Long-Term Neurobehavioral Consequences of Adolescent Social Isolation Restricted; Files Only
Hinton, Elizabeth (Fall 2019)
Published
Abstract
Adolescence is a developmental period during which significant prefrontal cortical (PFC) maturation occurs in tandem with emerging, age-typical changes in social behavior. Unperturbed, these maturational shifts collectively aid juveniles in the transition to adulthood. Clinical research suggests that perturbations during adolescence, such as experiencing social adversity, constitute a risk factor for certain neuropsychiatric-related outcomes in adulthood. The findings presented in this dissertation are situated upon decades of preclinical social isolation research in rodents, which have attempted to investigate these lingering neurobehavioral consequences of prior social insults. However, this research largely excludes females and assesses outcomes while animals remain in a state of isolation, precluding an understanding of lasting consequences that are present despite correcting the social environment. We hypothesize that isolation during adolescence disrupts ongoing PFC maturation, such as dendritic spine pruning processes. Further, dysregulated PFC-dependent behaviors (e.g. a premature reliance on habitual responding at the expense of goal-directed decision making) may emerge. We show that previously-isolated mice more readily engage in habitual response strategies and exhibit adolescent-like densities of dendritic spines in the orbital PFC as adults. We then show that correcting dendritic architecture by inhibiting the cytoskeletal regulatory factor Rho-kinase during the adolescent isolation period blocks decision-making deficits in mice with a history of isolation. Ahistory of isolation also shapes adult social interaction subtleties and medial PFC (mPFC) outcomes. We investigated dendritic spine densities and postsynaptic regulators of synaptic function, revealing elevated densities of thin-type dendritic spines and increased postsynaptic density-95 protein content. Finally, we use a chemogenetic approach to modulate the mPFC during a time in which animals should be consolidating information necessary to modify behavioral responses that no longer produce valued outcomes. This chemogenetic strategy blocks decision-making deficits and corrects anhedonic-like behavior in previously-isolated mice. Together, these findings implicate disrupted orbital PFC and mPFC function in the enduring neuropsychiatric-related behavioral deficits present following a history of isolation. Disruption of ongoing maturational processes during adolescence and associated impairments in related behaviors may constitute a mechanism by which social adversity experienced during adolescence becomes a risk factor for the occurrence of certain neuropsychiatric-related disorders in adulthood.
Table of Contents
CHAPTER 1 1
REVIEW OF THE LONG-TERM CONSEQUENCES OF SOCIAL ISOLATION DURING ADOLESCENCE
1.1 Context, Author’s Contribution, and Acknowledgement of Reproduction___ 2
1.2 Abstract_________________________________________________________ 2
1.3 Introduction______________________________________________________ 2
1.4 Prefrontal Cortical Development During Adolescence___________________ 5
1.5 Long-Term mPFC Outcomes Following Social Isolation During Adolescence_________________ 6
1.5.1 Synaptic and cellular changes following isolation during adolescence
1.5.2 Electrophysiological evidence for long-lasting changes in excitation/inhibition balance
1.6 Long-Term Behavioral Consequences_______________________________ 11
1.6.1 Depressive-related behavior following adolescent social isolation
1.6.1.1 Passive reactivity to acute stressors
1.6.1.2 Anhedonic-like behavior
1.6.2 Long-term consequences of adolescent social isolation on decision-making behavior
1.6.3 Anxiety-like effects of social isolation during adolescence
1.6.3.1Open field test
1.6.3.2 Elevated plus maze
1.6.4 Social behavioral consequences of adolescent isolation and resocialization
1.6.4.1 Resident-intruder test
1.6.4.2 Home cage social interaction observations
1.6.4.3 Free roaming social interaction test
1.7 Overview and Research Strategy of the Dissertation____________________ 25
