits and molecular mechanisms is of utmost translational importance.

Table of Contents

CHAPTER 1: HOW SOCIAL INFORMATION IMPACTS ACTION SELECTION IN RODENTS AND HUMANS: ROLE OF THE PREFRONTAL CORTEX

1.1      CONTEXT, AUTHOR’S CONTRIBUTION, AND ACKNOWLEDGEMENT OF REPRODUCTION

1.2      ABSTRACT

1.3      INTRODUCTION

1.4      SOCIAL DECISION MAKING IN HUMANS

1.4.1    Decision making in social contexts: deconstructing a complex process

1.4.2    Social decision making as an endophenotype for neuropsychiatric disease

1.4.3    Anatomical and functional subdivision of the mPFC in humans

1.4.4    Social and emotional recognition

1.4.5    Empathic processes

1.4.6    Social incentive and action selection

1.5      CAN RODENTS REALLY BE USED TO STUDY SOCIAL DECISION MAKING?

1.5.1    Anatomical and functional subdivision of the mPFC in rodents

1.5.2    Social and emotional recognition in rodents

1.5.3    Empathic-like processes in rodents

1.5.4    Incentive value of social interaction and action selection in rodents

1.6      THE CASE FOR ADOLESCENCE: DEVELOPMENT OF AMYGDALO-CORTICAL PROJECTIONS

1.7      OVERVIEW OF THE DISSERTATION

CHAPTER 2: CELL ADHESION FACTORS DURING ADOLESCENCE SUPPORT AMYGDALO-CORTICAL CONNECTIONS AND GOAL-DIRECTED ACTION LATER IN LIFE

2.1      CONTEXT, AUTHOR’S CONTRIBUTION, AND ACKNOWLEDGEMENT OF REPRODUCTION

2.2      ABSTRACT

2.3      SIGNIFICANCE STATEMENT

2.4      INTRODUCTION

2.5      RESULTS

2.5.1    Cell adhesion during adolescence optimizes goal-directed action in adulthood

2.5.2    BLAPL projections are necessary for the expression of learned goal-directed action

2.5.3    Morphological features of PL neurons positioned in a BLAPLDMS circuit

2.5.4    Cell adhesion control of dendritic micro-architecture occurs in a developmentally-specific manner

2.6      DISCUSSION

2.6.1    Cell adhesion activity during adolescence is required for goal-directed action later in life

2.6.2    Goal-oriented action requires BLAPL connections

2.6.3    Morphological features of PL neurons positioned in a BLAPLDMS circuit

2.6.4    β1-integrins stabilize dendritic micro-architecture in a developmentally-specific manner

2.6.5    Conclusions

2.7      MATERIALS AND METHODS

2.7.1    Subjects

2.7.2    Stereotaxic surgery and viral vectors

2.7.3    Immunoblotting

2.7.4    Instrumental response training

2.7.5    Instrumental contingency degradation

2.7.6    Outcome devaluation

2.7.7    Clozapine-N-Oxide (CNO) administration

2.7.8    Histology

2.7.9    Electrophysiology

2.7.10      Dendritic spine imaging

2.7.11      Statistics

2.8      ACKNOWLEDGEMENTS

2.9      SUPPLEMENTAL METHODS

2.9.1    Progressive ratio task

2.9.2    Locomotor monitoring

2.9.3    Novelty suppressed feeding

2.9.4    Marble burying

2.9.5    Open field activity

2.9.6    Sucrose consumption test

2.9.7    Forced swim test

2.9.8    Prepulse inhibition (PPI)

2.9.9    Three-chamber social interaction test

2.9.10      Statistics

CHAPTER 3: SHARED PREFRONTAL CORTICAL ENSEMBLES USE SOCIAL AND NON-SOCIAL INFORMATION TO GUIDE FUTURE CHOICE IN THE RODENT

3.1      CONTEXT AND AUTHOR’S CONTRIBUTION

3.2      ABSTRACT

3.3      INTRODUCTION

3.4      RESULTS

3.4.1    Social information is used to guide future operant choice

3.4.2    SIFC is pervasive and does not rely solely on olfactory or somatosensory cues

3.4.3    BLAPL and PLNAc projections are necessary for SIFC

3.4.5    PL neurons stimulated by social interaction control decision-making behavior

3.4.6    Recruitment of neurons in the posterior, but not anterior, PL predicts the capacity of social experience to drive future choice

3.5      DISCUSSION

3.5.1    Social information guides future choice

3.5.2    SIFC requires BLAPL and PLNAc connections

3.5.3    Shared cortical ensembles guide social and non-social decision making

3.5.4    The posterior compartment of the PL may be recruited for social decisions

3.5.5    Conclusions

3.6      MATERIALS AND METHODS

3.6.1    Subjects

3.6.2    Stereotaxic surgery and viral vectors

3.6.3    Instrumental response training

3.6.4    Social influence of future choice (SIFC)

3.6.5    Variants of SIFC and relevant sensory controls

3.6.6    Behavioral ethograms

3.6.7    Three-chamber social interaction and social memory test

3.6.8    Instrumental contingency degradation

3.6.9    Activity-dependent genetic labeling for future manipulation

3.6.10      Histology

3.6.11      Histological quantification of c-Fos

3.6.12      Clozapine-N-Oxide (CNO) administration

3.6.13      Statistics

3.7      FUNDING

3.8      ACKNOWLEDGEMENTS

CHAPTER 4: SOCIAL INFLUENCE OF FUTURE CHOICE REQUIRES CORTICO-AMYGDALAR CONNECTIONS AND MODULATES AMYGDALAR NEURON STRUCTURE

4.1      CONTEXT AND AUTHOR’S CONTRIBUTION

4.2      ABSTRACT

4.3      INTRODUCTION

4.4      RESULTS

4.4.1    PLBLA projections are required for SIFC, but not sociality or social memory

4.4.2    SIFC increases immediate-early gene content in the BLA

4.4.3    SIFC alters BLA neuron micro-architecture

4.5      DISCUSSION

4.5.1    PLBLA projections are necessary for SIFC

4.5.2    The formation of social associations stimulates immediate-early gene expression in the BLA and modulates the structure of “fear-OFF” BLA neurons

4.5.3    Conclusions

4.6      MATERIALS AND METHODS

4.6.1    Subjects

4.6.2    Stereotaxic surgery and viral vectors

4.6.3    Instrumental response training

4.6.4    Social influence of future choice (SIFC)

4.6.5    Three-chamber social interaction and social memory test

4.6.6    Euthanasia and histology

4.6.7    C-Fos Immunohistochemistry and quantification

4.6.8    Dendritic spine imaging

4.6.9    Clozapine-N-Oxide (CNO) administration

4.6.10      Statistics

4.7      FUNDING

CHAPTER FIVE: CONCLUSIONS AND FUTURE DIRECTIONS

5.1      ABSTRACT

5.2      CHAPTER 1

5.3      CHAPTER 2

5.4      CHAPTER 3

5.5      CHAPTER 4

5.6      CONCLUSIONS

APPENDIX A: PUBLICATIONS TO WHICH THE AUTHOR HAS CONTRIBUTED

REFERENCES

 

 

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
Keyword	behavior cell adhesion factors social neuroscience developmental neuroscience decision making
Committee Chair / Thesis Advisor	Shannon Gourley, PhD, Emory University
Committee Members	Robert Liu, PhD, Emory University David Goldsmith, MD, Emory University Victor Faundez, MD, PhD, Emory University Larry Young, PhD, Emory University

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