Long-term Neurobehavioral Consequences of Adolescent Stress Hormone Exposure Restricted; Files Only
Barfield, Elizabeth (Fall 2018)
Published
Abstract
Chronic stress during adolescence is associated with negative psychiatric outcomes in adulthood, including increased risk for, and greater severity of, depression and drug use disorders. The neurobehavioral processes that translate developmental stressor exposure into psychiatric vulnerabilities later in life are incompletely understood, but may involve the prefrontal cortex (PFC) and hippocampus, which mature during adolescence. Dysfunction of these cortico-limbic regions can impair the ability to flexibly adjust behavior when environmental contingencies change, resulting in maladaptive habits symptomatic of several psychiatric diseases. In excess, and with prolonged exposure, glucocorticoids released during stress can perturb neuronal morphology and disrupt tyrosine receptor kinase B (trkB) signaling in the PFC and hippocampus. We hypothesize that prolonged exposure to high levels of glucocorticoids (as occurs with chronic stress) during adolescence may produce enduring changes in trkB signaling and cortico-limbic neuronal morphology that underlie persistent impairments in behavioral flexibility. This dissertation first reports that exposure to elevated levels of the glucocorticoid, corticosterone (CORT), during adolescence in mice biases behavior towards inflexible habits in adulthood. These habit biases are associated with disrupted trkB signaling in the ventral hippocampus (vHC), and can be blocked by administration of a putative trkB agonist, as well as recapitulated by viral-mediated disruption of trkB in the vHC of naïve mice. Next, we show that CORT and trkB manipulations during adolescence have sex-dependent long-term effects on behavioral flexibility in an instrumental reversal task that depends on the orbital PFC (oPFC). Lastly, we demonstrate that adolescent CORT-induced impairments in the ability to use outcome-predictive associations to guide behavior extends to aversive circumstances, and are associated with enduring loss of dendritic spines – the primary sites of excitatory synapses – in the oPFC. Adolescent CORT exposure also degrades anatomical connectivity between the vHC and oPFC, necessary for the retention of associative memories that guide flexible, adaptive behavior. Together, these findings implicate a neurotrophin-regulated vHC-oPFC pathway in the enduring behavioral flexibility deficits following prolonged elevation of stress hormones during adolescence. Cortico-limbic dysfunction and associated impairments in outcome-based learning and memory may constitute a pathophysiological mechanism by which stressors during adolescence increase vulnerability to an array of psychiatric diseases.
Table of Contents
CHAPTER 1 1
PREFRONTAL TRKB AND GLUCOCORTICOID SYSTEMS IN STRESS AND DEVELOPMENTAL CONTEXTS
1.1 Context, Author’s Contribution, and Acknowledgement of Reproduction...........2
1.2 Abstract ....................................................................................................... 2
1.3 Introduction ....................................................................................................... 3
1.4 Structural Maturation of the PFC.......................................................................... 4
1.5 Stressor Exposure Impacts Neuronal Morphology in the PFC.............................. 6
1.6 BDNF-trkB Regulation of Dendritic Spines......................................................... 10
1.6.1 Structural studies using mutant Bdnf/Trkb mice
1.7 Glucocorticoid Regulation of Dendritic Spines................................................... 16
1.8 Developmental Trajectories of trkB and GR........................................................ 20
1.8.1 TrkB in the PFC across postnatal development
1.8.1.1 Sex differences
1.8.2 GR in the PFC and HPA axis activity across postnatal development
1.9 Altered PFC trkB and GR in Depression.............................................................. 28
1.10 Stress-Induced Alterations in PFC trkB and GR ................................................. 30
1.10.1 Effects of acute/chronic stressors or glucocorticoid exposure on trkB
1.10.1.1 Association with depressive-like phenotypes
1.10.1.2 Persistence of stress-induced changes on prefrontal cortical BDNF-trkB
1.10.2 Effects of chronic stressor exposure on GR
1.10.3 Restoration of both BDNF-trkB and HPA axis systems by antidepressants
1.11 BDNF-trkB and GR Systems in Stress-Related Metaplasticity............................. 46
1.11.1 HPA axis reactivity to adolescent experience
1.11.2 GR and BDNF-trkB interactions in stress contexts
1.11.2.1 Mutant models of GR disruption
1.11.2.2 Mutant models of BDNF disruption
1.11.2.3 Importance of individual differences
1.12 Conclusions ...................................................................................................... 54
1.13 A Brief Overview and Research Strategy of the Dissertation............................. 56
CHAPTER 2 66
REGULATION OF ACTIONS AND HABITS BY VENTRAL HIPPOCAMPAL TRKB AND ADOLESCENT CORTICOSTEROID EXPOSURE
2.1 Context, Author’s Contribution, and Acknowledgement of Reproduction......... 67
2.2 Abstract ...................................................................................................... 67
2.3 Introduction ..................................................................................................... 68