CHAPTER 2 38
CORRECTING THE DURABLE CONSEQUENCES OF ADOLESCENT SOCIAL ISOLATION
2.1 Context, Author’s Contribution, and Acknowledgement of Reproduction______________ 39
2.2 Abstract_________________________________________________________ 39
2.3 Introduction_____________________________________________________ 40
2.4 Materials and Methods____________________________________________ 42
2.4.2 Social isolation
2.4.3 Social interaction test
2.4.4 Social approach test
2.4.5 Open field test
2.4.6 Dendritic spine imaging and quantification
2.4.7 Immunoblotting for PSD95
2.4.8 Immunostaining for PSD95
2.4.9 Immunostaining for gephyrin
2.4.10 Surgery
2.4.11 Instrumental Conditioning
2.4.11.1 Instrumental response training
2.4.11.2 Instrumental contingency degradation
2.4.12 Sucrose consumption test
2.4.13 Clozapine-N-Oxide (dosing and timing relevant to behavioral testing)
2.4.14 Statistics
2.5 Results__________________________________________________________ 51
2.5.1 Social behavior in adulthood is influenced by social experience in adolescence
2.5.2 Elevations in specific dendritic spine sub-types and synaptic marker levels in the mPFC of socially-isolated mice
2.5.3 Gi-DREADDs stimulation in the mPFC corrects decision-making biases and anhedonic-like behavior in previously-isolated mice
2.6 Discussion______________________________________________________ 56
2.6.1 Isolation during adolescence shapes social behavioral subtleties in adulthood
2.6.2 mPFC dendritic spine density subtype changes following adolescent isolation
2.6.3 Improvement of action-outcome decision making following isolation during adolescence
2.6.4 Correcting isolation-induced anhedonic-like behavior
2.6.5 Conclusions
2.7 Acknowledgments________________________________________________ 64
2.8 Funding_________________________________________________________ 65
CHAPTER 3 72
SOCIAL ISOLATION DURING ADOLESCENCE DISRUPTS CORTICAL DEVELOPMENT AND GOAL-DEPENDENT DECISION MAKING IN ADULTHOOD, DESPITE SOCIAL REINTEGRATION
3.1 Context, Author’s Contribution, and Acknowledgement of Reproduction__ 73
3.2 Abstract_________________________________________________________ 73
3.3 Introduction_____________________________________________________ 74
3.4 Materials and Methods____________________________________________ 76
3.4.2 Social isolation
3.4.3 Corticosterone (CORT) ELISA
3.4.4 Adrenal and thymus gland extraction
3.4.5 Immunostaining for CNPase
3.4.6 Immunostaining for PSD95
3.4.7 Immunoblotting
3.4.8 Dendritic spine imaging and quantification
3.4.9 Surgery
3.4.10 Pharmacological treatments
3.4.11 Behavioral assays
3.4.11.1 Instrumental response training
3.4.11.2 Instrumental contingency degradation
3.4.11.3 Extinction
3.4.11.4 Conditioned taste aversion and reinforcer devaluation
3.4.11.5 Sucrose consumption test
3.4.11.6 Cocaine-induced locomotor activity
3.4.11.7 Elevated plus maze
3.4.11.8 Open field test
3.4.12 Statistics
3.5 Results____________________________________________ 87
3.5.1 Social experience in adolescence optimizes action-outcome response updating in adulthood
3.5.2 Social experience during adolescence is necessary for age-typical glucocorticoid tone and dendritic spine densities
3.5.3 Stimulating the ventrolateral OFC in healthy mice disrupts decision-making strategies
3.5.4 Inhibiting ROCK improves action-outcome response updating and normalizes dendrite architecture
3.5.5 Differential behavioral effects in male C57BL/6 mice
3.6 Discussion______________________________________________________ 97
3.6.1 Social interactions in adolescence optimize goal-directed behavior in adulthood
3.6.2 Neurobiological factors
3.6.3 Concluding remarks
3.7 Acknowledgements______________________________________________ 103
CHAPTER 4 117
CONCLUSIONS AND FUTURE DIRECTIONS
4.1 Abstract________________________________________________________ 118
4.2 Considerations for Future Isolation-Resocialization Protocols___________ 118
4.2.1 Adolescent social isolation timelines
4.2.2 Resocialization may influence outcomes in a sex-dependent manner
4.2.3 Post-isolation social environment
4.3 Concluding Remarks_____________________________________________ 121
REFERENCES 123
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