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PLoS Biol. 2017 Nov 29;15(11):e2003000. doi: 10.1371/journal.pbio.2003000. eCollection 2017 Nov.

Regulation of actions and habits by ventral hippocampal trkB and adolescent corticosteroid exposure.

Author information

1
Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.
2
Graduate Program in Neuroscience, Emory University, Atlanta, Georgia, United States of America.
3
Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.
4
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia, United States of America.
5
Graduate Program in Molecular and Systems Pharmacology, Emory University, Atlanta, Georgia, United States of America.
6
Department of Psychology, Graduate Program in Integrative Neuroscience and Program in Neuroscience, Stony Brook University, Stony Brook, New York, United States of America.

Abstract

In humans and rodents, stress promotes habit-based behaviors that can interfere with action-outcome decision-making. Further, developmental stressor exposure confers long-term habit biases across rodent-primate species. Despite these homologies, mechanisms remain unclear. We first report that exposure to the primary glucocorticoid corticosterone (CORT) in adolescent mice recapitulates multiple neurobehavioral consequences of stressor exposure, including long-lasting biases towards habit-based responding in a food-reinforced operant conditioning task. In both adolescents and adults, CORT also caused a shift in the balance between full-length tyrosine kinase receptor B (trkB) and a truncated form of this neurotrophin receptor, favoring the inactive form throughout multiple corticolimbic brain regions. In adolescents, phosphorylation of the trkB substrate extracellular signal-regulated kinase 42/44 (ERK42/44) in the ventral hippocampus was also diminished, a long-term effect that persisted for at least 12 wk. Administration of the trkB agonist 7,8-dihydroxyflavone (7,8-DHF) during adolescence at doses that stimulated ERK42/44 corrected long-lasting corticosterone-induced behavioral abnormalities. Meanwhile, viral-mediated overexpression of truncated trkB in the ventral hippocampus reduced local ERK42/44 phosphorylation and was sufficient to induce habit-based and depression-like behaviors. Together, our findings indicate that ventral hippocampal trkB is essential to goal-directed action selection, countering habit-based behavior otherwise facilitated by developmental stress hormone exposure. They also reveal an early-life sensitive period during which trkB-ERK42/44 tone determines long-term behavioral outcomes.

PMID:
29186135
PMCID:
PMC5724896
DOI:
10.1371/journal.pbio.2003000
[Indexed for MEDLINE]
Free PMC Article

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