2.4 Materials and Methods........................................................................................ 70
2.4.1 Subjects
2.4.2 Ethics statement
2.4.3 CORT exposure
2.4.4 Forced swim stress
2.4.5 Blood serum CORT
2.4.6 Gland harvesting
2.4.7 Dendritic spine imaging, reconstruction
2.4.8 Instrumental response training
2.4.9 Context shift
2.4.10 Reinforcer devaluation
2.4.11 Progressive ratio
2.4.12 Forced swim test
2.4.13 Locomotor monitoring
2.4.14 7,8-DHF
2.4.15 Immunoblotting
2.4.16 Surgery
2.4.17 p-ERK42/44 immunostaining
2.4.18 Statistical analyses
2.5 Results .................................................................................................... 79
2.5.1 Exogenous CORT exposure recapitulates several effects of stress: Validation of the method
2.5.2 Subchronic CORT exposure in adolescence, but not adulthood, induces habit biases
2.5.3 CORT shifts cortico-limbic trkB/trkB.t1 ratios and reduces p-ERK42/44 in the vHC
2.5.4 Blockade of CORT-induced habits and amotivation by trkB stimulation
2.5.5 Recapitulating the long-term effects of adolescent CORT exposure with Trkb.t1 overexpression
2.6 Discussion ..................................................................................................... 88
2.6.1 Adolescent CORT exposure has persistent neurobehavioral consequences
2.6.2 vHC Trkb.t1 overexpression induces habits
2.6.3 Conclusions
2.7 Acknowledgements.............................................................................................. 94
CHAPTER 3 117
ADOLESCENT CORTICOSTERONE AND TRKB PHARMACO-MANIPULATIONS SEX-DEPENDENTLY IMPACT INSTRUMENTAL REVERSAL LEARNING LATER IN LIFE
3.1 Context, Author’s Contribution, and Acknowledgement of Reproduction...... 118
3.2 Abstract ................................................................................................... 118
3.3 Introduction ................................................................................................... 119
3.4 Materials and Methods...................................................................................... 121
3.4.1 Subjects
3.4.2 CORT exposure
3.4.3 Forced swim stress
3.4.4 Instrumental conditioning
3.4.4.1 Instrumental reversal test
3.4.5 Drugs (dosing and timing)
3.4.6 Statistical analyses
3.5 Results .................................................................................................... 124
3.5.1 Early-adolescent corticosteroid exposure in females impairs response inhibition in adulthood
3.5.2 TrkB stimulation blocks CORT-induced errors
3.5.3 TrkB stimulation in adolescence improves behavioral flexibility in adulthood
3.5.4 Adolescent stressor exposure and trkB inhibition impair reversal performance
3.6 Discussion .................................................................................................... 128
3.6.1 Long-term, sex-dependent behavioral consequences of adolescent CORT exposure
3.6.2 TrkB manipulations in adolescence influence behavioral flexibility in adulthood
3.6.3 Broader considerations: sex differences in reversal performance
3.6.4 Conclusion
3.7 Funding .................................................................................................... 137
3.8 Acknowledgements............................................................................................ 137
CHAPTER 4 146
ADOLESCENT CORTICOSTEROID EXPOSURE DETERIORATES VENTRAL HIPPOCAMPAL-ORBITOFRONTAL CORTICAL INPUTS: FUNCTIONAL CONSEQUENCES
4.1 Context and Author’s Contribution................................................................... 147
4.2 Abstract .................................................................................................... 147
4.3 Introduction ................................................................................................... 148
4.4 Materials and Methods...................................................................................... 150
4.4.1 Subjects
4.4.2 CORT exposure
4.4.3 Surgery
4.4.4 Drugs
4.4.5 Instrumental conditioning
4.4.6 Fear conditioning
4.4.7 Dendritic spine imaging and reconstruction
4.4.8 Histology and axon terminal quantification
4.4.9 Statistical analyses
4.5 Results ..................................................................................................... 156
4.5.1 Adolescent CORT exposure has long-term behavioral consequences
4.5.2 Long-term CORT-induced dendritic spine loss in the oPFC
4.5.3 Adolescent CORT exposure diminishes vHC projections to the oPFC
4.5.4 vHC-->oPFC projections are involved in outcome-based decision making
4.6 Discussion ..................................................................................................... 162
4.6.1 Adolescent CORT exposure impairs the ability of mice to select actions according to anticipated outcomes
4.6.2 Enduring loss of dendritic spines and vHC terminals in the loPFC following adolescent CORT exposure
4.6.3 vHC-->loPFC inactivation weakens response-outcome memory
4.6.4 No effects on fear conditioning
4.6.5 Summary and broader implications
CHAPTER 5 178
CONCLUSIONS AND FUTURE DIRECTIONS
5.1 Summary of Results............................................................................................ 179
5.2 Integration of Findings with the Current Literature.......................................... 182
5.3 Implications and Future Directions.................................................................... 185
APPENDIX A 189
PUBLICATIONS
REFERENCES 190
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