Zusammenfassung
Summary
Acknowledgements
Content
List of figures
List of tables
List of equations
List of abbreviations
Publications
1 INTRODUCTION
1.1 Nature and nurture: genetic and environmental influences on behavior
1.1.1 Early scientific views: Nature vs. Nurture
1.1.2 Introduction of the gene + environment (G+E) model
1.1.3 Gene-Environment interactions (GxE)
1.1.4 Gene-Environment correlations (rGE)
1.1.5 Toward a dynamic understanding of behavior
1.2 Individual differences persist even when genotype and environment are held constant
1.2.1 The concept of shared and non-shared environments
1.2.2 Non-shared environment – differential experience – a gloomy prospect
1.2.3 Stochasticity and noisy developmental processes
1.2.4 Epigenetic variation
1.3 Environmental enrichment as a key paradigm for unraveling gene × environment interactions
1.3.1 Using ENR to look into the non-shared component – a solution to the gloomy prospect
1.4 Adult hippocampal neurogenesis: A phenotype of brain plasticity that is sensitive to experiences
1.5 Gap in understanding underlying mechanisms of enrichment and individuality
1.5.1 The role of non-shared environmental factors
1.5.2 Early theories: Handling, speedy maturation, stress and hormonal modulation
1.5.3 Social interaction and the role of ‘play’
1.5.4 The learning-memory hypothesis
1.5.5 Active interaction over passive exposure
1.5.6 Learning as the central mechanism
1.6 Aim and scope of thesis
1.6.1 Specific question 1
1.6.2 Specific question 2
1.6.3 Specific question 3
2 MATERIALS AND METHODS
2.1 Animal husbandry
2.2 IntelliCage (IC)
2.3 Large-scale CMOS-based biosensor and recording acquisition setup
2.3.1 Acute brain slice preparation and recovery
2.3.2 Electrical stimulation-evoked response recordings
2.3.3 Pharmacologically-induced response recordings
2.4 Tissue preparation and immunohistochemistry
2.5 Electrophysiology data analysis
2.5.1 Hippocampal-cortical structural clusters
2.5.2 Mean activity
2.5.3 Functional connectivity and causality
2.5.4 Network connectivity metrics
2.5.5 Graph map visualization
2.6 IC behavioral analysis
2.6.1 Roaming entropy (RE)
2.6.2 Learning and flexibility
2.6.3 Social interactions
2.6.4 Linear mixed effect models
2.6.5 Consistency and repeatability
2.7 Simulation and comparison of Reinforcement and Null Models
2.8 Morris water maze (MWM)
2.9 Statistical analysis
3 RESULTS
3.1 Learning as a catalyst for individuality: differential experiences shape brain connectomics and behavioral divergence in isogenic mice
3.1.1 IntelliCage acts as an enriched environment
3.1.2 Emergence of individuality in behavior
3.1.3 Stability in the face of change
3.1.4 Individuality in behavior correlates with individuality in brain plasticity
3.1.5 Conclusion
3.2 Beyond nature, nurture, and chance: Individual choices shape divergent learning biographies and brain plasticity
3.2.1 A video game-inspired self-paced learning framework in the IC
3.2.2 Mice develop divergent exploratory patterns in the adaptation phase prior to self-paced learning phase
3.2.3 Mice independently unlock successive task levels demonstrating variability in their learning speed and task progression
3.2.4 Task engagement correlates positively with task progression and learning rank
3.2.5 IC mice show stable inter-individual differences in adult hippocampal neurogenesis
3.2.6 IC mice show enhanced spatial learning and strategy use in the MWM task
3.2.7 Top-ranking IC mice perform better than the rest in MWM task
3.2.8 Conclusion
3.3 Social inequality in learning opportunities constrains behavioral diversity, impairs neurogenesis and shapes social hierarchies
3.3.1 Manipulation of Learning Opportunities and Social Experiences
3.3.2 Comparable patterns of exploratory individuality in learning and deprived groups during adaptation
3.3.3 Emergence of individuality is fortified by access to learning and stunted by deprivation
3.3.4 Inter-individual differences in adult hippocampal neurogenesis
3.3.5 IC mice show enhanced spatial learning and cognitive flexibility in the MWM task
3.3.6 Learning group showed slightly better performance in MWM task
3.3.7 Learning-deprived mice exhibit a competitively subordinate phenotype during the social dominance task
3.3.8 Conclusion
3.4 Impact of social interactions on learning and neurogenesis
3.4.1 Following events occur more often than by chance and reflect viable social behavior
3.4.2 Individuality in social behavior
3.4.3 A graph theory-based approach to represent social relationships
3.4.4 Conclusions
3.5 Beyond stochasticity: Reinforcement shapes behavioral divergence
3.5.1 Reinforcement model shows increase in mean performance and variance in the learning phase
3.5.2 Reinforcement model shows reduction in mean RE and increased variance in the exploratory phase
3.5.3 Conclusion
4 DISCUSSION
4.1 Mechanistic question – how do inter-individual differences emerge?
4.1.1 Non-shared environment – Dissection through IC no longer a gloomy prospect
4.1.2 Evidence for the ‘learning-memory’ hypothesis
4.1.3 Feedback loop between brain and behavior
4.2 Evolutionary question – why do inter-individual differences exist?
4.2.1 Consistent personality traits: Costs to flexibility
4.2.2 State–behavior feedbacks
4.2.3 Frequency-dependent selection
4.2.4 Brain and behavioral plasticity
4.3 Individuality
5 APPENDIX
5.1 Statistical estimates from experiment 1
5.2 Statistical estimates from experiment 2
5.3 Statistical estimates from experiment 3
5.4 Body weight
5.5 Correlation between exploration in adaptation phase and learning success in learning phase
5.6 Additional water maze parameters from experiment 2
5.7 Additional water maze parameters from experiment 3
5.8 Comparison of null and reinforcement models
5.9 Statistical equation modelling (SEM)
6 BIBLIOGRAPHY
7 DECLARATIONS